3 REVIEW 99 Cur3rrent treatment of cardiovascular 3invo 3olvement Systemic Lupus 3Ery 3ythematosus 3Bălu 3uţă Monica Mariana, Vintilă ORIGINA3AL PAPER

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1 3 REVIEW 99 Cur3rrent treatment of cardiovascular 3invo 3olvement Systemic Lupus 3Ery 3ythematosus 3Bălu 3uţă Monica Mariana, Vintilă ORIGINA3AL PAPERS 104 Iden3ntification of some radio-biochemical M.M.3 3 REPORT 3effe 3ects consecutive to boron neutron 3cap 3pture therapy at experimental 3hep 3patoma Laurenția, cells3gal3leș Gruia Maria Valentina, Vasilescu Monica, Iuliana,3Neg3goiță Bărbos D., Gruia I., Anghel Panait3Mar3rieta, 109 Ant3tiemetic therapy and3non3nhematologic G. Daniela, malignancies3geo3orgescu Popescu Mihaela, Rodica3 3Teve3et Mihaela, Murat Meilin, Niță 3Gab3briela Rahnea, Ciuhu Anda THERAPE3EUTICAL 116 Ove3er the counter drugs during pregnancy PRACTICE3 Natalia3 3- tip3ps for a correct D. Anca, approach3buz3zoianu Boca N. I. Corina3CASE ication 3Diagnosis in acute intoxi with 3entation 3methanol clinical prese 3vei 3Tănăsescu Andreea, Macov R., 3Ionică M., Tudosie s 3Synthetic psychotomimetics substances, 3hitoterapy, 3falsely associated with ph a 3e 3new presence among the substances 3of abuse 3ndra, 3Avram Oana, Avram Ruxan Caragea 3ă 3Gina, Forje Mărgărita, Truţă Elena, 3oicu 3Ionică M., Macovei R.A., Vo V.A ullary 3Radiotherapy in extramedu solitary 3opharinx 3plasmacytoma of the naso 3nsa, 3Mitulescu Ruxandra Ortan Anghel 3irjan 3Rodica, Dumitrache M., Ci 3scu 3Adriana, Oprea V., Mitules D oencephalitis 3Severe sepsis and meningo 3neumoniae 3with Streptococcus Pn 3old 3serotype 23F in a 5 year-o child with 3ele 3transethmoidal meningoce and CSF 3fistula 3Drăgănescu Anca, Bilașco Anuța, 3u 3Vișan Angelica, Negulescu Cristina, Andreea,3Boc3cşan 3a 3Vasile Magdalena, Condria E., Dogaru 3erisescu 3Cornelia, Slavu Diana, Me 3ca 3Mădălina, Luminos Monic

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3 Journal published in cooperation with: National Institute of Infectious Diseases "Prof. Dr. Matei Balş" Romanian Society of Pharmacology, Therapeutics and Clinical Toxicology Romanian Academy of Medical Sciences University of Medicine and Pharmacy "Carol Davila" Academic Medical Database: CNCSIS Category: B+ Code: 605 NLM (National Medical Library) SCOPUS EBSCOhost IndexCopernicus getcited Vol. XVIII Number 3 September 2014

4 Founders Emanoil Manolescu Mircea Angelescu Liviu Ioan Miclea Editor-in-Chief Therapeutics Adrian Streinu-Cercel (Professor, Member of Academy of Medical Science, Head of Department of Infectious Diseases, National Institute of Infectious Diseases "Prof. Dr. Matei Balş", University of Medicine and Pharmacy Carol Davila Bucharest) Editor-in-Chief Clinical Pharmacology and Toxicology Victor A. Voicu (Professor, Member of Romanian Academy, Head of Department of Pharmacology, Toxicology and Clinical Psychopharmacology, University of Medicine and Pharmacy Carol Davila Bucharest) Associate Editor Monica Luminos (Associate Professor, National Institute of Infectious Diseases "Prof. Dr. Matei Balş", University of Medicine and Pharmacy Carol Davila Bucharest) International Scientific Board Laure Aurelian (Professor, Senior Associate, The Johns Hopkins School of Public Health) Hege Christensen (Professor, School of Pharmacy, Uni-versity of Oslo, Norway) Jaime Kapitulnik (Professor, The Hebrew University of Jerusalem, Israel) Momir Mikov (Senior Lecturer, School of Pharmacy, University of Otago, New Zealand) Stanislav Yanev (Professor, Head of Department Drug and Toxicology, Bulgarian Academy of Science, Bulgaria) Olavi Pelkonen (Professor, Head of the Department of Pharmacology and Toxicology, University of Oulu, Finland) Olivier Patey (Professor, Chef de service des maladies infectieuses et tropicales CHI, Villeneuve-Saint Georges, France) George C. Rodgers (Professor of Pediatrics, Pharmacology and Toxicology, University of Louisville, Kentucky, USA) Robert Smith (Professor, Brown Medical School, U.K.) Jean Paul Stahl (Professor, Rédacteur en chef de Médecine et Maladies Infectieuses, Elsevier Maison, Grenoble, France) Michel Urbain (Chief of Research Department, Societe de Etude et de Research Biologique, Paris, France) Andrei Iagăru (Associate Professor, Department of Nuclear Medicine, Stanford University, USA) Serafim Kastanakis (Professor, University of Crete, Greece) Romanian Scientific Board Ioana Alina Anca (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Eduard Apetrei (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science) Ştefan Sorin Aramă (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Constantin Arion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science) Anca Buzoianu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca) Carmen Dorobăţ (Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy) Constantin Dumitrache (Professor, Member of Romanian Academy, University of Medicine and Pharmacy Carol Davila Bucharest) Leonida Gherasim (Professor, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Romanian Academy of Medical Science) Daniela Ion (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Ion Fulga (Professor, Head of Department of Pharmacotherapy and Pharmacology, University of Medicine and Pharmacy Carol Davila Bucharest) Sorin Leucuţa (Professor, University of Medicine and Pharmacy Oradea) Radu Macovei (Professor, Head of Department of ICU-Toxicology, University of Medicine and Pharmacy Carol Davila Bucharest) Mihai Gafencu (Assistant Professor, University of Medicine and Pharmacy Victor Babeş Timişoara) Nicolae Miu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca) Ostin C. Mungiu (Professor, Head of Department of Pharmacology and Clinical Toxicology, University of Medicine and Pharmacy Gr.T. Popa, Iassy) Lucian Negruţiu (Professor, University of Medicine and Pharmacy Victor Babeş Timişoara) Florian Popa (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Irinel Popescu (Professor, Head of Department of Surgery and Liver Transplant, University of Medicine and Pharmacy Carol Davila Bucharest, Member of Academy of Medical Science) Laurenţiu Mircea Popescu (Professor, Member of Romanian Academy, Head of Department of Celular Biology, University of Medicine and Pharmacy Carol Davila Bucharest) Florica Stăniceanu (Professor, Univeristy of Medicine and Pharmacy Carol Davila Bucharest) Dan Tulbure (Professor, Head of Department of ICU, University of Medicine and Pharmacy Carol Davila Bucharest) Doina Ţăţulescu (Professor, University of Medicine and Pharmacy Iuliu Haţieganu Cluj-Napoca) Coriolan Ulmeanu (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Doina Velican (Researcher, Member of Romanian Academy of Medical Science) Florin Căruntu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Adrian Gabriel Popescu (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Anca Drăgănescu (Pediatrician, INBI Prof. Dr. Matei Bals, Bucharest) Paraschiva Postolache (Associate Professor, University of Medicine and Pharmacy Gr.T. Popa, Iassy) Alexandru Rafila (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Adriana Hristea (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Gabriela Leşanu (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) Ion Lică (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) Raluca Papacocea (Lecture, University of Medicine and Pharmacy Carol Davila Bucharest) Adrian Lungu (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Maria Pasca (Associate Professor, University of Medicine and Pharmacy Targu Mures) Voichiţa Lăzureanu (Assistant Professor, University of Medicine and Pharmacy Victor Babeş Timişoara) Anca Macovei (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Anca Streinu-Cercel (Associate, University of Medicine and Pharmacy Carol Davila Bucharest) Andrei Tica (Professor, University of Medicine and Pharmacy Craiova) Laura Topor (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Mihail Tudosie (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Ionel Alexandru Checheriță (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Mihai Săndulescu (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Toma Papacocea (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Alexandru Ulmeanu (Assistant Professor, University of Medicine and Pharmacy Carol Davila Bucharest) General Registrar Of Editorial Board Victoria Aramă (Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Issue Editor Elisabeta Otilia Benea (Associate Professor, University of Medicine and Pharmacy Carol Davila Bucharest) Oana Săndulescu Ana-Maria Tudor Alexandra Mărdărescu Publishing Editor Mihaela Cristina Negulescu Editorial Office Institutul Naţional de Boli Infecţioase Prof. Dr. Matei Balş, Pavilionul IV, Etaj 4 1 Dr. Calistrat Grozovici Str., Sector 2, Bucureşti, C.P , O.P submit@therapeutics.ro cristina.negulescu@terapeutica.ro Published by SC Editura Rp. SRL CUI RO , RC J40/7184/1997 Address: 6 Codrii Neamțului Str., Bl. PM 26bis, Sc. A, Et. 8, Ap. 36, sector 3, Bucharest, Romania Tel/Fax: ; cristina.negulescu@terapeutica.ro Web: ISSN

5 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 REVIEW CURRENT TREATMENT OF CARDIOVASCULAR INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS 1 "Carol Davila" University of Medicine, Cardiology Department 2 "St. Pantelimon" Hospital, Bucharest Băluţă Monica Mariana 1, Vintilă M.M. 2 Abstract. Systemic lupus erythematosus (SLE) is an acquired connective tissue disease of unknown origin. SLE may determine rheumatic heart disease among many other systemic involvements. Any cardiac structure such as pericardium, myocardium, heart valves, the conduction system and the vasculature may be involved. Cardiovascular involvement may vary from subclinical to clinical with various complications that determine an increased morbidity and mortality in affected patients. The underlying diseases have plurifactorial etiologies among which inflammation plays a key role. Inflammation is a common pathway for rheumatic diseases and atherosclerosis, the main killer of the 21th century. Systemic lupus erythematosus (SLE) is known today as an important nontraditional risk factor for atherosclerosis. The treatment of cardiovascular involvement in SLE patients remains controversial and provocative. Nonsteroidal anti-inflammatory drugs increase the risk for cardiovascular adverse outcome. Even if old-fashioned, corticosteroids represent even today a rescue therapy for life-threatening SLE related cardiovascular conditions. Despite many controversies in literature about them, no other drug has been proved as safe and as effective as they can be in cardiovascular involvement. Besides the specific SLE treatment, cardiovascular involvements benefit from guideline recommended therapies for specific conditions established by international societies. Proper and early recognition together with aggressive treatment of the underlying rheumatic disease may prevent the development of cardiovascular involvement. Key words: Systemic lupus erythematosus, cardiac and vascular involvement, treatment Introduction Rheumatic heart disease in systemic lupus erythematosus (SLE) refers to the involvement of pericardium, myocardium, endocardium, conduction system and the vessel wall. Inflammation is a common pathway for SLE and atherosclerosis pathogenesis. It is known that beside the lipid hypothesis, inflammatory hypothesis is believed to play a role in atherosclerosis aetiology. The increased level of proatherogenic lipoprotein particle and the high systemic levels of proinflammatory cytokines favour the development of early atherosclerosis with accelerated pattern in SLE. Based on these findings, SLE is now considered a nontraditional risk factor for atherosclerosis. Cardiovascular involvement amplifies the mortality and morbidity of any rheumatic disorder and sometimes it is the first manifestation of the underlying diseases. In that situation, the cardiologist may be the first specialist that confronts with that pathology and needs to recognize the substrate and to start the Maria Mariana Băluță 340 Sos. Pantelimon, Bucharest, Romania monicabaluta@yahoo.com treatment for the cardiovascular complication. If the cardiac involvement is life threatening and is strictly related to a rheumatic disease, the patient requires also a prompt treatment to decrease the activity of the underlying disease. Therefore, basic knowledge of this pathology is required. Systemic lupus erythematosus is an autoimmune disorder of unknown etiology, with multiple presumed mechanisms such as genetic mutations, activation of adaptive and innate immunity, autoantibody and immune complex tissue aggression, complement deficiencies, increased expression of IFN1 inducible genes with subsequent type I interferon (IFN) production, all influenced by environmental factors.[1] SLE is a chronic disease that evolves with capricious periods of activities and remissions with unpredictable organ involvement that may have a highly variable course and prognosis. SLE affects more frequently younger women than men (9-15:1)[2][3] The incidence (1-10/ persons-year) and prevalence ( la 100,000 persons) are highly variable with age, sex and region.[3] Clinical presentation is typically with constitutional, musculoscheletal and skin symptoms, randomly associated with renal, cardiac, and neurologic manifestation or vasculitis. American College of Rheumatology (ACR) criteria are used to establish the diagnosis when four out of eleven XVIII, Vol.18, Number 3/

6 are found in a specific patient. Those criteria are: malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, serositis, neurologic disorder (seizures or psychosis), renal disorder, hematologic disorder, immunologic disorder (anti-dna, anti-smith, antiphospholipid antibodies) and positive antinuclear antibody.[3] The main cardiovascular involvements are pericarditis, myocarditis, valvular abnormalities and coronary artery disease. Pericardium involvement in SLE may be found in >50-60% of patients and it is generally asymptomatic. Acute pericarditis with symptoms appear in less than 20-30% of affected patients and usually occurs in active SLE.[3,4,5] The types of involvements are presented in Table 1. decreased slowly to prevent rebound phenomenon. Large effusions that may become life threatening need high doses of iv corticosteroids and pericardiocentesis. Pleuro-pericardial windows can be performed by the surgeon for recurrent large effusions.[4,5,6] Valvular abnormalities and Endocarditis in SLE. Valvular abnormalities are independent on the disease activity.[3,6] They are better detected by transthoracic (TTE) and transesophageal (TEE) echocardiography in almost 50% of SLE patients. Valvular abnormalities (Table II) consist in reduced mobility and valve thickening (50%), vegetation (43%) that determine often valve regurgitation (25%) and occasionally valve stenosis (4%). [7] Noninfective vegetations (Libman-Sacks endocarditis) are generally located on Type of involvement Treatment of symptomatic forms Asymptomatic Medical Thickened pericardium NSAID Small pericardial effusion Prednisone mg/day Symptomatic High doses corticosteroids Acute pericarditis (Intravenous) in life threatening (Fibrinous or exudative: pericardial effusion / Large effusions cardiac tamponade) Rare forms Surgical Constrictive pericarditis Pericardiocentesis Drug induced pericarditis Pleuro-pericardial windows + SLE specific therapy Table I. Pericardial involvement in systemic lupus erythematosus Clinical presentations consist in anterior chest pain, aggravated in decubitus and ameliorated while sitting, accompanied by pericardial friction rub on auscultation. The electrocardiogram (ECG) may reveal diffuse ST segment elevation in all the leads except avr, sinus tachycardia and occasionally supraventricular arrhythmias (atrial fibrillation or flutter). Echocardiography has replaced necroptic studies [4] and detect pericardial involvement in 37-42% of SLE patients.[5,6] Pericardial fluid is obtained by pericardiocentesis and in rare occasions, when surgical decompression is made for cardiac tamponade. It is fibrinous and exudative, have inflammatory cells, low complement activity, antinuclear and anti-dna antibodies.[6] Histopathologic specimens reveal inflammatory infiltrates (perivascular and intravascular) in the pericardium together with fibrinous changes, vascular proliferation and fibrosis. [6] Treatment Patients with acute pericarditis may benefit from nonsteroidal anti-inflammatory drugs (NSAID) if they do not have renal failure.[4] When symptoms are moderate to severe, corticosteroids provide benefits. Initial doses of mg Prednisone need to be the atrial side of the mitral valve and on the arterial side of the aortic valve. The role of antiphospholipid antibody in their pathogenesis remains a matter of discussion, although they are present in 50% of the patients.[3] Clinical expression of endocardial involvement is generally absent. Specific murmurs may appear when valvular abnormalities become hemodynamically significant. ECG and chest X-ray may have signs of cardiomegaly with longstanding valve dysfunction. TEE is superior in identifying small vegetation while routine transthoracic examination is recommended as screening method for evaluation of SLE patients endocardium.[8] TTE endocardial changes seem to be related to MRI detected cerebral infarcts.[9] Treatment. There is no specific treatment for valvular involvement unless they need valvular replacement or reconstructions. This surgical procedure has a double mortality rate in SLE patients. [10] There are controversies regarding the benefits of corticosteroidsbenefit in SLE valvular involvement.[5] An important problem consists in the recurrence of SLE lesions on the valve prosthesis and occurrence of prosthetic thrombosis.[4] Myocardial involvement. The etiology of myocardial involvement is complex and consists in chronic immune tissue aggression and ischemia due to coronary 100

