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Volume XIV, Number 2, 2010 - Therapeutics Pharmacology and Clinical Toxicology

Review


Pharmacogenomics impact on drugs toxicity

Anca Dana Buzoianu, Corina Ioana Bocsan, Claudia Militaru
Abstract: Pharmacogenomics developed mainly in the past 10 years, at the same time with the sequencing of the human genome and the introduction of the new technologies that made possible the analysis of more than one gene at the same time. Pharmacogenomics investigates the way that the variations of the human genome influence the specific responses to the medicines and allows the adaptation of the medication to the individual genetic constellation of a person, through -patient tailored- treatments, with increased efficacy and safety. The polymorphism of the genes that are involved in the metabolism of anti-epileptic drugs determine modified activity of the encoded enzymes; consequentially, differences result regarding the plasmatic concentration of the drugs, and there are also differences in the therapeutic efficacy and safety, more evident in the case of medicines with narrow therapeutic window. Genotyping CYP2C19 and CYP2C9 represents an alternative for traditional methods of investigation of the phenotype, and a predictive method for the low metabolizer status of the individual, status related to the increase of drugs toxicity and to more frequent side effects. Acenocoumarol is the main drug used for the prophylaxis and treatment of thromboembolic disease (TED) in Romania, although its adverse effects are causing 10% of the hospitalizations in the U.S.A. and Europe. There is a high inter-individual variability of the CYP2C9, with implications in the metabolism of acenocoumarol. Variability is caused mainly by the two frequent polymorphisms of the gene CYP2C9, CYP2C9*2 and CYP2C9*3. Patients carrying this polymorphism, G-1639A, can have an increased hemorrhagic risk, even with medium doses of acenocoumarol. Therefore, genotypic analysis seems to be a promising clinical approach for reducing the adverse effects of drugs and for increasing their efficacy, being an actual preoccupation of many research teams worldwide.

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Prophylaxis and treatment of hepatorenal syndrome

A. Niculae, I. Al. Checherita, Ileana Peride, Cristiana David, Al. Ciocalteu
Abstract: The hepatorenal syndrome is a syndrome of functional renal failure due to end stage liver disease. The ideal cure currently available for treating HRS is liver transplantation. Other therapeutic options appear to be those that reverse portal hypertension, splanchnic vasodilation, and/or renal vasoconstriction and renal replacement therapy. All the above mentioned represent a bridge towards liver transplantation.

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Original Papers


Mother to child HIV transmission in the north-east of Romania

Carmen Manciuc, Cristina Nicolau, A. Vata, L.J. Prisacaru, Diana Matei, Adina Boghian, Alexandra Largu, Carmen Dorobat
Abstract: The aim of the study was to mark the nature of HIV transmission to the newborns from the seropositive mothers in the NE area of Romania, monitored by The Regional Center for HIVAIDS in Iasi. Method. 92 HIV-positive pregnant women and their newborn babies were retrospectively analyzed and monitored between January 2005 - March 2010. Results: The incidence of the pregnant HIV- positive patients was 1.47/month in a female population of 638 seropositive-patients; the median age was 20.4 years; 72.1% were from suburban areas and 94.6% were HIV positive antepregnancy, 52.2% were with AIDS (72.8% with ARV treatment). In 22.5% of all cases, the ARV treatment was modified; the median CD4 count was 356/mmc (56-702/mmc), VL - 10700/ml. The prophylaxis of HIV transmission was performed for all of the children, six of whom were seropositive with a significant VL. Conclusions. Mother to child transmission could be avoided through a correct ARV therapy and prophylaxis of the newborn according to a working team comprised of an infectious diseases specialist, a neonatologist, a gynecologist, a social worker and a psychologist.

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Bacterial etiology of acute conjunctivitis

Maria Balasoiu, Adriana Turculeanu, Anca Ungureanu, Carmen Avramescu, Rodica Manescu, A.T. Balasoiu
Abstract: Acute conjunctivitis is the most frequent ophthalmological affection. The purpose of our study is to determine both the frequency and the drug-resistance of the bacteria involved in acute conjunctivitis etiology. Material and methods. We have isolated 85 bacterial strains coming from conjunctival prelevates, between 2006-2008 in the laboratory of Emergency Clinical Hospital of Craiova. The strains have been isolated and identified using modern bacterial methods. As for the drug-resistance, we used the standardized diffusimetric method, using CLSI/NCCLS standards. Results. The most frequent-isolated species were: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Peptostreptococcus. Drug sensitivity was different for each bacterial species. Conclusions. Our study proves that in infections etiology, the most important were Gram-positive bacteria, Gram-negative bacteria coming second. Drug sensitivity proved to be increased, because most strains were wild; the ones with intrahospital origin presented a higher level of drug resistance.

