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Volume XIV, Number 4, 2010 - Therapeutics Pharmacology and Clinical Toxicology


The influence of polymorphisms in CYP2C9 and VKORC1 genes on the efficacy and safety of oral anticoagulant treatment

Florentina Claudia Militaru, Anca Dana Buzoianu, Corina Ioana Bocsan
Abstract: Inherited variants of the enzymes involved in drug metabolism, transporters, receptors may play an important role in drug response. Genotyping prior to drug administration seems to be a promising clinical approach in order to reduce the adverse effects of the drugs and to increase their efficacy. Oral anticoagulants (OAs) are drugs largely used in the prevention and treatment of thrombo-embolic diseases. Patients under treatment with OAs present a high risk for severe haemorrhage. Irreversible inhibition of VKORC1 enzyme by OA blocks regeneration of vitamin K, which leads to unfunctional pro-coagulant factors. VKORC1*2 haplotype is linked to an excessive anticoagulation risk at average doses of OAs, while other polymorphisms of the gene are linked to the resistance to OAs. Acenocoumarol is inactivated by CYP2C9 enzyme, so people carrying at least one defective allele CYP2C9*2 but particularly CYP2C9*3 are susceptible to excessive anticoagulation at average doses of acenocoumarol. In conclusion, the combined analysis of CYP2C9 and VKORC1 allows the explanation of 30-40% of the individual variability in equilibrium dose of oral anticoagulants and, consequently, in treatment response.

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Original Papers

Periportal pericytes or fibrocytes

D. Sztika, Anca Streinu-Cercel, F. Pop, G.C. Curca, M.C. Rusu
Abstract: The hepatic stellate cells (HSCs) are the pericytes of the hepatic parenchyma, known as being immunopositive for GFAP, if quiescent, or for desmin, if activated. We attempted to identify by immunohistochemistry on paraffin-embedded specimens whether or not these phenotypes of the parenchymal HSCs can be identified also within the portal spaces and tracts. We used liver samples drawn from 6 autopsied human cadavers that were first immunostained for GFAP and desmin. As we identified desminpositive cells (DPCs) in the periportal areas of the large portal spaces, but not GFAP-positive cells, and those DPCs were not presenting cytoplasmic processes as the HSCs, we presumed them to be myopericytes and performed immunostaining for CD34 on successive slides. The respective DPCs appeared to be also CD34-positive and seemed to cluster within well-represented periportal capillary plexuses. As so, it appeared to us that a subpopulation of pericytes, namely myopericytes, different from the HSCs, can be considered as related to the large portal spaces and are presumably involved in angiogenesis that, in turn, is a key process in various chronic liver diseases.

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Heart failure consequences on chronic kidney disease progression

Ileana Peride, I.Al. Checherita
Abstract: Heart failure is a common disease, associated with increased mortality and an important cause of chronic kidney disease (CKD) progression, especially for population 65 years and older. The purpose of the following study is to emphasize the leading associated factors that contribute to CKD evolution and the best treatment to choose for a favorable outcome. Recent studies indicate that preexisting chronic kidney disease worsens the prognosis in case of associated major comorbidities, but we noticed that an early application of the right therapy and diet has improved the outcome of patients included in the present clinical study

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Optimal treatment in renoparenchymatous arterial hypertension and chronic renal failure

Georgeta Liga, I.Al. Checherita, Roxana Sandulovici, A. Niculae, Daniela Radulescu Al. Ciocalteu
Abstract: Chronic renal diseases are often accompanied by systemic hypertension, which, in turn, accelerates progression of renal dysfunction. The vast majority of actual guidelines recommend ACEI and/or ARB as first choice of antihypertensive treatment. The study presented compares the evolution of 157 patients with chronic renal failure and renoparenchymatous hypertension treated with different antihypertensive regimens.

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QEEG relative power findings in Epilepsy

Z.Z. Major, Anca Dana Buzoianu, Lacramioara Perju-Dumbrava, I. Marginean, Ioana Corina Bocsan, Kinga Andrea Major
Abstract: The objectives of this study were to compare the distribution of spectral power in a heterogeneous idiopathic epilepsy group, under antiepileptic treatment, versus healthy controls. Methods: Relative power values were calculated from EEGs obtained in wakefulness using Fast Fourier Transformation. The patient group was compared to an age-matched group of healthy controls, derivation by derivation, then regarding asymmetry, and considering the influence of epilepsy on the topographic distribution of the main frequency bands. Results: There are highly significant differences between the two groups: the spectral power of the slow frequencies is increased in epileptics versus controls, and for the fast domains there is a reduction of the relative power. No asymmetries were observed between the two hemispheres. Gross topography-dependent power changes did not interfere significantly with the epilepsy-induced power spectrum of the investigated domains, although a tendency was recorded for the delta band. Conclusion: Relative power findings were interpreted as a diffusely increased neuronal synchrony in the theta and delta frequency range, as an effect of the idiopathic epilepsy, influenced also probably by the effect of the concomitant antiepileptic drug therapy. Idiopathic epilepsy produces no asymmetries of the qEEG data. Idiopathic epilepsy shows no interference with the topographic distribution of qEEG markers, excepting such a tendency for the slow activities. Further research is needed to evaluate these changes, also compared with newly diagnosed, untreated epilepsy.