7 vasculitis. Hypertension due to renal involvement and valvular heart disease may also contribute. Subclinical involvement was reported from 50% (necroptic) to 64% (SPECT) in SLE patients.[6] Lupus cardiomyopathy is rare and the diagnosis is made by exclusion of other causes. Myocarditis was reported in 10% of the SLE patients, generally detected when SLE is active. Myocarditis can be acute or chronic and is associated commonly with pericarditis.[5] Chest pain, Atrioventricular conduction blocks of varying degrees are associated with specific antibodies (anti-ro, anti- U1RNP).[6] Congenital heart block is expected in newborns to mothers with SLE due to transmission of maternal anti-ro and anti-la antibodies. It is practically irreversible. Unexplained sinus tachycardia can occur in active SLE with or without myocardial involvement or ventricular dysfunction. It appears also in patients with antiphospholipid antibody syndrome Type of involvement Treatment of Symptomatic forms Endocarditis and valvular abnormalities SLE current treatment Valve thickening + Libman-Sacks endocarditis No specific treatment for slight valvular Regurgitation (Mitral and Aortic) involvement Infective endocarditis Valve replacement or reconstructions Rare involvement Valve stenosis due to vegetation Aortitis and aortic regurgitation Aortic dissection Corticosteroids: uncertain Recurrence of involvement on valve prosthesis Myocardial involvement Subclinical involvement Myocarditis (acute and chronic) Lupus cardiomyopathy Heart failure High doses of corticosteroids over a long period of time ±immunosuppressive therapy ±iv gammaglobulin Conventional heart failure therapy Table II. Endocardial and myocardial involvement in systemic lupus erythematosus fatigue and occasionally dyspnea determine the clinical suspicion. Cardiomegaly, regurgitation murmurs and gallop sounds are found in myocarditis together with sinus tachycardia, arrhythmias and conduction disturbances on ECG. Myocardial markers are rarely detected but when present the differential diagnosis with skeletal muscle involvement is difficult even in the presence of elevated troponins.[4,5] Echocardiography, scintigraphy and SPECT are useful in the detection of ventricular dysfunction and abnormal perfusion. Endomyocardial biopsy may be nonspecific. It is invasive and prone to side effects.[4,5]the prognosis of myocardial involvement without treatment is poor, while therapy provides benefits in 80% of the patients. [6] Treatment of SLE myocarditis consists in high doses of corticosteroids over long periods of time, sometimes associated with immunosuppressive therapy and iv gammaglobulin.[5,6] Conduction System Disease and Cardiac autonomic dysfunction in SLE Tachyarrhythmias and conduction system disturbances (Table III) are frequently associated with pericarditis and myocarditis. The conduction system may be replaced by fibrous tissue after the aggression of the conduction system resulted from local inflammatory processes and small-vessel vasculitis.[5] (APLA) with occult in situ pulmonary thrombosis.[4] Abnormal heart rate variability is seen in SLE patients due to occult myocarditis or to autonomic dysfunction in the absence of myocarditis.[4][6] Tachyarrhythmias and conduction system disturbances can be clinically asymptomatic (only on ECG) or symptomatic with palpitation, dizziness or syncope. Treatment. Unexplained sinus tachycardia resolves usually with the treatment of SLE. In acute symptomatic heart block, temporary cardiostimulation and high doses of corticosteroids are needed. Systematic screening in early pregnancy to detect fetal conduction system abnormalities is recommended. Dexamethasone and plasma exchange may be helpful to reverse the fetal myocarditis and are recommended based on expert consensus opinion, even if the evidence supporting this approach is lacking. If total AV block occurs after the birth a permanent pacemaker is almost always necessary.[4,5] Coronary artery disease and other vascular involvement. Coronary arteries stenosis and occlusions can be determined by accelerated atherosclerosis, coronary vasculitis, noninfective vegetation embolism or in situ. There is an estimated 50-fold higher incidence of coronary atherosclerotic disease (CAD) complicated with myocardial infarction in SLE young XVIII, Vol.18, Number 3/

8 Tachyarrhythmias Unexplained sinus tachycardia Any Tachyarrhythmia Decreased heart rate variability Autonomic system dysfunction Conduction system disturbances Atrio-ventricular heart bloc I, II, III Pulmonary hypertension Antiphospholipid antibody syndrome Valvular involvement Intracardiac thrombosis Thromboembolic coronary disease Cerebrovascular thromboembolism SLE current treatment High doses corticosteroids Temporary cardiostimulation Permanent pacemaker SLE current treatment Specific therapy with caution SLE current treatment Long term oral anticoagulation except pregnancy Aspirin, low molecular heparin in pregnancy Table III. Other involvement in systemic lupus erythematosus women as compared with control groups.[4,5,11] Acute coronary vasculitis related to active SLE is due to immune complex deposition in the vessel wall and is rarely associated with acute coronary events.[6] Chest pain and ECG ST-T changes can be detected. Differential diagnosis with atherosclerotic etiology is based on sequential coronary angiography which reveals dynamic luminal stenosis in vasculitis.[4] Rare vascular involvements are aortitis, in situ thrombosis and embolism from noninfective vegetation. Aortitis may complicate with aortic dissection and in situ thrombosis.[6] Accelerated atherosclerosis (AA) is the hallmark of SLE vascular involvement. Due to this involvement, SLE is considered now a nontraditional risk factor of atherosclerosis (ATS). AA can be subclinical or clinical, with high prevalence of carotid plaque or coronary artery calcification that become symptomatic as coronary artery disease, cerebrovascular diseases and peripheral vascular diseases. The AA prevalence is high (25-40%).[3] AA represents an important cause of mortality and morbidity in young women with SLE.[5] Subclinical atherosclerosis prevalence was reported as 30-40% in SLE.[6] It is determined by the association between SLE and traditional risk factors (an atherogenic lipid profile, hypertension). SLE is an independent risk predictor for CAD. The advanced age at SLE diagnosis, a long disease duration and the cumulative dose of corticosteroids contribute to ATS.[6]The common expression of subclinical ATS is endothelial dysfunction, increased arterial stiffness, increased intima-media thickness and carotid plaques. Coronary atherosclerotic disease has a multifactorial pathogenesis in SLE. Traditional risk factors are present almost always. They did not explain the accelerate pattern. [2,6] Lots of factors, such as active inflammation, premature menopause, 102 hypercoagulability, vasospasm may drive atherosclerosis. [2] The inflammatory hypothesis is supported by the fact that the severity of coronary calcium scores was associated with markers of inflammation in clinical research.[6] Clinical findings appear in 6-10% of the patients and consists in chest pain with different patterns depending on the disease form (stable and unstable angina, myocardial infarction) or their complication: heart failure or sudden death. [6] Diagnosis is made with rest and stress ECG test, phyechocardiography, perfusion scanning, and coronary angiography. The latert reveal fixed defects when atherosclerosis is the culprit finding. Except angiography none of the above diagnostic test can make the difference between vasculitis and atherosclerosis. [10] Cardiac CT can be used to establish the calcium score. Treatment addresses first SLE and seconds the cardiovascular involvement. The treatment of coronary vasculitis consists in high doses of corticosteroids [4] associated sometimes with cyclophosphamide [5]. In myocardial infarction of atherosclerotic origin without coronary vasculitis, corticosteroids should be used with caution because some reports emphasize the risk of cardiac rupture.[10]the treatment of atherosclerosis complication did not differ from guidelines for general population. Ischemic heart disease benefits from the strict control of concomitant traditional risk factors at the same time with specific treatment.[10] Statins and angiotensin converting enzyme inhibitors may provide supplementary benefits due to their complex mechanism of action. Interventional or surgical coronary revascularization may be necessary. Nonpregnant patients with APLA and with thrombotic complications have chronic oral anticoagulation indications. This can be impaired when thrombocytopenia is associated.[4] Pulmonary arterial hypertension (PAH) is a

9 rare complication of SLE characterized by a normal pulmonary capillary wedge pressure and elevated pulmonary capillary resistance. Signs and symptoms do not differ from other causes of PAH and the diagnosis is established based on right heart catheterization. In SLE patients PAH occurs more commonly in association with other conditions such as scleroderma, Raynaud s phenomenon or mixed connective tissue disease. The prognosis of PAH is poor, with at most 1 year chances of survival even with modern therapy. SLE treatment consists in glucocorticoids or hydroxychloroquine titrated in doses thatprovide disease control. Non-steroid anti-inflammatory drugs (NSAIDs) should be used with caution due to their increased risk of major coronary events and due to side effects on the renal function. In severe cases that are refractory to the first two mentioned therapies, immunosuppressive agents such as azathioprine, mycophenolatemofetil and methotrexate can be used in the treatment of SLE.[12] Major organ involvementnecessitate needs the addition of specific treatment as in the general general population. Prognosis of SLE patients is generally good when it is early recognized and treated. Survival rate is about 90% at 5 years and 85% at10 years. In the first years of evolution mortality can occur due to SLE itself, but in the late years, acquired comorbidities such as coronary artery disease, chronic kidney diseases and cancers influence prognosis.[2] Conclusions Cardiovascular involvement in SLE patients may be the consequence of underlying rheumatic disease and its treatment. Corticosteroids are still used in high doses in life threatening SLE cardiovascular involvement, even if there are no evidence-based data. Corticosteroids have also a well-known proatherogenic effects, but by decreasing the inflammatory process it is possible that they may reduce the cardiovascular complications as in rheumatoid arthritis.[4] Until larger clinical trial become available, aggressive control of traditional risk factors and SLE treatment according to EULAR guidelines are reasonable objectives. References 1. Crow MR. Etiology and Pathogenesis of Systemic Lupus Erythematosus. In: Firestein et al. Kelley s Textbook Of Rheumatology, 9 th Ed. 2013; Simard JF, Costenbader KH. Epidemiology and classification of systemic lupus erythematosus. In Hochberg et al, Rheumatology 5 th ed. 2011; Dall Era M, Wofsy D. Clinical Features of Systemic Lupus Erythematosus. In: Firestein et al. Kelley s Textbook Of Rheumatology, 9 th Ed. 2013; Villa-Forte A, Mandell BF. Rheumatic Diseases and the Cardiovascular System. In: Bonow et al. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 9 th Ed. 2012; Kaul MS, TapsonVF, St. Clair EV. Rhematologic Diseases and the Cardiovascular System, In: Fuster, et al, Hurst's The Heart, 13e, 2011; ( mhmedical.com/content.aspx?bookid=376&section id= ). 6. Vasudevan AR, Ginzler EM. Clinical features of systemic lupus erythematosus. In Hochberg et al, Rheumatology 5 th ed. 2011; Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. 1996;335(19): Roldan CA, Qualls CR, Sopko KS, Sibbitt WL Jr, Transthoracic versus transesophageal echocardiography for detection of Libman- Sacks endocarditis: a randomized controlled study, J Rheumatol 2008;35: Roldan CA, Gelgand EA, Qualls CR, Sibbitt WL Jr, Valvular heart disease by transthoracic echocardiography is associated with focal brain injury and central neuropsychiatric systemic lupus erythematosus. Cardiology 2007;108: Roldan CA. Connective Tissue Diseases and the Heart. In Crawford: Current Diagnosis & Treatment in Cardiology 2 nd Ed. 2002;33: Manzi S, Meilahn EN, Rairie JE, et al. Agespecific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997;145(5): XVIII, Vol.18, Number 3/

10 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 ORIGINAL PAPER IDENTIFICATION OF SOME RADIO-BIOCHEMICAL EFFECTS CONSECUTIVE TO BORON NEUTRON CAPTURE THERAPY AT EXPERIMENTAL HEPATOMA CELLS Galeș Laurenția 1, Gruia Maria Iuliana 1, Negoiță Valentina 1 Vasilescu Monica 1, Panait Marieta 1, Barbos D. 2, Gruia I. 3, Anghel Rodica 1 1 Institute of Oncology Prof. Dr. Alex. Trestioreanu Bucharest, Romania 2 Nuclear Research Center Pitesti Romania 3 University of Bucharest, Faculty of Physics, Bucharest-Romania Abstract. The purpose of this study is to identify some molecular mechanisms which occur after the boron neutron capture therapy has been applied to experimental hepatoma cells, compared with the normal surrounding tissues. The purpose is to obtain useful data that could improve the biological and biochemical treatment response. Material and methods: We used tumor cells from a chemically induced experimental hepatoma at Wistar rats. The tumor and normal tissue were removed in the dynamic of the growth and development of the tumor, (14, 21, 28, 35 and 42 days after the inoculation). From these tissues we isolated cells and we performed the determination of cell cycle phases, apoptosis and free radicals of oxygen levels. The cells were then irradiated in the prompt gamma device placed at the radial channel of the TRIGA-ACPR reactor from Pitesti-Romania. After the irradiations we reassessed the same parameters. Results and discussions: Our results show an increase of oxidative stress monitored at a higher level from the investigated parameters values. The cells were not identified in the G0 phase of the cellular cycle, instead we identified apoptotic cells (the apoptosis rate increase to 54.75% and 70.42% after 1800 and 2700 seconds irradiation respectively, compared to an initial value of 11.48%), this suggesting the initiation of irreversible bond breakage, irreparable, mediated by oxygen free radicals. Key words: oxidative stress, cell cycle, apoptosis Introduction An important paradigm in radiation biology has been that energy deposition from radiation into a cell and/or water molecules causes either direct or indirect ionization by oxygen free radicals in order to elicit radiobiological effects. It has been implied that the radiobiological consequences only affect the cells irradiated directly from irradiation and/or water radicals while non-irradiated cells do not generate radiobiological effects. Radiation-induced genomic instability can be observed in cells at a delayed period after irradiation [1]. This can also be the result of the cell signalling pathways mediated by the free radicals of oxygen. Oxidative stress can activate numerous intracellular signalling pathways via ROS-mediated modulation of various enzymes and critical transcription factors [2]. In one scenario, transcription factors activated in response to an increase in ROS or oxidative damage travel from Laurenția Galeș 252 Sos. Fundeni, Bucharest, Romania laurentia.gales@yahoo.com 104 the cytoplasm to the nucleus within a cell and bind to promoter regions of particular genes. As a result, these stress-activated pathways can have a significant impact on gene expression, which will ultimately affect the fate of a cell (e.g. apoptosis, proliferation, cytokines production) [3]. The balance between ROS production, cellular antioxidant defenses, activation of stress-related signalling pathways, and the production of various gene products, as well as the effect of aging on these processes, will determine whether a cell exposed to an increase in ROS will be destined for survival or death [4]. The aim of this study is to identify some biochemical mechanisms which occur after the boron neutron capture therapy applied to experimental hepatoma cells, in a view to obtain useful data to improve the treatment and the biological and biochemical response. Materials and Methods RS1 hepatoma-alveolar type used in our experiments is a chemically induced tumor, obtained by 2-acetylaminofluorene administration in rats food. Initially obtained and transplanted by serial grafts, the tumor was a hepato-cholangio-carcinoma and