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Comparative study on the efficiency of the angiotensin converting enzyme inhibitors and angiotensin ii receptor antagonists in reducing serum C-reactive protein levels in patients with essential arterial hypertension

Gabriela Cioca, Minerva Boitan, Alina Zaharie, L. Safta
Abstract: The past decade has shown an increase in the relevance of inflammation and its mediators in vascular biology. It is more likely that the inflammation remains one part of the complex pathophysiology linking hypertension to vascular disease. Plasma levels of circulating inflammatory molecules, such as the C-reactive protein (CRP), have been shown to be predictive of future cardiovascular disease (CVD), and drugs which modify their levels can reduce the risk of myocardial infarction and stroke. Methods. For the comparison of the efficiency of the angiotensin II converting enzyme inhibitors (ACEi) and the angiotensin II receptor antagonists (ARAs) on the plasma C-reactive protein (hs-CRP) we administered Enalaprilum or Candesartan for a period of 12 months to 64 patients with arterial hypertension degrees 1, 2 and 3. This was a comparative clinical study, open, randomized, non-interventional on parallel groups of subjects. Results. In the group treated with Candesartan (35 patients) we observed a significant decrease in the plasma level of hs-CRP from 2.29±2.39 to 1.02±0.88 mg/dl (p<0.001) and in the group treated with Enalaprilum (29 patients) the plasma hs-CRP level decreased from 3.04±2.12 to 1.70±1.87 mg/dl (p<0.001). Between the two groups we have not observed a statistically significant difference in lowering the plasma levels of hs-CRP. There were no significant correlations between hs-CRP and systolic blood pressure, diastolic blood pressure and lipoprotein levels. There was a significant correlation between initial hs-CRP and waist size (r = 0.32). Conclusions. The present results show that 12 months of Candesartan or Enalaprilum therapy improved plasmatic levels of hs-CRP. In conclusion, the angiotensin II converting enzyme inhibitors and the angiotensin II receptor antagonists have the ability to positively influence cardiovascular outcomes of essential arterial hypertension.

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Experimental research on the effects of nano-vesicles encapsulating Ketoprofen in a visceral pain model in mice

Liliana Tartau, R.V. Lupusoru, D. Bindar, V. Melnig
Abstract: Nanoparticles designed for drug delivery are defined as submicrometer-sized colloidal particles in which the active principle is dissolved, entrapped or encapsulated, and to which the active principle is absorbed or attached. Generally, nanoparticles can be used to provide targeted delivery of active substances, to sustain drug effect in target tissue, to decrease its adverse effects. Ketoprofen is one of the most potent non-steroidal anti-inflammatory drug frequently prescribed worldwide. Literature data describe various possibilities for the design of ketoprofen nanoparticulate formulations, which are characterized and studied regarding active substances delivery, but only a few were investigated for the in vivo effects. Aim: This study investigated the effects of ketoprofen lipid vesicles in a visceral pain model in mice. Method: The soft matter vesicles made of lipid-ketoprofen-chitosan were prepared using an original method, and were physicochemically analyzed using a Malvern Zetasizer Nano ZS, ZEN-3500 model. The experiments were carried out on white Swiss mice (20-25 g), divided into 3 groups of 7 animals each, treated orally: Group I (Control): distilled water 0.3 ml, Group II (KET): 15 mg/kbw ketoprofen, Group III (KET-ves): 15 mg/kbw ketoprofen entrapped in vesicles. The nociceptive visceral testing was performed using the mouse model of acute pain writhing test. The experimental protocol was implemented according to the recommendations of the University Committee for Research and Ethical Issues, and to the guidelines of IASP Committee for Research and Ethical Issues. The data were statistically analyzed with SPSS software for Windows version 17.0 and ANOVA method. Results: It was demonstrated that the soft matter vesicles are capable to entrap ketoprofen water solution, with a large efficiency. The vesicles dimensions vary from tens of nanometers to hundreds, and the solution has a moderate stability. Oral administration of ketoprofen resulted in a decrease of behavioral manifestations induced by chemical noxious stimuli, statistically significant immediately in the experiment, effect present for 120 minutes. Using soft vesicles entrapping ketoprofen, we obtained the reduction of writhes number with an onset at 3 hours and prolonged for 5 hours after substance administration. Conclusions: The use of soft matter vesicles as carriers for ketoprofen presented the advantage of drugs sustained release, compared to nonentrapped substances in the writhing test.