11 these characteristics remained stable even after serial passages. At the present, the tumor is maintained by subcutaneous grafts in Wistar rats. It has days latency and after 50 days from the graft the diameters expand to 3x6cm. The shape is ovoid, well delimitated and isolated by a smooth and glowing capsule. The color is yellow-pink. The appearance in cross section is lobular, well delimitated, and greasy with white necrosis area or dark-pink hemorrhagic areas. After subcutaneous graft the tumor does not produce metastasis and the survival of experimental animals reaches days Irradiation facilities The neutron source is a nuclear reactor TRIGA- ACPR type. The filtering collimation assembly of the prompt gamma spectrometry device was designed and mounted at the radial channel of the reactor. Irradiation time ranges between 1800 and 2700 seconds, thermal fluency 1.418*109 and 2.13*109 n/cm2, and epithermal fluency 1.145*105 and 1.472*105 n/cm2 after BPA 5% fructose solution administration. 2.2.Preparation of cells. Cells isolated from the tumor tissue were centrifuged in gradient density (Ficoll-Hypaque-from Sigma), washed and removed in standard growth medium (10% fetal calf serum, 2nm L-glutamine, 25UI/ ml antibiotics). After irradiation the cells were stained with AnexinV-Alexa-fluor, Acridin-Orange (Sigma) and Ethidium homodimer-1 (EthD-1, Molecular Probes) for a triple coloration. The analysis was performed with Zeiss microscope equipped with CHROMA filter corresponding set. The internalization degree in tumor cells is depending on the Boron concentration; 20-40μg/ml B for cell provides a good value. After the incubation, the cells were washed to eliminate the excess of unincorporated BPA and the cell culture was initiated to determine the apoptosis level Biochemical assays Lipid peroxides were measured with TBARS reaction, cooper-oxidative activity of caeruloplasmin was detected by Ravin method [5], total SH groups were monitored by Schosinsky assay [6], total antioxidant activity was measured by the ability of biological sample to reduce the iron (FRAS) method involving the Felll TPTZ-Fell TPTZ reaction. All the assays were performed on cells removed from tumor and normal tissues, maintained in culture Flow citometry measurements The nucleus was marked with propidium iodine in hypotonic buffer (triton X-100 0,1% and propidium iodine 50 μg/ml in sodium citrate 0.1%). The samples were read by FACS Calibur flow cytometer using a Cell quest soft, and for the countering of apoptotic cells we use WinMDI programme; for the analysis we aquirred events The histograms type graphics represent the DNA quantity distribution which is expressed by a function between the FL2-H fluorescence detector measurement and the total cell number. Results and Discussion We analyzed at least 300 cells per sample taken from the cultures. Morphological classification of microscopically examined cells included apoptotic cells (Fig.1.a.) (With and without membrane permeabilisation), necrotic cells (Fig.1.b.) (with modified membrane) and viable cells. Cells with intact membrane, are coloured in green -yellow by AO; normally the EthD- 1 does not enter in the cell. In this category there are viable but also apoptotic cells in the intermediate stage. Differentiation between these two categories is easy by observing morphological changes which are typical to the nucleus and cell membranes. [7] The permeability of the membrane has changed after being irradiated, after which they are colored orangered by acridin-orange and ethidium homodimer-1, both markers having access to the cell nucleus. In this category cells enter the final apoptotic stage (secondarynecrotic) necrotic cells themselves being included. However, necrotic cells are easily distinguished as the cell volume has increased and the nucleus is lost. Therefore it should be mentioned that this method can only characterize the apoptotic cells located mainly in the stage of degradation. In the apparently viable cells category some early stage apoptotic cells can be included using this method. This optical analysis demonstrates the initiation of degradation reactions, especially degradation of cell membranes, without a quantification of BNCT efficiency. Figure 1. Optical determination of apoptotic (a) and secondary necrotic cells (b) One of the best known toxic effects of oxygen radicals is the damage to cellular membranes (plasma, mitochondrial and endomembrane systems), which is initiated by a process known as lipid peroxidation. A common target for peroxidation is unsaturated fatty acids present in membrane phospholipids. Peroxidation of membrane lipids can have numerous effects, including increased membrane rigidity, decreased activity of membrane-bound enzymes (e.g. sodium pumps), altered activity of membrane receptors and altered permeability. [8, 9] In addition to effects on phospholipids, radicals can also directly attack membrane proteins and induce lipid-lipid, lipid-protein and protein-protein cross-linking, all of which obviously have effects on membrane function. Following the BPA administration and the irradiations, there is an increase of free radicals of oxygen production, indirectly from the lipid peroxidation reaction but not in a dose dependent manner. Thus the reaction diminishes after their substrate (the polyunsaturated acids as from the XVIII, Vol.18, Number 3/

12 membranes) is consumed. (Fig.2) 2700 sec 2700 Sec 1800 sec 1800 Sec 0 sec 0 Sec Figure 2. Lipid peroxides level after irradiations (normal range 2-5 μmoli/100 ml) The same variation can be observed in the ceruplosmin Cu-oxidase activity, which also increases above normal ranges after the BPA administration and irradiation and diminished later on. (Fig. 3) Figure 4. Total thiol groups level (normal range μmol/ml) 2700 Sec 1800 Sec 0 Sec 2700 sec 1800 sec 0 sec Figure 3. Ceruloplasmin Cu-oxidase activity (normal range U.I.) The action of active oxygen metabolites upon the structural protein or enzymes induces their denaturation [10]. Interactions frequently occur with protein thiol groups with radical formation, which in turn can undergo oxidation or disulphide formation, namely sulphonic acid derivates. A decisive factor in this reaction of oxidation of protein-sh groups by ROS is the steric one. Exposure of protein thiols is essential. [11, 12] This explains the increased sensitivity to oxidation of denatured proteins (this property is used as an effective method of identifying thiol groups content, and also to identify the secondary and tertiary structure of the proteins). In our analysis we found a decrease of thiol groups concentration meaning that the proteins are not the first molecules attacked by the reactive oxygen species (ROS); for a maximum efficiency of the BNCT, in this case a higher flux of neutrons could be more useful. (Fig. 4) The second obtained effect is the induction of the natural antioxidant defense system activity, in the same manner (Fig.5) Figure 5. Total antioxidant activity (normal range μmol/l) The analysis by flux - cytometry of cell cycle shows a decrease of the cell population found in proliferation; that means the reduction of the percent of cells in S and G2/M phases indicating the initiation of cell cycle arrest in a dose dependent manner (a. after 1800 second irradiation and 2700 second irradiation (Fig 6.a.and b). Figure 6.a. Tumoral cells cycle determination after 1800 sec. irradiation During BNCT, the tumor cells can be destroyed by apoptosis (programmed cell death). The apoptosis is characterized by specific morphological modifications, one of them being the nuclear DNA cleavage by 106

13 endonucleases activation during the cell death time. As a result of fragmentation, the apoptotic cells lose a part of DNA. [13] The colouring with propidium iodine (fluorochrome which is stoechiometricaly intercalated between the basis of double helix and which emits a Figure 7.c. Histogram of apoptosis after 2700 second of irradiation Figure 6.b. Tumoral cells cycle determination after 2700 sec. irradiation red light after the ecitation with laser beam) permits the detection of cell population with a reduced DNA content hipoploid (subdiploid) compared to the normal cell population G0/G1 with euploid (biploid) DNA content. The existence of a subdiploid DNA peak shows the presence of an apoptotic cell population. [14, 15, 16] As a result, the identification and quantification of the apoptotic cells can be made by flow citometry analysis. We obtained an increase of the apoptosis from 11.48% at the baseline level (non-irradiated cells) to 54.75% after 1800 seconds irradiation and 70.42% after 2700 seconds irradiation, (Fig. 7a.b.c.) this showing a high efficiency of BNCT. Figure 7.a. Histogram of apoptosis at non-irradiated cells Figure 7.b. Histogram of apoptosis after 1800 second of irradiation The molecular attack to the DNA may be by adducts obtained after serial reactions mediated by free radicals of oxygen (in the first phase of irradiation we registered high values of their production). Conclusions Therapeutic irradiations through neutron capture by boron involves biochemical mechanisms mediated by oxygen reactive species. This information is very useful to identify the anaerobic tumors where the BNCT it is not efficient. The consequences of ROS production are the cells cytotoxicity by direct attack, due to structural lipid and protein degradation and also DNA-adducts formation. ROS also activate the apoptosis signalling pathways but among the consequences there is the activation of natural antioxidant defense system. For a maximum efficiency of BNCT it is important to localizedoxidative stress which induces apoptosis, citotoxicity and cell lysis without the migration of these reactive species, so that they to induce chain reaction at the normal cell level. References 1. Brahme A. Recent advances in light ion radiation therapy, Int. J.Radiat.OncolBiol.Phys, (2): Fruehauf JP, Meyskens FL., Reactive oxygen species: A breath of life or death? Clin Cancer Res. 2007;13, Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol. 2003;15: Halliwell B, Oxidative stress and cancer: Have we moved forward? Biochem J. 2007; 401: Smith C., Marks A.D., Lieberman M. Mark`s basic medical biochemistry a clinical approach second edition- Lippincott W. and Wilkins, Schosinsky K.L, Leman H.P, Balber M.F, Measurement of thiols from oxidase activity in serum by use of o-diamizidine, Clin, Chem, 20, , Seo YH, Carroll KS.Facile synthesis and biological evaluation of a cell-permeable probe to detect redoxregulated proteins. Bioorg Med Chem Lett. 2009; 19: Schumacker PT. Reactive oxygen species in cancer cells: Live by the sword, die by the sword.cancer Cell. 2006;10: Weinberg F, Chandel NS, Reactive oxygen XVIII, Vol.18, Number 3/

14 species-dependent signaling regulates cancer. Cell Mol Life Sci Dec;66(23): Epub 2009 Jul Cross JV, Templeton DJ.Regulation of signal transduction through protein cysteine oxidation. Antioxid Redox Signal. 2006; 8: Seo Y.H., Caroll K.S., Profiling protein thiol oxidation in tumor cells using sulfenic acid-specific antibodies, Proc Natl Acad Sci U S A. 2009; 106(38): Leichert LI, et al. Quantifying changes in the thiol redox proteome upon oxidative stress in vivo.proc Natl Acad Sci USA Hengartner MG. The biochemistry of apoptosis. Nature, 2000; 407: Wiseman H, Halliwell B.Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J., 1996; 313: Hengartner MG. The biochemistry of apoptosis. Nature, 2000; 407: pp Acker H. Mechanisms and meaning of cellular oxygen sensing in the organism. Respir Physiol, 1994; 95: 1-10,

15 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 ORIGINAL PAPER ANTIEMETIC THERAPY IN HEMATOLOGIC AND NONHEMATOLOGIC MALIGNANCIES Georgescu G. Daniela 1, Popescu Mihaela 1, Tevet Mihaela 1, Murat Meilin 1, Nita Gabriela Rahnea 2, Ciuhu Anda Natalia 2 1. Department of Hematology, Clinical Hospital Colentina, Bucharest, Romania 2. Department of Oncology, Palliative Care for Chronic Patients, Chronic Disease Hospital St. Luke, Bucharest, Romania Abstract. Nausea is an unpleasant sensation associated with aversion to food and impending feeling of vomiting. Vomiting represent the oral expulsion of gastric contents, and is preceded or not by nausea. In hemato - oncology, there are multiple etiological factors of emesis. The antiemetic measures imply to identify and treat reversible causes. Antiemetic drugs can be classified as: antiemetics acting on the central nervous system and double-acting antiemetics. Chemotherapeutic regimens used in the treatment of hematologic and non-hematologic malignancies are accompanied by a degree of emesis. Corroborating the data in the literature, individualized approach is required in the antiemetic treatment adapted to each patient, current guidelines directing the clinician in deciding on the anti-emetic prophylaxis. We analyzed a group of 17 patients aged between 20 and 83 years, eight men and nine women, undergoing cytostatic chemotherapy for hematological and non-hematologic malignancies, hospitalized in the Hematology Department of Clinical Hospital Colentina and the Department of Oncology and Palliative Care, Chronic Disease Hospital "St. Luke" from Bucharest. Patient selection was based on the type of chemotherapy, being selected mainly patients undergoing moderate or high emetogenic chemotherapy. In Table 1 there are presented patient characteristics: age, sex, diagnoses, type of diet, anti-emetic scheme, the degree of emesis and the occurrence of adverse reactions to antiemetic therapy. There are presented the conclusions on the use of Palonosetron in the analyzed patients (Table 2). The therapy was well tolerated with no significant side effects and the drug efficiency conforms to the data in the literature, both for hematological and non-hematological malignancies. Conclusions: Anti-emetic prophylaxis is a challenge for clinicians. Beyond current developments, nausea and vomiting after chemotherapy are still the major factors affecting quality of life and compliance with treatment. The Scientific Committees of developing international guidelines are being debated on the strict formal recommendations for the use of antiemetics associated to chemotherapy treatments. Key words: degree of emesis, nausea and vomiting after chemotherapy, anti-emetic therapy, anti-emetic prophylaxis guidelines Introduction Proper use of antiemetic agents, guided by the recommendations of therapy guidelines, should lead to the total prevention of occurrence of nausea and vomiting in patients receiving chemotherapy. However there is still a significant group of patients in whom nausea and emesis induced by chemotherapy are poorly controlled. [1] In hemato - oncology, etiological factors of emesis are multiple: locally advanced malignancies (ie: stomach, Anda Natalia Ciuhu Sos. Stefan cel Mare, Bucharest, Romania andadum@yahoo.com pancreatic, pharyngeal neoplasm), liver metastases, peritoneal carcinomatosis, esophageal obstruction or compression, intestinal obstruction (mechanical or peristaltic failure), brain tumors or metastases with intracranial hypertension, vestibular tumors, autonomic neuropathy (paraneoplastic syndromes: gastroparesis (paraneoplastic visceral neuropathy), diabetes, alcoholism), kidney or liver failure, hypercalcemia, hyponatremia, treatment: medication (including chemotherapy) and radiation [2]. Antiemetic measures consist in identifying and treatment of reversible causes. Antiemetic drugs can be classified as: antiemetics acting on the central nervous system (Levomepromazine, Haloperidol, Lorazepam, Aprepitant) and antiemetics with dual action on the central nervous system and the digestive tract: Metoclopramide, Ondansetron, XVIII, Vol.18, Number 3/

16 Granisetron, Palonosetron, Dexamethasone. [3] Chemotherapeutic regimens used in the treatment of hematologic and non-hematologic malignancies are accompanied by a degree of emesis. MASCC (Multinational Association for Supportive Care in Cancer) has developed a classification system for anticancer agents based on emetogenic potential of each individual agent (acute emetogenic risk - in the first 24 hours after chemotherapy, without a concomitant antiemetic treatment). [4] The decision on the antiemetic prophylaxis is based on the emetogenic potential of the therapy and the presence of a significant risk of developing delayed emesis (more than 24 hours after administration of antineoplastic agent). [5] Intravenously antineoplastic agents were classified into 4 emetogenic risk categories: high, moderate, low and minimum. [6] Emetogenic risk of oral agents, commonly used in multi-day regimens, was classified on the basis of a full course of treatment assessed clinically. [7] On the other hand patients receiving combination therapy may have a higher emetogenic risk than patients receiving only one antineoplastic agent. NCCN Guidelines states that "patients receiving chemotherapy treatment administered in several consecutive days are at risk of developing both acute and delayed emesis based on the emetogenic potential of each agent and the sequence of their administration". [8] Other important factors in choosing optimal antiemetic therapy are patient characteristics and concomitant medications. Risk factors for acute emesis are: young age (under 50 years), history of motion sickness, depression, low consumption or no alcohol intake history; risk factors for late emesis are: inpatients versus outpatients, treatment with multi-day chemotherapy regimens; risk factors for the occurrence of both acute and late emesis are: female sex, history of nausea in pregnancy, anxiety, fear of occurrence of vomiting, exposure to previous cycles of chemotherapy, uncontrolled / poorly controlled emesis during the previous cycle, concomitant medication like intravenous antibiotics and / or antifungal, opioids, antidepressants, ergot alkaloids, amifostine, bisphosphonates, NSAIDs. [9] It is shown that the doctor perception often differ from the reality experienced by the patient. Usually health professionals underestimate the incidence of acute emesis by approximately 30% and incidence of the delayed emesis by 50%. [10] Corroborating presented data, an individualized approach of antiemetic therapy centered on each patient is required, the current guidelines directing the clinician in deciding on the anti-emetic prophylaxis. [11] Materials and methods Lot features We analyzed 17 patients aged between 20 and 83 years, eight men and nine women, undergoing cytostatic chemotherapy for hematological and non-hematologic malignancies, hospitalized in Hematology Department of Clinical Hospital Colentina and Oncology Department and Palliative Care of Chronic Disease Hospital "St. Luke" from Bucharest. Patient selection was based on the type of chemotherapy, being selected mainly patients undergoing moderate or high emetogenic chemotherapy. In Table 1 there are presented patient characteristics: age, sex, diagnoses, type of diet, anti-emetic scheme, the degree of emesis and the occurrence of adverse reactions to antiemetic therapy. In terms of diagnosis, there were analyzed 10 patients with solid tumors and 7 patients with hematologic malignancies. The 10 patients with solid tumors were evenly distributed in terms of sex: 50% women and 50% men, aged between 53 and 65. Diagnoses were as follow: 6 patients with lung cancer, including one patient with lung cancer associated with oral floor cancer and one patient with lung cancer and liver metastases (M1 liver); two patients with pleural involvement, one with pleural mesothelioma and one with neoplastic pleural effusion and bone metastases (M1 bone); a patient with ovarian cancer and neoplastic ascites and one patient with M1BRA post-radiotherapy (RT) status. The 7 patients with hematological malignancies were distributed approximately equally in terms of sex: 4 women and 3 men, aged between 20 and 83 years. Diagnoses were: a patient with Hodgkin's disease (BH); a patient with acute myeloid leukemia (AML), 5 patients with non- Hodgkin lymphoma (NHL): a patient with T-cell NHL, HTLV1 positive and chronic hepatitis C (HCV) and 4 patients with B-cell NHL of which one patient with gastric involvement. Patients received high or moderate emetogenic cytostatic therapy in multiday and repeated courses. Antiemetic medication consisted of 5-HT3 receptor antagonists plus dexamethasone for acute phase of nausea and vomiting and dexamethasone for delayed symptoms, a patient received therapy with selective antagonist, with high affinity for neurokinin 1 (NK1) for human substance P (Emend) and one patient received intravenous metoclopramide. Results We noted that patients which had received platinumbased regimens had a higher degree of emesis. Patients treated with at least 2 prior chemotherapy regimens with high or moderate emetogenic potential, often multiday courses, who additionally required other emetogenic drugs, including intravenous antimicrobial therapy and opioids, that maintain emesis, received therapy with longacting antagonist of 5-HT3 receptors - Palonosetron - with dexamethasone, followed by dexamethasone in the coming days, as recommend MASCC / ESMO guidelines. The same is observed in patients with aggressive lymphomas, undergoing high-dose salvage chemotherapy, DHAP-type. The patient with acute leukemia undergoing remission induction therapy, to whom the discontinuation of gastrointestinal mucosa was expected as side effect in the aplastic period following chemotherapy and the occurrence of nausea and vomiting as late events, received anti-emetic prophylaxis with Palonosetron with favorable evolution. Patients with severe digestive involvement, either by determination of disease: oral floor cancer, gastric NHL, either by hepatic metastasis, neoplastic ascites or association of HCV chronic hepatitis, received anti-emetic prophylaxis, resulting in a low degree of emesis after chemotherapy. 110

17 No, initials Sex Age Diagnoses No of ChT Series 1. MD F BG F 58 Diffuse pleural mesethelioma Neoplastic pleural effusion and bone metastasis M1 3. LE F 64 M1BRA RT NC M PM M 65 Bronchopulmonary neoplasm Bronchopulmonary neoplasm ChT scheme Gem + Cisplatin x 2 Gemcitabine x 2 Pemetrexed + Cisplatin Pemetrexed + Cisplatin Pemetrexed + Carboplatin x 3 Pemetrexed + Carboplatin x 5 Pemetrexed + CDDP x 4 Pemetrexed + CDDP Antiemetic scheme Emeses grade (VAS Scale) Adverse Events (AE) Granisetron 2 no Ondansetron 2 no Manitol + 2 no Ondansetron Palonosetron 0 no Palonosetron 0 no Ondansetron 1-2 no Ondansetron 1-2 no Ondansetron + Emend 0 no Gem +CDDP Granisetron 1 no Gemcitabine Granisetron 1 no VLB +CBPx2 Granisetron 1 no VLB x 2 Granisetron 1 no VLB p.o. Ondansetron 1 no VLB p.o. x 8 Palonosetron 0 no VLB + CBP Ondansetron 2 no VLB +CBPx4 Palonosetron 0 no VP no Ondansetron CBPx7 VP16+CDDP 1-2 no Granisetron x 6 VP 16+CDDP Palonosetron 0 no VP16 + 0/1 no Palonosetron CBPx5 VP no Ondansetron CDDP VLB + 1 no Ondansetron CBPx4 VLB p.o. x 3 Palonosetron 1 no PTX + CBPx2 PTX + CBPx4 Palonosetron Ondansetron 0 no 1-2 no DTX Ondansetron 2 no Zoledronic acid Ondansetron 1 no XVIII, Vol.18, Number 3/

18 No, initials Sex Age Diagnoses No of ChT Series 6. GI M CG F ZD M RE F BD M ICF F IM F 66 Bronchopulmonary neoplasm M1 liver Ovarian neoplasm stage II B, neoplastic ascites Oral floor neoplasm/ bronchopulmonary neoplasm Bronchopulmonary neoplasm Bronchopulmonary neoplasm T Cell-NHL stage IV B (BM+), HTLV1 +, HCV + DLBCL gastric involvement 13. SG F 83 DLBCL ChT scheme Antiemetic scheme Emeses grade (VAS Scale) Adverse Events (AE) VLB +CBP Palonosetron 0 no x4 VLB+CBPx6 Ondansetron 1 no VLB + CBP Metoclopramid 1 no VLB x 4 Ondansetron 1 no CBP + CTX Palonosetron 0 no DTX + CBPX3 Palonosetron 0-1 no PTX + CDDP Palonosetron 1 no Erbitux Palonosetron 1 no PTX + CBPx6 Palonosetron 0-1 no CBP Granisetron 1 no Cetuximab Granisetron 1 no Cetuximab Ondansetron 1 no Cetuximab x 3 Granisetron 1 no VP + CBP x2 Palonosetron 1 no VP + CBP x4 Granisetron 2 no VP +CDDPx4 Granisetron 2 no VP +CDDPx2 Palonosetron 1 no EPIRUBICIN + CTX X 2 Granisetron 1-2 no VLB + CBP Ondansetron 1 no VLB x 7 p.o. Palonosetron 0 no VLB + 0 no Palonosetron CBPx2 DTX + CBP Granisetron 1 no DTX x 4 Granisetron 1 no CHOP x5 Ondansetron 1 no DHAP Palonosetron 1 no R-CHOP x5 Ondansetron 1 no R-CHOP Palonosetron 0 no R-CHOP x2 Ondansetron 1 no R-COEP X 7 Ondansetron 1 no R-COEP Palonosetron 0 no 112

19 No, initials Sex Age Diagnoses No of ChT Series 14. PI M HD M 58 B Cell-SLL stage IVB Bronchopulmonary neoplasm M1 liver 16. BC M 33 AML ChT scheme Antiemetic scheme Emeses grade (VAS Scale) Adverse Events (AE) R-CVP x4 Ondansetron 1 no R-CVP Palonosetron 0 no R-CVP Ondansetron 0 no R-CHOPx6 Ondansetron 1 no R-ICE x 3 Granisetron 0 no R-ICE x 3 Granisetron 0 no R-DHAPx2 Palonosetron 0 no DA 3/7 Palonosetron 0 no S-HAM Palonosetron 0 no ABVD Ondansetron 1 no 17. BIL F 20 HD 6 Palonosetron 0 no NB: - p.o.: both cytostatic and anti-emetic were administered orally Table I. Patient characteristics NCCN Guidelines suggest that Palonosetron - 5-HT3 receptor antagonist with long duration action - can be used before starting a course of multiday chemotherapy to replace repeated daily doses of antiemetic.(8) We analyzed the group of the 17 patients from the perspective of Palonosetron action. Table 2 presents our findings on the use of Palonosetron in patients analyzed. Discussions Patients received high or moderate emetogenic cytostatic therapy in multiday and repeated courses, simple or multidrug, both intravenous and oral applications, with or without cortisone. Palonosetron was administered intravenously and orally, from the first cycle of chemotherapy (initial), but also on the following cycles after another antiemetic. High emetogenic chemotherapy was associated with a slightly higher degree of emesis (1 on VAS scale), despite antiemetic therapy. The patient with acute leukemia undergoing remission induction therapy, to whom the discontinuation of gastrointestinal mucosa was expected as side effect in the aplastic period following chemotherapy and the occurrence of nausea and vomiting as late events, received anti-emetic prophylaxis with Palonosetron, both initially and during salvage therapy with high-dose chemotherapy with favorable evolution. Palonosetron therapy was well tolerated with no significant side effects observed and the drug efficiency corresponds to literature data for both hematologic and non-hematologic malignancies. No, initials Sex Age Diagnoses and no of ChT courses 1. MD F 58 Pleural mesothelioma BG F 58 Neoplastic pleural effusion/ M1 bone - 20 Type of ChT High/moderate emetogenic When Palonosetron was associated: first ChT cycle or further after another antiemetic Simple or multidrug regimen, with or without cortisone High Continuation Multidrug + cortisone High Continuation Multidrug+ cortisone Moderate, oral regimen Continuation, orally Simple without cortisone Grade of emesis AE 0 no 0 no 0 no XVIII, Vol.18, Number 3/

20 No, initials Sex Age Diagnoses and no of ChT courses 3. LE F 64 M1BRA RT NC M PM M GI M CG F ZD M RE F BD M ICF F IM F 66 Bronchopulmonary neoplasm - 8 Bronchopulmonary neoplasm - 8 Bronchopulmonary neoplasm l M1 liver - 15 Ovarian neoplasm/ neoplastic ascites - 4 Oral floor neoplasm/ Bronchopulmonary neoplasm -14 Bronchopulmonary neoplasm -14 Bronchopulmonary neoplasm -15 T cell-nhl stage IV B (BM+), HTLV1 +, HCV - 6 DLBCL/ gastric involvement SG F 83 DLBCL PI M 50 B cell-sll stage IVB HD M 40 DLBCL - 13 Type of ChT High/moderate emetogenic When Palonosetron was associated: first ChT cycle or further after another antiemetic Simple or multidrug regimen, with or without cortisone High Continuation Multidrug +cortisone Moderate, oral regimen Continuation, orally Simple without cortisone High Initial Multidrug +cortisone High Initial Multidrug +cortisone High Initial Multidrug +cortisone High Initial Multidrug +cortisone High Initial Multidrug +cortisone Moderate, oral regimen Continuation Simple without cortisone High Continuation Multidrug +cortisone High Moderate Moderate Moderate High Continuation: cycle 6 Continuation: cycle 6 Continuation: cycle 8 Continuation: cycle 5 Continuation: cycles 10 and 11 Multidrug+ cortisone Multidrug+ cortisone Multidrug+ cortisone Multidrug+ cortisone Multidrug+ cortisone Grade of emesis AE 0/1 no 1 no 0 no 0 no 0/1 no 0/1 no 1 no 0 no 0 no 1 no 0 no 0 no 0 no 0 no 114

21 No, initials Sex Age Diagnoses and no of ChT courses 16. BC M 33 AML BIL F 20 HD - 6 Type of ChT High/moderate emetogenic 1 cycle DA: Moderate 1 cycle S-HAM: High High When Palonosetron was associated: first ChT cycle or further after another antiemetic Initial Initial Continuation: cycle 6 Simple or multidrug regimen, with or without cortisone Multidrug without cortisone Multidrug without cortisone Multidrug+ cortisone Grade of emesis AE 0 no 0 no 0 no Table II. Conclusions regarding the use of Palonosetron Conclusions Chemotherapeutic regimens used in the treatment of hematologic and non-hematologic malignancies are accompanied by a degree of emesis. Corroborating the data in literature, an individualized approach centered to each patient of antiemetic therapy is required, the current guidelines directing the clinician in deciding on the anti-emetic prophylaxis. In the group of the 17 patients analyzed, antiemetic therapy was well tolerated with no significant side effects and its effectiveness conforms to the data in literature, in both hematologic and non-hematologic malignancies. Anti-emetic prophylaxis is a challenge for clinicians. Beyond current developments, nausea and vomiting after chemotherapy are still the major factors affecting quality of life and compliance with treatment. The Scientific Committees of developing international guidelines are being debated on the strict formal recommendations for the use of antiemetics associated to chemotherapy treatments. References 1. Rahnea Nita G et al, Aspecte de teorie si practica in ingrijirea paliativa, Editia I, Editura Universitara, Bucuresti, 2013: Rhodes VA et al, Nausea, vomiting, and retching: Complex problems in paliative care, CA A Cancer Journal for Clinicians 2001; 51: Loewen PS et al, 5-HT3 receptor antagonists vs traditional agents for the prophylaxis of postoperative nausea and vomiting, Can J Anaesth 2000; 47(10): Grunberg SM et al, Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity an update, Supp Care Cancer 2005; 13: Hesketh PJ, Chemotherapy-induced nausea and vomiting, N Engl J Med 2008; 358: Kris MG et al, American Society of Clinical Oncology guideline for antiemetics in oncology: update J Clin Oncol 2006; 24: Roila F et al, Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nuasea and vomiting: results of the Perugia consensus conferences, Ann Oncol 2010; 21 [suppl 5]: v232-v243; January 3, NCCN Guidelines for Supportive Care: Antiemesis v Lohr L, Chemotherapy-induced nausea and vomiting, Cancer J. 2008; 14: Grunberg SM et al, Incidence of chemotherapyinduced nausea and emesis after modern antiemetics, Cancer 2004; 100: Hallenbeck J et al, Fast Fact and Concept: Treatment of nausea and vomiting, End of Life Education Project. XVIII, Vol.18, Number 3/

22 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 THERAPEUTICAL PRACTICE OVER THE COUNTER DRUGS DURING PREGNANCY- TIPS FOR A CORRECT APPROACH Buzoianu D. Anca 1, Boca N. Andreea 1, Bocşan I. Corina 1 1. University of Medicine and Pharmacy Iuliu Haţieganu, Department of Clinical Pharmacology, Cluj-Napoca, Romania Abstract. From the viewpoint of pharmaco-therapeutic approach, pregnancy is a period that deserves special consideration. Health care providers face concerns regarding the safety and efficiency of drugs for both mother and fetus. Ethical considerations limit clinical testing during pregnancy, so there is an important lack in safety data. There is a general misconception that all drugs are harmful to the fetus, therefore mothers expose themselves to high risks refusing medication in life threatening medical conditions. On the other hand, although they are readily available, over-the-counter (OTC) drugs should not be used by pregnant women without the physician s advice. While there is a fairly good safety record for some commonly used OTC medication like short-acting NSAIDs, calcium based antacids, Chlorpheniramine, or PPIs, the misuse of others can be harmful to the fetus. Therefore it is very important to always assess that benefits overweight the risks while using OTC drugs during pregnancy. Introduction Pregnancy is a physiological condition characterized by multiple pharmacological particularities for the embryo, fetus and mother. The use of drugs during pregnancy and lactation remains a controversial issue, with serious medical and emotional implications. Health care providers deal with concerns related to the safety and efficiency of therapy, both for the mother and for the fetus. [1,2] The unfortunate experience with thalidomide in the early 60's had multiple consequences, among which: development of clinical pharmacology as a discipline, reconsidering the way drugs are used during pregnancy and preclinical testing of new drugs for both efficacy and toxicity.[3] Preclinical studies are without doubt a powerful tool, minimizing drugs toxic effects on patients. Animal reproductive studies are extremely useful in preventing the release of drugs with significant pregnancy risks, but they have certain limitations due to pharmacokinetic and pharmacodynamic differences between humans and animals. Therefore clinical testing of drugs is also mandatory, providing vital data regarding safety and efficacy. [4, 5] The risk of toxic effects on both mother and fetus led to serious limitation of clinical testing during pregnancy. Therefore, due to ethical consideration, a significant Andreea Boca 6 Pasteur St, Cluj-Napoca, Romania boca.andreea@umfcluj.ro number of drugs are marketed without relevant information of their use in pregnant women.[6] On the other hand, medical conditions can occur at any time during pregnancy. Acute or chronic underlying diseases require adequate control to ensure optimal health of both mother and fetus, cases in which the use of drugs will be necessary. A study by Andrade and colleagues in 2004 showed that a pregnant woman is prescribed 3-5 drugs during pregnancy, and 64% of pregnant women receive at least one drug during pregnancy: antibiotics, antiemetics, tranquilizers, analgesics, etc.[7] Numerous other studies on this topic also underline the frequent use of medication in pregnancy.[1,8,9,10] Unfortunately not only drugs prescribed by doctors are used by pregnant women, but also self chosen OTC medication, herbals and dietary supplements, which they consider to be totally safe and therefore misuse.[11,12] At the opposite side, fearing side effects, a number of pregnant women stop their chronic treatment without medical advice, sometimes with serious life threatening consequences.[13] Overall, if medical conditions require it, medication should be used during pregnancy and lactation only under strict medical supervision, with systematic monitoring pre, intra and post-partum. Pharmacokinetic and pharmacodynamic changes in pregnancy As a study by Loebstein and collaborators underlines, absorption, distribution, biotransformation, clearance, and especially adherence to therapy strongly influence the outcome of medication during pregnancy.14 Since classical methods like collecting repetitive blood samples 116