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Assessment of immunological therapy with Infliximab and Etanercept in the treatment of psoriasis arthropathy

Liana Suciu, Carmen Cristescu, Mirela Voicu, Maria Suciu, B. Bumbacila
Abstract: Psoriasis arthritis is a seronegative chronic inflammatory arthropathy, which occurs in patients with psoriasis and is accompanied by characteristic symptoms. Shortcomings of conventional therapy, frequent and sometimes severe side effects induced by classical immunomodulatory substances (methotrexate, cyclosporine, leflunomide), lack of ethyo-pathogenic theories has been leading to research on new therapeutic perspectives in psoriasis, including for psoriasis arthropathy. Pathogenesis of psoriasis has highlighted a number of changes related to keratinocytes, T lymphocytes, dermal fibroblasts and a number of genes encoding several types of proteins involved in proliferation of keratinocytes. The aim of the present study was to highlight the effectiveness of therapy with biological agents (infliximab and etanercept), assessed by improvement of PASI score, and to assess the incidence of adverse effects detected in patients during the study group. Patients enrolled in the study were selected by eligibility criteria and the final number was 14, from which eight patients were treated with infliximab and six were treated with etanercept in Dermatology Clinic from Timisoara. In the infliximab - treated group to whom the drug was administered iv 5mg/kgc for two hours at weeks 0, 2, 6 and 8 weeks thereafter until week 24, a rate of 62.5% of cases showed a 75% improvement in index PASI, in 12 weeks. Evaluation performed at week 24 showed improvement of symptoms (objective by index steps) to 87.5% of patients, thus proving efficacy. Administration over 24 weeks resulted in adverse effects: myalgia and fever in 32% of patients, the increase of transaminases in 25% of patients. No patient treated with infliximab did not show de novo appearance of antibodies antiADN DC. The group of patients treated with Etanercept, administered in doses 25mg/twice a week, for 24 weeks, were obtained the following results: after 12 weeks of treatment PASI index improved to 50% of cases, after 24 weeks the percentage of patients which occurred improvement was 66.66. Adverse effects in this group were represented by: transient leukopenia and thrombocytopenia (one case), autoimmune events (one case) and local reactions as redness and induration at the site of administration, delivered spontaneously (two patients). This study has shown considerable clinical effects in psoriasis arthropathy, but it is not considered a first-line therapy because of the incidence of adverse events which has to be monitored and interpreted in the context of each patient`s clinical condition on such therapy and not least because of the extremely high cost of the treatment.

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Alcohol consumption and the violent death among children from Iasi county

Odetta Duma, Solange Tamara Rosu, Liliana Tartau
Abstract: This paper represents an analysis of the main features of the alcohol consumption identified in violent deaths among children aged 0-18 years, registered in Iasi county, between 2004-2008. The data source was gathered from the medico-legal files of the corpses, recorded at the Iasi Medico-Legal Institute. The study has a descriptive character and aims to identify the following characteristics in connection with the consumption of alcohol: personal, temporal, spatial and death mechanism. From a total number of 274 violent deaths of children under 18 years, 126 children were suspected of alcohol drinking and tested, and 30 cases were found positive. A significant increase of alcohol consumption has been recorded during the summer, especially in July (p-value=0.01). The teenager alcohol consumers profile was: 14-15 year-old child, male, rural area, who suffered a violent trauma at the end of the week, during summer, by drowning, place of death represented by running rivers. The study can be considered as a foundation for elaborating preventive strategies.

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Therapeutical Practice


Diagnostic challenges in two cases of cutaneous vasculitis

N. Iagaru, Tania Cristodulo, Monica Darmanescu, Irina Margaritescu, A. D. Chirita
Abstract: To distinguish those cases of local cutaneous vasculitis in children very difficult to diagnose and classify in the absence of other clinical characteristic findings. Materials and methods. Two patients presenting with unusual cutaneous chronic vasculitis in children with early onset in the first decade of life are reported. Results. Clinical features (livedo reticularis), histopathologic changes (presence in the reticular dermis of fibrin in the wall of venules and thrombi within their lumen) and the evolution (healing with atrophie blanche) were necessary to identify the diagnosis in each case, in order to exclude other types of vasculitis. Complex laboratory investigations were done in order to do this. Finally, the diagnosis in both cases was livedoid vasculitis. Conclusions. Proper diagnosis of livedo reticularis with recurrent ulcers of the lower extremities that heal to leave hyperpigmentation and atrophie blanche is very important, because ulcers may result from a variety of small vessel vasculitis which do not require the same treatment. Patients with livedoid vasculitis may be associated with various systemic diseases including hypercoagulable states, so a complete evaluation is required.

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A short review of drugs which present an increased iatrogenic risk in elderly patients

Carmen Cristescu, Maria Suciu, Mirela Voicu, Liana Dragan, B. Bumbacila, Liana Suciu
Abstract: Elder patients are cumulating multiple risk factors that are exposing them more for druginduced iatrogenic events: physiological variations associated to the ageing process, multiple morbidities and multiple medications-taking, are frequent in aged people and can significantly modify the pharmacological properties of the used drugs. Different interactions between these factors are responsible for a high prevalence and for a potential severity of the iatrogenic pathology in this age category. Most of the undesired consequences in patients over 65 years old can be avoided if the clinical situations and the high-risk drugs are pre-identified. For an optimization of the medical prescription in elderly process some of the following measures are to be taken: evaluating of the benefit/risk ratio for each of the recommended drugs, follow-up evaluating and regular updating of the chronic prescription, ranking the therapeutic goals taking into account the evolution of the disorder, its symptoms and their impact on the patient and the etiological or preventing character of the drugs being used. Also, a better therapeutic co-operation between the prescription-writers (general practitioners and specialists) who are consulting and prescribing for the same patient seems to be indispensable.