23 for assessing pharmacokinetic changes is not suitable during this delicate period, new investigative methods like hair analysis are being studied.[15, 16] Absorption of drugs can be affected due to decreased intestinal motility and delayed gastric emptying time. Another limiting factor is the gastric acidity, which decreases on average by 40% during pregnancy. Nausea and vomiting can cause delayed or incomplete absorption of nutrients and medication. Evening doses can partially overcome this. Underlying chronic conditions like inflammatory bowel disease can also lead to decreased absorption.[17] Distribution is another process that can be modified under this particular condition. Increased body weight, plasmatic volume and cardiac output during pregnancy can lead to a relative decrease in plasma concentration. During the third trimester the serum albumin concentration decreases, causing an increase in free form of the drugs that extensively bind to it. This can ultimately result in higher efficacy, but also possible toxic effects of such medication.[18] Metabolic changes have also been noticed during pregnancy, but their mechanism remains partially unknown. The hepatic metabolism of drugs can be influenced by the increased level of hormones and also by the modified activity of cytochrome enzymes, which can be increased (CYP3A4, CYP2D6, and CYP2A6) or decreased (CYP1A2, CYP2C19) in pregnant women. [19] During pregnancy higher clearance rate for drugs which are renally excreted can be noticed. This is due to increased glomerular filtration (up to 50%) and can require dose adjustment.[18] As the pregnancy advances, the placental barrier s permeability increases up to ten times. Therefore most drugs administrated to the mother, cross into the fetal circulation, raising safety concerns. For better understanding and predicting this process, placental perfusion models are currently under study.[20] Adherence to therapy has been suggested as an important limiting factor, since a number of pregnant women refuse to follow prescribed therapies fearing side effects. The consequences are serious, sometimes even lethal.[15] Pharmacodynamic modifications can also occur during this period due to decreased immunity, increased risk of nausea and vomiting, depression, acute condition induced by pregnancy, etc. Therefore, clinical studies that have not been conducted on pregnant women may not be relevant to them, and therapeutic regimens can require adjustment. [15, 19] Concluding, knowledge on pharmacokinetic changes together with pharmacodynamic variability and eventual underlying medical conditions, should be integrated for designing an optimal individualized therapeutic plan for each pregnant patient. Selection of drugs in pregnancy Although a number of drugs have been proven to have teratogenic effects, so unnecessary exposure should be avoided, this shouldn t limit the correct use of medication during pregnancy. As discussed above, when medical conditions require it, drugs should be given even during pregnancy. A study by Brent showed that exposure to drugs during pregnancy is responsible for producing congenital malformations in less than 1% of cases.[21] Therefore patients should be informed that not all medication can cause birth defects, and in correctly chosen cases the benefit outweighs the risks.1 Some factors are very relevant and should be carefully considered for an optimal therapeutic plan. Beside the drug itself, the route of administration, dosage, posology and gestational age can influence the safety profile of medication.[22] During the first 2 weeks pregnancy goes by the law "all or nothing", so if the embryo undergoes teratogenic changes due to drug exposure, it is spontaneously eliminated. Between 18 and 60 days after conception (organogenesis stage), improper medication can cause structural abnormalities such as growth impairment, CNS abnormalities, or even death. Different classes of drugs are known to have these risks: chemotherapeutic agents (methotrexate, cyclophosphamide), sex hormones (diethylstilbestrol), lithium, retinoids, thalidomide, some antiepileptics, coumarin derivatives, etc. On the other hand, drugs considered safe in the first trimester, can be contraindicated in the third. This is the case of the most used OTC medication, NSAIDs.[23, 24] A review by Lo and Friedman showed that in 2002 teratogenic information was still unknown for more than 90% of the medication approved by the FDA between 1980 and 2000.[25] Even when information is available, the access to it is still, many times, delayed due to the lack of a common data base or proper labeling containing all relevant data.[8] These indicate that accessible and up-to-date drug information should be available to health care providers and also to women. This would decrease the exposure to unnecessary toxic risks, and pregnant women with medical conditions that require drug therapy wouldn t refuse to follow it due to the fear of unknown teratogenic effects.[8, 26] A first step in this direction was taken in 1979 by the Food and Drug Administration (FDA), whom at that time introduced specific regulations regarding the administration of drugs in pregnancy and lactation, as response to the 1962 thalidomide cases. This has lead to a classification according to the presence or absence of data on the effect of drugs in pregnancy, source of such data (animal or human), and results of studies (positive or negative). The five categories that drugs were classified in are shown in the table below.[28] The above classification is far from an optimal one, with many weak points among which: - One could assume that classification of drugs in the same category implies that all carry the same type, severity or incidence of fetal anomalies, which is not the case - In class B there is no clear difference in relevance if the data is collected from animals or humans - Categories are seen as a scale for risk increase, without looking into the risk/benefit balance.[28, 29] These lacks were underlined during the FDA public hearing in 1997, leading to the Proposed Rule for Pregnancy and Lactation Labeling in It was concluded that dividing into categories wouldn t be the optimal solution, but a narrative labeling model, with the separation of clinical information from animal data. XVIII, Vol.18, Number 3/

24 Labeling for pregnancy and lactation would stipulate drug data referring to: - fetal risk (for both systemically and not systemically absorbed drugs, based on animal data and, when available, human data) - clinical considerations (inadvertent exposure, risk for pregnant and the fetus due to the medical condition or to the drug, effects of exposure, dose and duration of treatment, potential neonatal complications effects during labor and birth) - data (human data first, than animal data, including description of the study) [28, 29] Since this is not a labeling law yet, and there is no complete source that gathers all available information on correct management of medication for pregnant women, doctors should consult multiple sources, besides the drug label. Reliable and up to date for this purpose are case reports and follow-up case-control studies presented during conference meetings, medical literature (Sheppard s Catalog of Teratogenic Agents, REPROTOX), on-line data bases (REPROTEX, TERIS), and different informatics systems REPRORISK, etc.[8] General recommendations for over-the-counter drugs (OTCs) during pregnancy Self-care and active participation are becoming issues of awareness in many of life s aspects, including pharmacotherapy. For this mater, in the last decades OTC s have been gaining territory over prescription drugs. A lot of previously prescribed medication is now marketed over-the-counter. As a result, approximately 60 percent of the drugs on the United States market are OTC s.[30] This is valid also for pregnant women, studies showing that 80% of them take at least one OTC drug during the gestational period.[31] Around 60 % of them use nonprescription drugs as advised by a physician, but the rest use auto medication, which can result in adverse effects for both mother and fetus.[23] Among OTC drugs pregnant women most frequently use non, steroidal anti-inflammatory drugs (NSAIDs) rank among the first positions, these including aspirin, mostly for pain relive.[23] Available data concerning their safety during this delicate period lacks consensus. For example, regarding the risk of miscarriage, a clinical study by Li concluded that the use of aspirin increases this risk, while one published three years later by Keim proved the opposite.[32, 33] Although so far NSAIDs are not known to have teratogenic effects on humans, due to the maternal and fetal possible risks they should be used in the lowest effective doses, and discontinued in the last 6-8 weeks of pregnancy. Different studies indicate as possible fetal risks premature closure of the ductus arteriosus, intracranial bleeding, renal dysfunction, and oligohydramnios. Especially in high doses (over 3g of aspirin) these drugs increase the risk of maternal anemia, prolonged gestations by inhibiting uterine contractions, and peri partum hemorrhage. [23, 24, 34] Used in small doses for its antiplatelet effect, acetylsalicylic acid (eventually in combination with heparin) is the most effective therapy in patients with anti-phospholipid syndrome and a history of 118 spontaneous abortion.[24,35,36] Clinical studies have proved that in low doses aspirin is also beneficial for preventing preeclampsia and intrauterine growth restriction.[24,37] Acetaminophen is an analgesic frequently used during pregnancy due to its good safety profile. It does not increase the risk of miscarriage, fetal intracranial hemorrhage, or maternal bleeding (no antiplatelet effect), but maternal abuse or chronic over dosage can lead to acute liver failure. Some studies suggest that short-acting NSAIDs, with inactive metabolites, such as diclofenac and ibuprofen, are safer for pregnant women. [23, 24] Nausea and vomiting are common conditions during pregnancy. Although they are regarded as normal problems especially during the first trimester, selected cases can require therapy. Therapeutic options go from lifestyle changes, to antiemetic drugs, severe cases requiring hospitalization. When non-pharmacological options like dietary changes fail to control nausea and vomiting, and they become a health threatening problem, drug therapy becomes mandatory. Since pregnant women have been excluded from most clinical trials, limited data is available on the safety of antiemetics during pregnancy. OTC medication such as vitamin B6 (pyridoxine), antihistamines (diphenhydramine, dimenhydrinate), dopamine antagonists like metoclopramid and phenothiazines (prochlorperazine, chlorpromazine, promethazine) are currently used for these conditions with good results and no reported congenital abnormalities.[38,39,40] Ondansetron, a serotonin antagonist, has also been proven efficient for hyper emesis gravidarum.[41] Natural therapies such as ginger are also used for their antiemetic effect during pregnancy. Studies which have looked into the safety and efficiency of this traditional remedy, agree on its antiemetic properties, and no teratogenic effects have been noticed so far.[42, 43] Nausea and vomiting can also be caused by acid reflux and heartburn. In such cases, acid-reducing medication should be considered.[44] Proton-pump inhibitors and H2 blockers are efficient for this matter and so far clinical studies did not show any fetal risks related to them. Antacids can also be used symptomatically and are considered safe, but due to the tocolytic properties of magnesium sulfate and the general concerns about aluminum, the agents containing calcium seem a safer choice. [23, 45, 46] Due to immunologic changes pregnant women are more susceptible to medical conditions such as common colds. Therapeutic options include OTC drugs such as NSAIDs (already discussed above), antihistamines, decongestants and expectorants. Antihistamines such as diphenhydramine are used not only for common cold, but also for allergies, nausea, sedation, although few data confirm their safety during pregnancy. Furthermore, in high doses the drug has been shown to have oxytocin-like effects. With a better safety profile, the American College of Obstetricians and Gynecologists recommended chlorpheniramine. [23] Oral decongestants like pseudoephedrine and phenylephrine, as well as local decongestants like

25 xylometazoline and oxymetazoline are considered safe during pregnancy, with no malformations reported in clinical studies.[47, 48] Expectorants like guaifenesin are also used during pregnancy, although some studies suggested that their use during the first trimester could increase the risk of neural tube defects.[23, 49] Conclusion For the majority of OTC drugs no clinical studies have been conducted on pregnant women, all safety data being initially obtained through animal studies, and further on from case-reports and follow-up studies. Therefore, to correctly assess the risk/benefit, healthcare providers should access all complementary sources that become available once the drugs are marketed, not only the safety data provided by the producing company. Another aspect to be underlined concerns the fear of medication among pregnant women. They should indeed avoid self medication, but there is no justification for not taking or discontinuing pharmacotherapy when this is being recommended by the physician. This attitude can have serious consequences for both mother and fetus, and should be overcome by offering complete information on the medication that is being prescribed. References 1. Knoppert D. Safety and efficacy of drugs in pregnancy. J Popul Ther Clin Pharmacol. 2011;18(3):e Epub 2011 Nov Mehta N, Larson L. Pharmacotherapy in pregnancy and lactation. Clin Chest Med Mar;32(1): Ward SP. Thalidomide and Congenital Abnormalities. Br Med J September 8; 2(5305): Brent RL. Utilization of juvenile animal studies to determine the human effects and risks of environmental toxicants during postnatal developmental stages. Birth Defects Res B Dev Reprod Toxicol Oct;71(5): Suvorov A, Takser L. Facing the challenge of data transfer from animal models to humans: the case of persistent organohalogens. Environ Health Nov 13;7: Domínguez V, Ramos N, Torrents A, García D, Carné X. Clinical trials during pregnancy: what has been done. Eur J Clin Pharmacol Nov 11. [Epub ahead of print]. 7. Andrade SE, Gurwitz JH, Davis RL, Chan KA, Finkelstein JA, Fortman K, McPhillips H, et al. Prescription drug use in pregnancy. Am J Obstet Gynecol Aug;191(2): Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication Use during Pregnancy and Lactation: An Urgent Call for Public Health Action. J Womens Health, 2005 Feb:2: Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1. Teratology. Obstet Gynecol Jan;113(1): Lalonde AB. Drugs indicated for use during pregnancy. J Popul Ther Clin Pharmacol. 2011;18(3):e Epub 2011 Nov Low Dog T. The use of botanicals during pregnancy and lactation. Altern Ther Health Med Jan- Feb;15(1): Conover E, Buehler BA. Use of herbal agents by breastfeeding women may affect infants. Pediatr Ann Apr;33(4): Einarson A. Abrupt discontinuation of psychotropic drugs following confirmation of pregnancy: a risky practice. J Obstet Gynaecol Can Nov;27(11): Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet Nov;33(5): Koren G. Pharmacokinetics in pregnancy; clinical significance. J Popul Ther Clin Pharmacol. 2011;18(3):e Epub 2011 Nov Gray T, Huestis M. Bioanalytical procedures for monitoring in utero drug exposure. Anal Bioanal Chem Aug;388(7): Epub 2007 Mar Heetun ZS, Byrnes C, Neary P, O'Morain C. Review article: Reproduction in the patient with inflammatory bowel disease. Aliment Pharmacol Ther Aug 15;26(4): Pavek P, Ceckova M, Staud F. Variation of drug kinetics in pregnancy. Curr Drug Metab Jun;10(5): Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10): Hutson JR. Prediction of placental drug transfer using the human placental perfusion model. J Popul Ther Clin Pharmacol. 2011;18(3):e Epub 2011 Nov Brent RL. Utilization of developmental basic science principles in the evaluation of reproductive risks from preand post-conception environmental radiation exposures. 33 rd Annual Meeting of the National Council on Radiation Protection and Measurements. April 2 3, 1997, Arlington, VA. Teratology, 59 (1999), pp Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: Part 2. Drugs with minimal or unknown human teratogenic effect. Obstet Gynecol Feb;113(2 Pt 1): Black RA, Hill DA. Over-the-Counter Medication in Pregnancy. Am Fam Physician Jun; 67(12): Janssen MM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med Mar 13;160(5): Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol Sep;100(3): Coverdale JH, McCullough LB, Chervenak FA. The ethics of randomized placebo-controlled trials of antidepressants with pregnant women: a systematic review. Obstet Gynecol Dec;112(6): Briggs GG, et al. Drugs in Pregnancy and Lactation. 7 th ed. Philadelphia: Williams & Wilkins, Feibus KB. FDA's proposed rule for pregnancy and lactation labeling: improving maternal child health through well-informed medicine use. J Med Toxicol Dec;4(4): Food and Drug Administration, HHS. Requirements on content and format of labeling for human prescription drug and biological products. Final XVIII, Vol.18, Number 3/

26 rule. Fed Regist Jan 24;71(15): Jacobs LR. Prescription to over-the-counter drug reclassification. Am Fam Physician May 1;57(9): Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive toxicology. 2 nd ed. New York: Raven, 1995: Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ Aug 16;327(7411): Keim SA, Klebanoff MA. Aspirin use and miscarriage risk. Epidemiology Jul;17(4): Ostensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother Mar;5(3): Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol Sep;100(3): Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev Jan 21;(1):CD Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguère Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol Aug;116(2 Pt 1): Badell ML, Ramin SM, Smith JA. Treatment Options for Nausea and Vomiting During Pregnancy. Pharmacotherapy. 2006;26(9): Tan PC, Khine PP, Vallikkannu N, Omar SZ. Promethazine compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol May;115(5): Tan PC, Omar SZ. Contemporary approaches to hyperemesis during pregnancy. Curr Opin Obstet Gynecol Apr;23(2): Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG Sep;111(9): Tiran D. Ginger to reduce nausea and vomiting during pregnancy: Evidence of effectiveness is not the same as proof of safety. Complement Ther Clin Pract Feb;18(1): Boone SA, Shields KM. Treating pregnancy-related nausea and vomiting with ginger. Ann Pharmacother Oct;39(10): Epub 2005 Aug Gill SK, Maltepe C, Mastali K, Koren G. The effect of Acid-reducing pharmacotherapy on the severity of nausea and vomiting of pregnancy. Obstet Gynecol Int. 2009;2009: Epub 2009 Jul Matok I, Levy A, Wiznitzer A, Uziel E, Koren G, Gorodischer R. The Safety of Fetal Exposure to Proton- Pump Inhibitors During Pregnancy. Dig Dis Sci Oct 30. [Epub ahead of print]. 46. Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Uziel E, Levy A. The safety of H(2)- blockers use during pregnancy. J Clin Pharmacol Jan;50(1):81-7. Epub 2009 Sep Kallen BA, Olausson OP. Use of oral decongestants during pregnancy and delivery outcome. Am J Obstet Gynecol. 2006;194(2): Rayburn WF, Anderson JC, Smith CV, Appel LL, Davis SA. Uterine and fetal Doppler flow changes from a single dose of a long-acting intranasal decongestant. Obstet Gynecol Aug;76(2): Erebara A, Bozzo P, Einarson A, Koren G. Treating the common cold during pregnancy. Can Fam Physician May;54(5):

27 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 CASE REPORT DIAGNOSIS IN ACUTE INTOXICATION WITH METHANOL CLINICAL PRESENTATION Tănăsescu Andreea 1,2, Macovei R. 1,2, Ionica M. 3, Tudosie M. 1,4 1. University of Medicine and Pharmacy "Carol Davila" Bucharest 2. ICU Toxicology. Emergency Hospital Bucharest 3. University Politehnica Bucharest, Optoelectronics Research Centre 4. Army Center for Medical Research Abstract. Methyl alcohol poisoning usually occurs through accidental ingestion or confusion of the containers. Accidental industrial exposure to methanol vapors could be the cause of poisoning. Methanol is obtained by destructive distillation of wood and used as solvent, antifreeze solvents for paints and additives [1]. We present a patient who was admitted to hospital with a symptomatology limited to eyes and CNS and with mild metabolic acidosis which led to the assumption that the patient ingested methanol. The diagnostic was confirmed by toxicological analysis. The patient ingested concomitant ethanol, overlapping with methanol for alcohol dehydrogenase, the first enzyme in the degradation pathway, with reduction of methanol toxic metabolites of. The presence of methanol metabolites completed the patient s clinical picture at the time of presentation at hospital.. The patient showed ocular disorders which persisted after discharge.. It is known that these ocular disorders may still persist 6 month after intoxication and in some instances could be irreversible. The prognosis in methanol poisoning is theoretically good if the treatment is started early, is directly dependending on the severity of intoxication, the time since ingestion of methanol and admission to hospital. A successful medical management is based on early recognition of the extent of methanol metabolites toxicity of in each patient. This assessment is critical in determining the necessity of ADH inhibition and hemodialysis. The antidotal therapy with ethanol is readily available in most hospitals; it is inexpensive, and can be administered orally as well as intravenously. Keywords: acute poisoning with methanol, alcohool dehydrogenase, formic acid, ethanol, hemodialysis Introduction Methyl alcohol poisoning usually occurs through accidental ingestion or confusion of the containers. Accidental industrial exposure to methanol vapors could be the cause of poisoning. Methanol is obtained by destructive distillation of wood and used as a solvent, antifreeze, solvents for paints and additives[1]. Toxicodynamic mechanisms. Absorption and distribution of methyl alchocol issimilar with ethyl alcohol andis metabolized by the same enzymes that metabolize ethyl alcohol: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. Mihai Tudosie 8 Calea Floreasca St., Bucharest, Romania mihailtudosie@yahoo.com Upon ingestion, methanol is quickly absorbed in the gastrointestinal tract and metabolized in the liver. In the first phase of degradation, methanol is transformed into formal dehyde by ADH enzyme (Figure 1.). This reaction is slower than the next phase, the transformation of formaldehyde into formic acid via the enzyme aldehyde dehydrogenase. This may explain the reason for the latency of symptoms between ingestion and effect. The half-life of formaldehyde is estimated to be 1-2 minutes [2], [3]. Formic acid is further oxidized to carbon dioxide and water in the presence of tetrahydrofolate. The metabolism of formic acid is very slow; thus, formic acid often accumulates in the body, which results in metabolic acidosis[2], [3]. Oxidation of the methyl alcohol can also be carried out in the kidney and it is also independent of serum concentration. The symptomtomatology has a latency of 8-36 hours. At this time the patient could be without signs of intoxication with methanol. XVIII, Vol.18, Number 3/

28 Figure 1. Metabolism path of methanol Clinical Case Presentation We present the case of a 68-year-old patient, who was admitted to the Emergency Hospital Bucharest with psychomotor agitation and visual disorder after ingestion of methanol and ethanol at an unknown date. The patient's medical history includes chronic alcoholism. He denies any other drug use. The clinical examination revealed: altered general condition, conscious with psychomotor agitation and visual disorder; pupils equal, round and reactive to light, sclera anicteric. Skin: no skin abnormalities identified. Breathing spontaneously, no other abnormal sounds noted over the lung area. Cardiac: rhythm was regular; no murmurs or extra heart sounds noted. He remained hemodynamically stable with initial vital signs: blood pressure = 120/70 mmhg, heart rate= 84 beats /min. Abdominal: symmetric appearing; soft, flat, non-tender; no palpable masses. Extremities: No evidence of cyanosis or oedema. Diuresis presented. Due to psychomotor agitation the patient has been sedated. Initial laboratory data obtained from serum revealed the following: glycaemia=158 mg/dl; urea=32 mg/dl; creatinine=1,2mg/dl; AST=58 U/L; ALT=51U/L; LDH=538 U/L; Na= 146mmol/L; K= 3.5 mmol/l; WBC= 4200/mm3 ; Hb= 10,8 g/dl; PLT= / mm3; Acido-basic balance: ph = 7,27 pco2=45mmhg; po2=145 mmhg; HCO3=22,8mmol/l; BE=2.7mmol/l. Serum and urine toxicology screens were negative for cocaine, salicylates, barbiturates, benzodiazepines and other volatile alcohols, but positive for alcohol ethylic and methanol. Chest X-ray did not reveal pleuropulmonary lesions. Nephrological examination: present diuresis, creatinine 1.2mg/dl; without recommendation of hemodialysis at the the time of examination.ophthalmic examination after 4 days of admission: mild photophobia and scotoma. Urgent 122 measures of intensive therapy associated with general nursing were established and taken. Gastric lavage was performed for decontamination and removal of toxic agents in the body. The patient received antidotal treatment - ethanol in infusions g/kgb to block ADH, vitamin therapy and gastric protective treatment. Following these measures the condition of the patient improved significantly. Metabolic acidosis was corrected, serum creatinine level remained within the ranges mg/dl, and serum bicarbonate remained meq/l. The patient did not receive any form of dialysis. The patient was discharged after 7 days of hospitalization with improved general condition. Ophthalmic examination at discharge highlighted persistence of scotoma with recommendation on regularly ophthalmologic examinations. Discussions In acute intoxication with methanol there is a latent period of about hours. The interval between ingestion and the occurrence of symptoms correlates to the volume of methanol ingested and the amount of ethanol concomitantly ingested; competitive inhibition exists between the 2 compounds[4]. The most important effect of methanol before its metabolization is CNS depression. Ocular disorder may be represented by scotoma, difficulty with light adaptation, decreased visual field and photophobia, these symptoms being the direct cytotoxic effects of metabolites. In acute methanol poisoning the patient may have visual symptoms in parallel with other symptoms and sometimes it could precede general symptoms. Impaired visual acuity is accompanied by correspondingly impaired pupillary response to light; pupils continue to react normally to accommodation. The visual symptoms described range from spots in the visual field and flash lights, or

29 mistiness of vision, to evident reduced visual acuity and complete blindness [5]. In the acute phase, visual acuity is typically impaired by central scotomata. In the early phase, these are rarely accompanied by constriction of peripheral fields[5]. Hyperaemia of the optic disc is the most common abnormality on retinoscopy in the acute stage and emerges from 2 to 7 days. Peripapillary oedema is also frequent but develops more slowly and persists for longer (up to 8 weeks) than optic disc hyperemia [6]. The subsequent course can range from complete recovery, with disappearance of retinal oedema and return of normal vision, to persistent oedema of the retina for as long as 2 months. Optic atrophy can develop in 1 to 2 months and vision may be lost [5].Accumulation of formic acid is responsible for ocular toxicity. In patients whose vision does not recover, the scotomata in the central field remains and, as optic atrophy develops, the peripheral fields may constrict [5]. Electro retinography in methanol poisoning has shown minor alterations (reduction of the b-wave), and in many cases was essentially normal although the patients remained blind. This is consistent with the methanol's principal injurious action on retinal ganglion cells and optic nerve fibres[5]. In severe intoxication with methanol up to 25% of the patients may experience a persistence of the ocular disorder. The patient with acute methanol poisoning could have pale skin and the extremities could be cold and clammy [6], [7]. Pulse rate and blood pressure are usually well maintained until late in the course of poisoning when cardiovascular failure, bradycardia, hypotension, and myocardial infarction can supervene (observations from the Milan Poison Centre). The patient could present Kussmaul's respiration. This type of respiration is present in only 25% of cases [6]. Hyperpnoea represents a compensate mechanism for severe acidosis, common in acute methanol poisoning. In the initial stage inebriation and drowsiness may appear. These signs are milder than those caused by ethanol [8], [9], [10]. In later stages motor restlessness, vertigo, headache and weakness may occur. Before the drowsiness or coma, the patient may have a phase of excitement with delirium. Convulsions occur occasionally [6], [9]. Dilated pupils with sluggish or absent light reflex are characteristic, and impaired pupillary response to light is accompanied by correspondingly impaired visual acuity [5].Cerebral oedema and necrosis in the putamen have been documented[11]. Nuchal rigidity and other meningeal signs have been reported [12]. The patient may have discomfort and abdominal pain. Nausea and vomiting appear in 50% of cases. Abdominal pain may precede acute pancreatitis associated with hyperamylasaemia and hyperamylasuria[7], [13]. The kidney is usually not considerate as target organ in methanol poisoning. Acute renal failure accompanied by oliguria may occur during acute methanol poisoning. However, acute renal failure was described in few case reports and it was related to terminal complications of methanol poisoning, but reversible episodes were also documented [14]. In methyl alcohol poisoning severe metabolic acidosis is characteristic, similar with metabolic acidosis from acute intoxication with ethylene alcohol. Accumulation of formic acid is responsible for metabolic acidosis. In a more advanced stage it is also sustained by lactic acidosis. The serum bicarbonate levels and the base excess value are early and reliable indices of the severity of poisoning [9],[10].In fact, serum bicarbonate levels are inversely correlated with the accumulation of formate [15]. Methanol-poisoned patients present with an early increased osmolal gap metabolic acidosis which can be amplified by hyperkalaemia or rhabdomyolysis. Toxicological Analysis Determination of substances during acute intoxication depends on the laboratory s technical equipment. Methanol could be determined both quantitatively and qualitatively through spectrophotometric method, gas chromatography, liquid chromatography or osmolarity tests. Except ethanol which has very good determination results by spectrophotometric methods, the rest of alcohols are better determined through gas chromatography mass spectrometry (GC-MS), within head-space injection technique or Liquid chromatography mass spectrometry (LC-MS), or alternatively HPLC-MS [16]. Methanol concentration could be determined by gas chromatography or colorimetry (spot test).rapid procedures to detect methanol in blood (spot test): Protein-free filtrate of serum (1 ml) is added to 0.1 ml KMnO4 solution (5 g in 100 ml H2O). The test tube should be gently swirled and, after 5 minutes, sufficient powdered sodium bisulfite should be added to decolourise the permanganate. Freshly prepared chromotropic acid solution (0.2 ml, 0.5 g in 100 ml H2O) and 6 ml concentrated H2SO4 should be added mixed and heated in a boiling water bath for 5 minutes. A red-violet colour is positive and specific for methanol [17]. Level of formic acid/formate in blood and in urine could also be determined by enzymic method. Additionaly there are laboratory tests which could be used during metahol poisoning. Severe metabolic acidosis is characteristic for methyl alcohol poisoning. Initially acidosis is caused by formic acid but in advanced stages it is sustained by possible lactic acidosis. Lactic acidosis is induced by inhibition of cytochrome oxidase due to formic acid and cell hypoxia [10]. The concentration of formic acid is proportional with the increase of anion gap; levels of serum bicarbonate and the amount of excess base are reliable indicators of severe poisoning with methanol. Differential Diagnoses The differential diagnosis of methanol intoxication depends on the following conditions: ethylene glycol intoxication, cocaine poisoning, carbon monoxide poisoning, pseudoseizure, arsenic poisoning, any cause of altered mental status with acidosis and potential cardiovascular collapse. Treatment of intoxication During an acute intoxication, along with antidote therapy a very important step is the initial stabilization of the patient. Vital signs are measured, with immediate correction of life-threatening disorders. Airway obstruction may be the result of accumulation XVIII, Vol.18, Number 3/

30 of secretions or the mucosa swelling. First aid measures presuppose removal of foreign bodies, aspiration of secretions, avoiding posterior movement of the tongue by positioning the patient in a position of safety, pipe Guedel, ventilation by mask, endotracheal intubation, assisted mechanical ventilation. Measures to stabilize the cardiovascular system include: peripheral venous catheterization, administration of macromolecular solutions - dextran, Hemacel, Haes; administration of vasoactive substances - dopamine, dobutamine, norepinephrine; ECG monitoring. Central nervous system aims are administration of 10% glucose (glucose prior testing), thiamine, 100mg; mg naloxone (up to 10 mg); administration of diazepam in the case of seizure (5-10 mg iv); administration of oxygen to all depressed patients. Antidote therapy. The backbone of treatment for methanol intoxication is administration of ethanol[18], [19]. Ethanol is given in doze of g/kgb, orally or intravenously, followed by a maintenance dose of mg/kgb/hour[20]. Ethanol acts by competing with ethylene glycol for alcohol dehydrogenase, the first enzyme in the degradation pathway. Because ethanol has a higher affinity for alcohol dehydrogenase, about a 100-times greater raffinity, it successfully blocks the breakdown of ethylene glycol into glycolaldehyde, which prevents further degradation[21,22]. Likewise, folic acid acts as a cofactor for the oxidation of formic acid to carbon dioxide and water. It is given in doses of 50 mg to every 4 hours [23]. Fomepizole(4 metilpirazol) is, as well, a potent inhibitor of alcohol dehydrogenase; similar to ethanol, it acts to block the formation of the toxic metabolites[24]. The dose is: 15 mg/kg loading dose and 10 mg/kg maintenance every 12 hours up to 4 dose and then 15 mg/kg every 12 hours. In Romania this treatment is unavailable for patients. Excess of methanol could be removed from the body through hemodialysis. Hemodialysis accelerates the elimination of both methanol and formic acid and also assists incorrection of the metabolic acidosis. In general, dialysis should be employed in all cases developing ocular manifestations and in all cases with renal impairment, regardless of symptoms. A peak methanol level higher than 50 mg/dl has frequently been cited as an indication for dialysis [25,26,27,28]. Conclusion The analysed clinical case displayed a symptomatology limited to eyes, CNS and mild metabolic acidosis upon admission in hospital which led to the assumption that the patient ingested methanol. The diagnostic was confirmed by toxicological analysis. The patient ingested concomitant ethanol, this acting by competing with methanol for alcohol dehydrogenase, the first enzyme in the degradation pathway, with reduction of methanol toxic metabolites. Despite concomitant ingestion of methanol and ethanol, toxic methanol metabolites of were nonetheless released, because the level of ethanol in the blood didn t have a constant and high enough concentration prior to hospitalization, in order to complete alcohol dehydrogenase inhibition. The presence of methanol 124 metabolites shaped the clinical picture of the patient at the time of admission. The patient presented ocular disorders which persisted after discharge from hospital. It is known that these ocular disorders may persist 6 month after intoxication and in some instances could be irreversible. The prognosis in methanol poisoning is theoretically good if the treatment is started early/ Also it is known to be directly dependent to the severity degree y of intoxication and the time frame between ingestion of methanol and admission to hospital. Input from family members and co-workers may be required to help establish the exact time of the ingestion. A successful medical management is based on early recognition of the extent of toxicity of methanol metabolites in each patient. This assessment is critical in determining the necessity of ADH inhibition and hemodialysis. Antidotal treatment with ethanol is readily available in most hospitals, it is inexpensive, and can be administered orally as well as intravenously. Most patients however, are admitted to hospital at a late stage and often without appropriate facilities for analyzing methanol which causes delays in diagnosis and possibly leads death [10]. References 1. Voicu V. Toxicologie Clinica, Editura Albatros, Bucuresti, 1997, Bitar Z.I., Ashebu S.D., Ahmed S. Methanol poisoning: diagnosis and management. A case report. Int. J.ClinPract., Nov., 2004; 58(11): Coulter C.V., Farquhar S.E.,McSherry C.M., Isbister G.K., Duffull S.B. Methanol and ethyleneglycol acute poisonings - predictors of mortality. ClinToxicol (Phila). Dec. 2011;49(10): Rathi M., Sakhuja V., Jha V. Visual blurring and metabolic acidosis after ingestion of bootlegged alcohol. Hemodial. Int. Jan. 2006; 10(1): Morton Grant W. Toxicology of the eye. Third. ed. Charles C. Thomas, Springfield, Proudfoot A. Diagnosis and management of acute poisoning. Blackwell Scientific Publications, London, Winchester J. Methanol, isopropylalcohol, higheralcohols, ethyleneglycol, cellosolves, acetone andoxalate. Chapter 35 in: Haddad L.M., Shannon M., Winchester J.F. Clinical management of poisoningand drug overdose. WB Saunders Co., Philadelphia, Baselt R.C. Disposition of toxic drugs and chemicals in man. 2nd ed. Biomedical Publ. Davis, California, 1982: Bozza-Marrubini M. Collective poisoning by methanol-adulterated wine in Italy. Newsletter of the European Association of Poison Control Centres, Jacobsen D., McMartin K.E., Methanol and ethyleneglycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med. Toxicol.,1986;1: McLean D.R., Jacobs H., Mielke B.W. Methanol poisoning: a clinical and pathological study. Ann. Neurol. 8, 1980: Litovitz T. The alcohols: ethanol, methanol, isopropanol, ethyleneglycol. Ped. Clin.North. Am.,