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Case Report


Acute myocarditis due to leptospira icterohaemorrhagiae

Iunia - Elena Ciuchi - Nicolau
Abstract: We report the case of a 29-year-old man who, after having been exposed to non-potable water, had developed an acute myocarditis due to a Leptospira icterohaemorrhagiae leptospirosis, a severe form with renal, hepatic and hematologic involvement (Weils disease). The clinical signs at hospital admission were: fever, jaundice, hemorrhagic syndrome and oligoanuria. The etiological diagnosis was confirmed by the serological microagglutination test, which was positive for Leptospira icterohaemorrhagiae. An electrocardiography revealed an atrial flutter with variable block and an echocardiography identified a medium hypertrophy of the left ventricle and a medium systolic dysfunction, these findings leading to the diagnosis of acute myocarditis. The clinical status of the patient was not suitable for electroconversion of the atrial flutter, and thus the cardiologist prescribed diltiazem. The evolution was slowly favorable under treatment with ceftriaxone, dexamethasone and diltiazem, with full recovery of the patient, including that of the cardiologic parameters. The early diagnosis of leptospiral myocarditis is important because of its potential severity and its reversibility under appropriate antibiotic therapy and also because of the necessity of its initial management in a specific infrastructure.

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Diagnosing and treating the functional problems of the patient with upper single denture

Oana-Cella Andrei, Ioana Radu
Abstract: The edentulous state of the oral cavity is equivalent to the absence of any other body part with specific morphological and psychological sequelae. This case presents a patient with an edentulous maxillary arch opposing a dentate mandibular arch. The dentist has a difficult mission in evaluating the biomechanical differences in the supporting tissues for the two arches and applying the appropriate procedures to produce and maintain the conditions necessary for long-term treatment success. The dental literature evidences suggest that the maxillary arch exhibits earlier tooth loss due to various factors and that the mandibular anterior teeth are preserved the longest, so this case focuses on the oral condition in which the maxillary arch is edentulous and opposed by a natural and partial restored mandibular dentition. The main problem is that there are important qualitative and quantitative differences between natural tooth and complete denture support: the natural dentition is capable of specialized responses to occlusal demands that preserve its function, whereas mucoperiosteal bone is not and it will respond in a variable way depending on age, sex and racial category. Therefore, the replacement of the missing maxillary dentition must provide an optimum distribution of the occlusal forces in order to minimize the negative effects in the compromised edentulous arch.

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The role of HTLV in oncogenesis

Victoria Birlutiu, Cristina Rezi
Abstract: Adults T cell leukemia/lymphoma is an endemic pathology in South-Eastern Asia, Japan and the Caribbean area, generated by the infection with Human T Leukemia Virus 1 (HTLV-1). We present the case of a 62-year old patient, diagnosed with T cell leukemia, with positive anti HTLV-1 antibodies and comorbidities with unfavorable evolution. Although the evolution of HTLV-1 infection is generally considered as being slow, posing a moderate risk, our patients evolution was rapidly progressive in the absence of antiviral therapy, with acute hepatic failure possibly secondary to an association of chronic C hepatitis.

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Lyme disease - peculiar aspects

Alexandru Crisan, Ruxandra Laza
Abstract: Lyme disease is caused by Borrelia burgdorferi and it manifests as a localized infection of the skin (erythema migrans), followed by heart, joints and nervous system involvement. Seventh nerve palsy is by far the most common. The authors present the case of a 19-year-old female who developed low grade fever, aseptic meningitis and facial palsy and was admitted to the Clinical Hospital of Infectious Diseases and Pneumophtysiology "Dr. Victor Babes" Timisoara. Diagnosis of Lyme borreliosis was established by serologic testing (ELISA) that revealed high titers of IgM and IgG. Clinical outcome was good after treatment with ceftriaxone. Changes of biological features, diagnosis and differential diagnosis difficulties and peculiar aspects of evolution are presented. In the presented case the incubation period was longer than usual, the chronic migratory erythema was absent and the patient remembered the tick bite very late. The clinical course was dominated by symptoms of upper respiratory tract infection, serous meningitis and Bell palsy. Lyme disease must be kept in mind in the differential diagnosis of aseptic meningitis and facial palsy as it can be the first and only sign of disease.

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