31 1986; 33: Gosselin, Smith Hodge, Clinical Toxicology of Commercial Products. Fifth ed., David Verhelst, Department of Nefrology, CliniquesST-Luc, Brussels, Belgium Acute renal Injury following methanol poisoning: analysis of a case series; abstract. 15. McMartin K.E., Ambre J.J., Tephly T.R. Methanol poisoning in human subjects: role for formic acid accumulation in the metabolic acidosis. Am. J. Med., 1980; 63: Victor A. Voicu, Radu Macovei, Liviu Miclea, Diagnostic şi tratament în intoxicaţiile acute, Editura Brumar, Timişoara, 2006, Bozza-Marrubini M., Brucato A., Locatelli C., Ruggeroni M.L., Joanna Tempowski, International Programme on Chemical Safety, IPCS Geneva, Information Monograph, May 2002; Keyvan-Larijarni H., Tannenberg A.M. Methanol intoxication. Comparison of peritoneal dialysis and hemodialysis treatment. Arch. Intern. Med., 1974; 134: McCoy H.G., Cipolle R.J., Ehlers S.M. Severe methanol poisoning. Application of a pharmacokinetic model for ethanol therapy and hemodialysis. Am. J. Med., 1979; 67: Victor A. Voicu, Radu Macovei, Liviu Miclea, Diagnostic şi tratament în intoxicaţiile acute, Editura Brumar, Timişoara, 2006; McCoy H.G., Cipolle R.J., Ehlers S.M. Severe methanol poisoning. Application of a pharmacokinetic model for ethanol therapy and hemodialysis. Am. J. Med.,1979; 67: Peterson C.D., Collins A.J., Himes J.M. Pharmacokinetics during therapy with ethanol and hemodialysis. N. Engl. J. Med., 1981, 304: Victor A. Voicu, Radu Macovei, Liviu Miclea, Diagnostic şi tratament în intoxicaţiile acute, Editura Brumar, Timişoara, 2006; Bruno Mégarbane, Stephen W. Borron, Frédéric J. Baud, Current recommendations for treatment of severe toxic alcohol poisonings, European Society of Intensive Care Medicine Volume 31, Issue 2 / February, 2005, Osterloh J.D., Pond S.M., Grady S. Serum formate concentrations in methanol intoxication as a criteria for hemodialysis. Ann. Intern. Med., 1986, 104: Kulig K., Duffy J.P., Linden C.H. Toxic effects of methanoi, ethyleneglycol, andisopropytalcokol. Topics Emerg. Med.,1984; 6: Keyvan-Larijarni H., Tannenberg A.M. Methanol intoxication. Comparison of peritoneal dialysis and hemodialysis treatment. Arch. Intern. Med.,1974; 134: Tobin M., Llanos E. Hemodialysis for methanolintoxication. J. Dial,1979, 3: XVIII, Vol.18, Number 3/

32 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 CASE REPORT SYNTHETIC PSYCHOTOMIMETICS SUBSTANCES, FALSELY ASSOCIATED WITH PHITOTERAPY, A NEW PRESENCE AMONG THE SUBSTANCES OF ABUSE Avram Oana 1,2, Avram Ruxandra 3, Caragea Gina 3, Forje Mărgărita 3, Truţă Elena 2, Ionică M. 2,4, Macovei R.A. 1,2, Voicu V. 1,5 1. University of Medicine and Pharmacy Carol Davila Bucharest 2. Clinical Emergency Hospital Bucharest 3. Army Center for Medical Research 4. University Politehnica Bucharest, Centre for Optoelectronics Research 5. Romanian Academy Abstract. In recent years, synthetic psychotomimetic drug abuse has experienced an increasing popularity, especially among young people. The most important enablers to this phenomenon are: easy product purchase, lack of information about the potential threat posed by their consumption and the difficulties of identifying analytes in biological products through simple techniques Thus developing the proper methods to identify these substances has become a priority. m. The expansion in consumption has outlined a complex pathology, given both their psychogenic and addiction effect. Symptoms can often be mistaken for pathology affective disorders. The clinical picture of acute intoxication with synthetic psychotomimeticsfrequently includes major imbalances of vital functions that require urgent remedial measures. Keywords: synthetic psychotomimetics, identification, addiction, intoxication Background Consumption of substances of abuse is primarily a disease of lifestyle, and has lately become a universal problem, both in terms of social and health systems. Serious health complications, amputated social values, the recent explosion of family violence cases and increased mortality among drug addicts are just some of the consequences of the disease. The dependence presupposes the existence of three distinct and independent components: - Psychological dependence - characterized by an irresistible desire and psychological imperative need to continue consuming a drug in order to relive the effects of psychoactive substances and to remove psychological discomfort, installed in the case of disrupted consumption; - Physical dependence - a pathological condition of the body caused by repeated administration of the drug developed only as a consequence of discontinuation or dose reduction of sudden sharp. The body's response is to change the conditions of Mărgărita Forje 8 Calea Floreasca St., Bucharest, Romania margarita_forje@yahoo.com 126 loss of balance in different systems and to restore the natural equilibrium; - Tolerance - the body's resistance to the effects of the drug under conditions of repeated administration of doses resulting from increasing use until, physically, one gets the same effects observed in the initial dose [Voicu V. 2005]. Use of psychotomimetic substances has experienced significant growth in recent years, especially among youth, most often without knowing the risks they are exposed to both acute and long-term Furthermore this represents a challenge to upgrade current approaches for the monitoring and control of new psychoactive properties of synthetic substances. We aim to present some aspects related to the use of the so-called " medicinal herbs", which are the vector for synthetic substances abuse discovered in recent years. However, the media and the public know this substance as ethnobotanical, which is incorrect as the definition clearly reflects: "Study of the popular names of plants" (DEX '09, 2009). These products contain mixtures of synthetic psychoactive substances; most based synthetic cannabinoids, which have great potential in the development of psychological and physical dependence as early as the first use. Their market launch aroused great interest among

33 both consumers of substances of abuse, and researchers who have tried to identify as accurately as possible these new psychotomimetic substances, given that their market is innovative, evolving and t orientation to the discovery of new marketing strategies. Material and methods We discuss three cases admitted with suspected consumption of synthetic psychoactive substances in the Toxicology Intensive Care Unit from the Emergency Hospital Bucharest.. For toxicological assays, urine samples were collected, which were analyzed on a gas chromatography system coupled to mass spectrometry (GC-MS) Model GC/MS-Saturn 2000 in order to identify the mass spectra obtained; library mass spectra were used in: PMW, NIST and Wiley. Results Clinical case 1 Male, 28 years old was brought to the emergency room for extreme agitation with suspected poisoning from unknown substance. The patient s previous medical history revealed: heroin dependence syndrome- 5 years ago, amputation of the left upper limb distal to post paravenous heroin injection, chronic HBV infection. The patient denied the use of heroin, while claiming that he only used alcohol just during the previous night. The patient was agitated, diaphoretic and aggressive. The average laboratory tests reflected ALT = 650 U/L, AST = 589 U/L; Cranial CT examination normal. After stabilization, the patient was admitted to YOU Toxicology, he was debilitated, conscious but temporo - spatial disoriented with psychomotor agitation, hallucinations and anxiety. He presented conjunctiv hyperemia, mydriasis, spontaneous breathing with polipnee, FR = 24/min, SaO2 = 97%, tachycardia AV = 120B/min, BP = 148/95 mmhg. Under specific intensive care treatment (volume depletion, electrolyte and acid-base rebalancing, antiemetic, stomach and liver protection, sedatives) evolution was slowly favorable, with respiratory and hemodynamic balance, but with persistence of memory impairment and spatial and time disorientation After 36 hours of continuous monitoring and a psychiatric evaluation the patient was discharged. The toxicological urine sample by GC-MS, identified JWH-018substance, a synthetic cannabinoid type involved in cannabis-like symptoms that our patient also experienced. Fig. 1. displays ion chromatogram, total and mass spectrum of synthetic cannabinoid JW018. Clinical case 2 Patient 20 years old, who came to the hospital with general malaise, headache and dizziness accusing several hours during a party in a club. The ambulance staff that accompanied the patient to the hospital reported the presence of vomiting and convulsions at home. At presentation the patient was febrile C, diaphoretic, intermediate pupils, slow reactive respiratory examination revealed polypnea with FR = 22B/min, bilateral vesicular murmur present, but with Chromatogram Plot File: d:\date de la gc_ms3\ninja ;04;18 pm.sms Sample: urine 2/18/13 12:04 PM Sample Notes: upu Operator: C Scan Range: Time Range: min. 100% 75% 50% 25% 51 0% MCounts Spect min. Scan: 1881 Chan: 1 Ion: 2667 us RIC: BC m/z RIC all ;04;18 PM.SMS JWH 018 bronchial rales in both lung fields, predominantly right SaO2 = 93 % exclusion of oxygen Cardiac examination was within normal limits, except for sinus tachycardia with AV = 119 b/min, BP = 108/63 mmhg. Rebalancing required replete fluids, antiemetic therapy, oxygen 6L/min facial mask, monitoring of vital functions, harvested samples for biochemical and toxicological analyzes. Clinical case 3 Patient, 19 year old, presented to the hospital accusing restlessness, dizziness and sweating, nausea, palpitations and tremor of the extremities. The patient was accompanied by a friend who confirmed the patient s use of 'Spice' products, approximately 2 hours prior to submission and denied any drug or alcohol consumption in recent history. Clinical examination was normal, except for increased heart rate AV = 126 B/min. Biochemical results, acid-base balance within normal range, rapid screening negative for THC. The urine sample outlined the presence of GC-MS prolintane metabolite. Fig. 3. shows ion chromatogram of urine sample and mass spectrum of prolintane metabolite. The patient refused further hospitalization and was monitored in the emergency department. After approximately 4 hours, symptoms resolved, respiratory and hemodynamic rebalanced. Discussions New synthetic substances use, produces changes minutes Scans Figure 1. The mass spectrum of synthetic cannabinoid JWH 018 XVIII, Vol.18, Number 3/

34 Figure 2. The mass spectrum search result for pirovalerone and mass spectrum from libraries Chromatogram Plot File: d:\ \ MD.sms Sample: MD 1/28/12 12:05 AM Sample Notes: urina UPU Operator: Margarita+Cristina Scan Range: Time Range: min. 100% 75% 50% 25% 0% MCounts Spect min. Scan: 416 Chan: 1 Ion: 57 us RIC: BC Prolintan -M (HO-Phenyl-) AC Midazolam [SI] RIC all MD.SMS minutes Scans Figure 3. The total ion chromatogram of the urine sample and the mass spectrum of prolintane metabolite in the cognitive function and perception, behavior disturbances, homeostasis of the body, up to a critical condition that can endanger the patient's life. As new compounds appear on continuous basis, they are not part of any list of banned substances. The highest incidence of poisoning cases admitted with new psychoactive substances synthesis was m/z recorded in , and was correlated with the existence of market specialized stores selling various medicinal herbs, bath salts, plant nutrients under different names: Magic, Pure, Ninja, Spice Gold, Puff, Strong, Spice Diamond, Class, Eclipse, Mr. Smiley, Mamba, Insomnia, Spice Silver, Jamaica, Cox Special, Special, K2, Genie, Yucatan Fire, et al. These are usually smoked or snorted, less frequently ingested, although the labels mention "banned for human consumption". Even if the packaging of these products, sold both in specialty stores and on the internet, mention the presence of a mixture of traditional herbs such as maritime Canavalia, Nymphaea caerulea, Scutellaria nana, Pedicularis densiflora, Leonotis Leonurus, Zorn latifolia, Nelumbo nucifera Leonurus sibiricus specialized laboratories have identified specific substances such as plants. Following investigations on 15 December 2008, the German pharmaceutical company THC Pharm found that the consumers described hallucinogenic effects are caused by JWH018, a synthetic cannabinoid, found in at least three of these products "ethnobotanical" (EMCDDA, 2010) In 2009, 24 new synthetic substances were identified for the first time in Europe, while in 2010 another 15 substances were released, including catinonele synthetic, synthetic cannabinoids and synthetic derivatives like cocaine and amphetamines (EMCDDA, 2010). Analytical laboratories using GC-MS systems or liquid chromatography systems coupled with LC- MS mass spectrometers have identified a number of substances responsible for the hallucinogenic effects described by consumers. (Voicu V., et al, 2013). Among them, the most widely used substances on the market in Romania are: - HU-210 (6aR, 10aR) -9- (hydroxymethyl) -6,6dimethyl-3- (2-methyloctan-2-yl) -6, 7,10, 10atetrahydrobenzo [c] chromen-1-ol (6) mentioned first in the UK, a synthetic cannabinoid agonist acting non selectively on CB1 and CB2 receptors (EMCDDA, 2010) - JWH-018 (naphthalene-1-yl- (1-pentylindol- 3-yl) methanon, a cannabinoid CB receptor agonist, aminoalkilindolilor family, synthesized for the first time in 1995 in experiments, the chemical structure quite different from the tetrahydrocannabinol, but more potent than this (EMCDDA, 2010). - CP (5- (1,1-Dimethylheptyl) -2 - [(1R, 3S) -3-hydroxycyclohexyl] -phenol) - a cannabinoid CB1 receptor agonist with a potency of up to 28 times higher than that of THC, which together with its counterparts dimethylhexyl, dimethyloctyl and dimethylnonyl were added to the list on substances involved in this phenomenon, first identified in 2009 in Spice-type products (EMCDDA, 2010) - JWH-073 naphthalen-1-yl-(1-butylindol-3-yl) methanone, JWH-018 naphthalen-1-yl-(1-pentylindol-3-yl) methanone, analogue in turn partial agonist of the CB1 and CB2 receptors. It was identified in Denmark and the Netherlands in 2009 (EMCDDA, 2010). Depending on the dose and the degree of tolerance developed the most common psychological effects are:

35 euphoria, relaxation, floating sensation, disinhibition, omniscience sensation, sensory illusions, visions autoscope, failing in concentration, depersonalization, impaired reasoning anxiety, hallucinations, panic attacks sometimes feeling imminent death, paranoid thoughts, temporo-spatial disorientation, environment with non-possession, or schizophrenia-like crisis that can trigger schizophrenia in predisposed people. From the physical point of view, consumers have the following symptoms: dizziness, lack of appetite, insomnia, tremor, agitation, hypertension or hypotension, bradycardia, tachychardia or, nausea, vomiting, fever, sweating, dilated pupils, muscle pain, muscle weakness, convulsions followed by coma and death. Pirovalerone (4-Methyl-a-ketone-prolintane) is a psychoactive substance with stimulant that acts as a norepinephrine reuptake inhibitor, dopamine (NDRI) and engaged in increasingly frequent pathology of addiction syndromes with substance abuse (Forges M., et al, 2012). The most common effects are: insomnia, tremor, anxiety, and loss of appetite. Prolintane 1-(1-benzylbutyl)pyrrolidine), also known as Catovic also presents neurotropic stimulant properties, entering the category of norepinephrinedopamine reuptake inhibitors, similar in structure to pirovalerone, but used more frequently alone than in combination of "Spice" type, namely not along with other psychoactive substances (Forges M., et al, 2013). Conclusions Psychotomimetics substances synthesis evolved greatly from their first appearance on the consumer market, representing a continuing challenge for the field of toxicology. These substances may be mixed with different psychotomimetics plants for use in therapy (for weakeness, controlling colds and other common medical conditions), or with various other substances for cultivation of plants (fertilizer) or personal hygiene (bath salts). All these products, plants, plant nutrients, bath salts are usually smoked. Faced with the growing number of severe poisoning cases with new substances of abuse, with important implications both at individual and social level, Government banned the sale of a number of products and substances with similar narcotic effects. However, there are new substances that are not included on any list and which can be legally sold to suppliers of products for tangible or plant maintenance "phytotherapy". A major problem that arises in these patients is the lack of real information on the composition of these products, impeding the physician to establish a direct causal relationship between intoxication and substance incriminated in the etiology of the patient's symptoms. Their precise identification and classification in most hospitals is very difficult due to the the lack of appropriate technical facilities and requires new detection methods of involved analytes for solving this type of consumption. Differential diagnosis with psychotomimetics synthesis poisoning is the most commonly specified psychiatric pathology, patients presenting signs and symptoms similar to those found in the category of affective disorders, and consumption of marijuana. Literature suggests that presence of adverse effects of synthetic psychotomimetics substances, especially synthetic cannabinoids are similar, but more severe than those given by cannabis. (Gurney, 2014). Despite the similarity of symptoms related to the consumption of synthetic cannabinoids by immunofluorescence, tests do not reveal a positive toxicological result for D9-tetradidrocanabinol (THC). In terms of laboratory, these substances can sometimes give phenomena of liver dysfunction, renal dysfunction, rabdomyolysis, usually transient, but can sometimes aggravate preexisting pathology of various organs and systems. Combination treatment of substance use is primarily symptomatic, with no specific antidote for poisoning with synthetic cannabinoids or synthetic psychoactive substances. In most cases, that agitation or aggression associated with benzodiazepines for sedation treatment is beneficial. Aspiration pneumonia is a frequent complication in the pathology of acute poisoning, especially in poisoning sedatives, and in emesis and convulsions associated cases. When it appears in clinical tests, it obviously leads to prolongued hospitalization, which automatically triggers labor costs and increased morbidity and mortality among these patients. Besides the severity of symptoms, associated to psychotomimetics consumption or substance abuse, another problem emerges when we talk about the hospitalization of these patients, specifically about the lack of agreement on admission. In extreme cases, it can resort to involuntary hospitalization if it turns out that the remaining methods have been tried and that the patient is a danger to himself or his entourage. Recognizing the signs and symptoms of poisoning psychotomimetic substances synthesis is important for an optimal assessment of their severity and for the application of proper therapeutic approache. References 1. Forje M., Caragea G., Truţă E., Macovei R., Ionică M. Metode analitice de determinare a substanţelor de abuz. Al X-lea Simpozion de psihologie militară aplicată. Psihomil X, Bucureşti, Forje M., Voicu V., Macovei R., Dănescu I, Avram O, Tudosie M., Ionică M NEW DRUG-ABUSE new entry nostalgic LSD-like structures. Al XIX-lea Congres de Medicină Militară Balcanică BMMC, Plovdiv, Forje M., Voicu V., Macovei R.A., Dănescu I., Burlacu D., Ionică M., New Drug-Abuse Psychotomimetics Substances Al XVII Congres de Medicină Militară Balcanică BMMC Belgrad Gurney SMR & col: Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs; Forensic Sci Rev 26: 53; Hudson S., Ramsey J., King L. Use of highresolution accurate mass spectrometry to detect reported and previously unreported cannabinomimetics XVIII, Vol.18, Number 3/

36 in herbal high. J Anal Toxicol 2010; 34(5). 6. Voicu V., Psihofarmacologia şi toxicologia clinicş a drogurilor de abuz, Editura Academiei Române, Voicu V., Macovei R., Dănescu I., Forje M, Caragea G, Truţă E., Stroe R., Macovei-Oprescu A.M., Avram O., Ionică M. Substanţe de abuz. Al X-lea Simpozion de psihologie militară aplicată. Psihomil X, Bucureşti, ***. Raportul anual 2010 al Observatorului European pentru Droguri și Toxicomanie (OEDT) privind situaţia drogurilor în Europa ***. DEX '09 Dicționarul explicativ al limbii române, ediția a II-a revăzută și adăugită, Academia Română, Institutul de Lingvistică Iorgu Iordan - Alexandru Rosetti, Editura Univers Enciclopedic, ***. EMCDDA. European Monitoring Centre for Drug Addiction, Understanding the Spice Phenomenon Toxichem Krimtech 2010; 77(1):

37 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 CASE REPORT RADIOTHERAPY IN EXTRAMEDULLARY SOLITARY PLASMACYTOMA OF THE NASOPHARINX Mitulescu Ortansa Ruxandra 1,2, Anghel Rodica 1,2, Dumitrache M. 2, Cirjan Adriana 2, Oprea V. 2, Mitulescu D Department of Oncology, Carol Davila University of Medicine and Pharmacy, Bucharest 2. Alexandru Trestioreanu Institute of Oncology, Bucharest Abstract. Plasmacytomas are monoclonal proliferation of plasma cells. Extramedullary plasmacytoma (EMP) is a rare tumor (3-4% of all plasma cell tumors) that forms in soft tissues. The most common site for EMP is the head and neck (HN) region representing 0,4% of all HN malignant tumors. There are no set guidelines for the management of this disease due to it s rarity. For most of the cases radiotherapy is the standard treatment. We present a case of a 41 years old female diagnosed with extramedullary solitary plasmacytoma of the nasopharinx. Keywords: extramedullary plasmacytoma, nasopharinx, radiotherapy Introduction Plasmacytomas are monoclonal proliferation of plasma cells. Most of the plasma cell tumors (multiple myeloma and solitary bone plasmacytoma) arises in the myeloid tissue of the bone. Extramedullary plasmacytoma (EMP) is a rare tumor (3-4% of all plasma cell tumors) that forms in soft tissues, characterised be the presence of focus of monoclonal plasma cells in the soft tissue in the absence of systemic disease. EMP was first described by Schridde et al in [1,3,4] The most common site for EMP is the head and neck (HN) region representing 0,4% of all HN malignant tumors, more frequently in paranasal sinuses, nasal fossa and nasopharinx. Symptoms are related to local tumor effects: epistaxis, nasal obstruction, pain, anosmia, nasal congestion. For the diagnosis of EMP it is necessary to exclude multiple myeloma, by performing serum protein electrophoresis, urinalysis for Bence-Jones protein (rarely seen in EMP), skeletal radiological assessment and bone marrow biopsy (less then 5% plasma cells in the bone marow in EMP). Differential diagnosis should exclude benign tumor, carcinoma, lymphoma. The clinical behavior can be transformation to multiple myeloma, local recurrence, distant metastasis. [2,5,6,7] There are no set guidelines for the management of this disease due to it s rarity. Surgical management can achieve local control, but it is limited to the cases Ruxandra Mitulescu 252 Sos. Fundeni, Bucharest, Romania rmitulescu@gmail.com when radical excision is possible. There are no data that chemotherapy as primary treatment improve survival or reduce relapses in EMP. Plasmacytomas are radiation sensitive therefore the main treatment in EMP is radiotherapy. Doses varies in the range of 40 to 60 Gy over 4 6 weeks with a threshold of 40 Gy for local control. The policy of nodal irradiation remains controversial but there are data arguing in favour of treating only the primary tumor and involved nodes. [9,10,11] Patient, Methods and Results We present a case of a 41 years old female with personal and family history N/A. She was evaluated in a otorhinolaryngology service for progressive nasal obstruction, epistaxis and discharge. After initially surgery for adenoids, the symptoms where persistent, further investigations showed a tumor in the nasopharinx. A biopsy was performed and the morphology & immunophenotype confirmed the diagnosis of a plasmacytoma. The serum protein electrophoresis showed increased value of IgA, the bone marrow biopsy confirmed less then 5% plasma cells and the skeletal survey didn t fiind any abnormalities. Head and neck MRI noticed the thickening of the nasopharinx mucosa, with no enlarged lymph nodes. The final diagnosis was extramedullary solitary plasmacytoma of the nasopharinx. Additional workup include thoracic CT, posterior rhinoscopy, abdominal ultrasound, laboratory tests. After submitting the case to the tumor board (head and neck surgeon, haematologists, radiation oncologist) the recommendation was radiotherapy. XVIII, Vol.18, Number 3/

38 We performed 3D conformal radiotherapy with CT planning. For positioning and immobilization the patient was supine with neck extended, with the use of an aquaplast mask to immobilize head and shoulders. CT scan was performed with i.v. contrast, 3 mm thick slices, from vertex to aortic arch. For treatment volume delineation we choose the CTV including the whole nasopharinx, according to the data that plasmacytoma frequently disseminates by submucosal way. There was no GTV delineated (in this case difficult to delineate a tumor with only thickening of the nasopharinx mucosa on MRI and CT). We choose not to include the nodal areas. (fig.1) Figure 1. CT axial and sagittal slice showing CTV (red), PTV (pink) and dose distribution (color wash) The organs at risk was also delineated: optical structures, parotids, brain stem, spine, pituitary, temporomandibular joints, cochleas. Verification and approval of the plan was made after checking the dose distribution and the dose volume histogram. (fig2) 132 For treatment delivery we used a linear accelerator, with multiple 6 MV photons beams. Verification was performed with portal imaging system, with images taken on days 1-3 and then weekly. The dose/fractionation schedule was 2 Gy/ fraction, 1 fraction/ day, 5 days/ week, to a total dose of 50 Gy in 25 fractions over 5 weeks. During treatment the patient experienced acute side effects: grade 1 dermatitis and dysphagia. Follow up after treatment for 2 years ( clinical examination, MRI, rhinoscopy) showed no evidence of disease. Discussion Figure 2. Dose volume histogram Extramedullary solitary plasmacytoma of the nasopharinx is usually treated with radiotherapy. The role of surgery remains limited due to the impossibility to perform radical excision. Chemotherapy didn t prove to reduce relapses or improve the survival.[12,13,14] There are limited data regarding radiation treatment in EMP of the head and neck region, with no prospective studies and only few retrospective studies. Doses in the range of 40 to 60 Gy usually achieve good local control. There is a controversy regarding the role of elective nodal irradiation.[12] Long term folow up is recommendable due to data showing progression to multiple myeloma even 15 years after completion of radiotherapy.[12,13,14] In our case we choose 3D conformal radiotherapy to a total dose of 50 Gy in 25 fractions over 5 weeks, treating only the nasopharinx with no elective nodal irradiation. The treatment was well tolerated. The patient is free of disease after 2 years. Conclusion Due to its rarity, extramedullary solitary plasmacytoma of the nasopharinx poses a challenge for physicians, regarding diagnosis and treatment. There are no set guidelines for the management of the ESCCs and prospective trials are warranted. References 1. Schridde H. Weitere Untersuchungen uber die Kornelunger der Plasmazellen. Centralbl Allg Pathol Anatol. 1905; 16: Wiltshaw E. The natural history of extramedullary plasmocitoma and its relation to solitary mieloma of bone and myelomatosis. Medicine. 1976; 55: Kapadia SB, Desai U, Cheng VS. Extramedullary plasmacytoma of the head and neck: a clinicopathologic study of 20 cases. Medicine 1982; 61: Susnerwala SS, Shanks JH, Banerjee SS, Scarfee JH, Farrington WT, Slevin NJ, Extramedullary plasmacytoma of the head and neck region: clinicopathologic correlation in 25 cases. Br J of Cancer; 1997; 75: Nofsinger YC, Mirza N, Rowan PT, Lanza D, Weinstein GS, Head & neck manifestations of plasma cell neoplasms. Laryngoscope; 1997: 107: Bachar G et al. Solitary extramedullary plasmacytoma of the head and neck--long-term outcome analysis of 68 cases. Head Neck Aug; 30(8): Kilciksiz et al. Clinical and prognostic features of plasmacytomas: a multicenter study of Turkish Oncology Group-Sarcoma Working Party. Am J Hematol Sep; 83(9): Mendenhall CM, Thar TL, Million RR. Solitary plasmacytoma of bone and soft tissue. Int J Radiat Oncol Biol Phys. 1980; 6: Alexiou C, Kau R, Dietzfelbinger H, et al, Extramedullary Plasmacytoma tumor occurrence and therapeutic concepts. Cancer; 1999; 85: Soutar R, Lucraft H, Jackson G, et al, Guidelines on the diagnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. British J of Haematology 2004; 124: Kumar S. Solitary plasmacytoma: is radiation therapy sufficient? Am J Hematol Sep; 83(9): V J Michalaki. Definitive radiotherapy for extramedullary plasmacytomas of the head and neck,

39 The British Journal of Radiology, 76 (2003), Soesan M, Paccagnella A, Chiarion-Sileni V, Salvagno L, Fornasiero A, Sotti G, et al. Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 1992; 3: Alexiou C, Kau RJ, Dietzfelbinger H, Kremer M, Spiess JC, Schratzenstaller B, et al. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts. Cancer 1999; 85: Jyothirmayi R, Gangadharan VP, Nair MK, Rajan B. Radiotherapy in the treatment of solitary plasmacytoma. Br J Radiol 1997; 70: XVIII, Vol.18, Number 3/

40 Vol XVIII, Number 3, September 2014 Pages: Copyright reserved 2014 CASE REPORT SEVERE SEPSIS AND MENINGOENCEPHALITIS WITH STREPTOCOCCUS PNEUMONIAE SEROTYPE 23 F IN A 5 YEAR-OLD CHILD WITH TRANSETHMOIDAL MENINGOCELE AND CSF FISTULA Drăgănescu Anca 1, Bilasco Anuța 1, Vișan Angelica 1,2, Negulescu Cristina 1, Vasile Magdalena 1, Condria E. 1, Dogaru Cornelia 1, Slavu Diana 1, Merisescu Mădălina 1,2, Luminos Monica 1,2 1. University of Medicine and Pharmacy Carol Davila Bucharest 2. INBI "Prof. Dr. Matei Bals", Bucharest Abstract. Invasive pneumococcal disease (IPD), defined as isolation of Streptococcus pneumoniae from any normally sterile body site, continues to remain a major health problem, especially in the countries where pneumococcal vaccine was not introduced in the national immunization programs. Factors that increase the risk for IPD are young age, chronic conditions like humoral immunodeficiency, functional or anatomic asplenia, the presence of cochlear implants, CSF fistula and in child day care attendance. The most common serotypes involved in IPD were 14, 6B, 19F, and 23F in the pre vaccine era and 1, 19A, 3, 6A, and 7F since the introduction of PCV7. Methods & Results: We report the case of a 5-year-old girl admitted to our clinic with the diagnosis of Severe sepsis with Streptococcus pneumoniae serotype 23F, Severe Meningoencephalitis, with medical record of left trans-ethmoidal meningocele with CSF fistula. Conclusion: We present this case in order to highlight the importance of pneumococcal immunization in preventing serious infections with Streptococcus pneumoniae, especially in patients with increased risk factors for IPD and recurrent bacterial meningitis. Keywords: Streptococcus pneumoniae, invasive pneumococcal disease, CSF fistula, meningocele Introduction Invasive Pneumococcal Disease (IPD) is a leading cause of morbidity and mortality among children under 5 years of age, with an overall annual incidence in children from Europe of 31/ [6] Invasive pneumococcal disease, defined as isolation of Streptococcus pneumoniae from a normally sterile body site (blood, cerebrospinal fluid, less commonly joint, pleural or pericardial fluid), continues to remain a major health problem, especially in the countries where pneumococcal vaccine was not introduced in the national immunization program.[5] Factors that increase the risk for IPD are young age, chronic conditions like humoral immunodeficiency, functional or anatomic asplenia, the presence of cochlear implants, CSF fistula and child day care attendance. [3] The most common serotypes involved in IPD in the pre vaccine era were 14, 6B, 19F, and 23F and since the introduction of PCV7: 1, 19A, 3, 6A and 7 F. [6] The most serious manifestation of IPD is meningitis, with an overall mean annual incidence in children of 7.5/ [6] Diana Slavu 1 Dr. Calistrat Grozovici, St., Bucharest, Romania diana_maria_slavu@yahoo.com 134 Case presentation We report the case of a 5-year-old girl admitted to our intensive care unit, with a 24 hour history of high fever (39 C) and vomiting, which rapidly progressed to altered mental status and meningeal syndrome. Her personal medical history revealed intermittent cerebrospinal fluid rhinorrhea, with a diagnosis of ethmoidal CSF fistula made 2 years ago, based on measurement of beta-2-transferrin in the nasal fluid and after performing a cerebral MRI. On admission the child was comatose, with a GCS of 10/15, febrile (38.1 C), pale, without cutaneous eruptions, with a heart rate of 90 beats per minute, a blood pressure of 130/80 mmhg, and was polypneic with a respiratory rate of 42 per minute. Oxygen saturation measured by pulse oximetry was 98% while breathing ambient air, with no pulmonary rales. Her abdomen showed no signs of peritoneal irritation; she had oliguria. Neurologic examination revealed intense meningeal syndrome, little reaction to tactile stimuli, spontaneous movement of limbs, decreased muscle strenght symmetrically, bilateral Babinski reflex, right palpebral ptosis with anisocoria (right pupil with mydriasis), horizontal nystagmus, normal pupillary light reflex. Laboratory blood tests showed increased leukocyte count (19.800/mm 3 ), highly increased inflammatory

41 markers (C reactive protein=342 mg/l, Fibrinogen= 753mg/dl, Procalcitonin=200 ng/ml), electrolyte disturbance, decreased prothrombin concentration (29%), with normal transaminases value and normal renal function, serology testing for HIV was negative and immunoglobulin and complement levels were Figure 1. Palpebral ptosis normal. The blood culture came back positive for Streptococcus pneumoniae serotype 23F. Brain magnetic resonance imaging was compatible with ethmoidal meningocele with inflamed meninges at this level and inflammatory changes and fluid collection in the left otomastoid bone. Figure 4. Figure 5. Figure 2. Figure 3. Figure 2,3,4,5 showing thin section brain MRI left ethmoidal meningocele. Due to neurological signs of brain stem dysfunction, the lumbar puncture was postponed and the patient was started on antibiotic treatment with IV Meropenem 120mg/kg/day and Linezolid 30 mg/kg/day for 21 days, IV mannitol and dexamethasone, IV immunoglobulins, under gastric protection with IV H2 receptor inhibitor. The lumbar puncture, performed after resolution of neurological signs, revealed a clear, normal pressure CSF, with 7 cells /mm 3, normal protein and glucose level, with negative bacterial cultures as expected, due to antibiotic treatment. Otorhinolaryngological examination revealed a left ethmoidal plate mass, without any CSF rhinorrhea at the time of examination. Neurosurgical examination agreed to the necessity of a surgical procedure to close the ethmoidal bone defect and suggested an intranasal endoscopic procedure. Chest X-ray, abdominal echography and echocardiography were within normal limits. Clinical evolution was slowly favorable with the cost of neurologic sequelae of right oculomotor nerve palsy. Discussions Pneumococcal meningitis is one of the most severe forms of invasive pneumococcal disease with a high XVIII, Vol.18, Number 3/