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Bacterial infections in patients with chronic hepatitis C treated with Peg-interferon and Ribavirin

I. Marincu, L. Negrutiu, I. Iacobiciu, R. Neghina, Sorina Laitin, Adriana Maria Neghina
Abstract: Treatment with peg-interferon (Peg-IFN) and ribavirin in patients with chronic hepatitis C (CHC) represents current standard therapy, although it is accompanied by multiple side effects. Objectives. The present study aims at analysing the prevalence and etiology of acute bacterial infections in patients with CHC who are following peg-interferon and ribavirin combination therapy. Patients and methods. We have retrospectively investigated the medical records of 62 patients with CHC who were managed at the Hospital of Infectious Diseases in Timisoara, Romania. We have included in the study the patients who presented detectable HCV RNA, normal or increased alanine aminotransferase levels, histological rate = 1, fibrosis and were aged = 65 years. All patients were treated with Peg-IFN a-2a (Pegasys, Roche), 180 µg/week and ribavirin (Copegus, Roche, 1 tablet = 200 mg), 1000-1200 mg/day (1000 mg/day for patients under 75 kilos and 1200 mg/day for patients over 75 kilos) for 48 weeks. The patients have been evaluated monthly clinically and biologically and different explorations were carried out in selected cases in accordance to the disease management protocol. Results. In the study group, 22 (35.5%, male=10, female=12) patients with acute bacterial infections were diagnosed as follows: 5 patients with staphylococcal infections, 3 with urinary infections, 3 with acute bronchitis, 2 with bacterial pneumonia, 3 with acute sinusitis, 4 with acute tonsillitis and 2 with acute angiocholitis. The development of acute bacterial infections in our study group was associated with an advanced stage of liver fibrosis (F3-F4 - 16 patients), neutropenia (N-II - 11 patients), anemia (AII - 16 patients) and advanced thrombocytopenia (TII - 18 patients). Conclusions. The high prevalence (35.5%) of acute bacterial infections in patients with chronic hepatitis C treated with Peg-IFN and ribavirin requires a rigorous clinical, laboratory and therapeutic monitoring of the patients during this period.

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Antiviral therapy and metabolic syndrome in patients with chronic hepatitis C

Manuela Arbune, P. Dascalescu
Abstract: Hepatitis C virus (HCV) infection affects 3% of the people all over the world. The heterogeneous viral genotypes correlate with prognosis of the disease. Genotype 1 is characterized by the low response to interferon and prevails in Romania. The relation between metabolic syndrome (MS) and the effectiveness of treatment with Peg Interferon and Ribavirin was assessed in 57 patients with chronic hepatitis C recorded in the Infectious Diseases Hospital Galati during 2007-2009. The retrospective study was based on analysis of medical records, therapeutic protocols and the criteria of metabolic syndrome. The virologic response was 92% at 24 weeks and it was sustained at 72 weeks in 56.16% of cases. MS was diagnosed in 31% of patients with HCV and it was significantly correlated with weak viral response at 24 weeks. The study concluded that failure of treatment with Peg Interferon and Ribavirin is related to MS in patients with chronic hepatitis C. Systematic assessment and improvement of metabolic syndrome before the antiviral treatment should optimize the virologic response of HCV.

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Microbiological changes in orthodontically treated patients

Th.C. Vizitiu, Ecaterina Ionescu
Abstract: Orthodontic appliances, both fixed and removable, impede the maintenance of proper oral hygiene and result in plaque accumulation. Many studies report that changes in the dental flora occur after starting the orthodontic treatment. The aim of this study was to evaluate the changes of the oral microbial flora during the orthodontic treatment. Materials and Methods. 24 young patients, aged 7-16, who were going to start the orthodontic treatment, have been selected. Group I was formed by the 24 patients before wearing any orthodontic appliance (T0) and group II was represented by 15 patients from the initial group, 3 months after the beginning of the treatment (T1). Coronary and subgingival plaque was collected for isolation and identification of the bacterial species involved. For the isolation of the bacteria, growth mediums were used: Todd Hewitt broth, Columbia agar, Schaedler broth and agar. The serial dilution method was used to determine the concentration of the bacteria (CFU/sample) from the aerobic and anaerobic flora. Conventional methods were used for the identification of the species and the isolated strains that are involved in pathological processes have been preserved for further study using molecular methods (PCR-based). Results and conclusions. The concentration of the aerobic and anaerobic bacteria has increased during the first 3 months of orthodontic treatment. The lactobacilli were isolated in a smaller proportion in group II (80% vs. 87% before the treatment). The oral streptococci and anaerobic bacteria isolation percentage increased after the beginning of the treatment. For the bacteria involved in pathogenic processes, an increase of the isolation rate has been observed for the patients wearing an orthodontic appliance, from 8.3% to 13.3% for S. mutans and from 4.2% to 6.7% for Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. These results are not statistically significant and they are preliminary. Both study groups will be extended; dental microflora will be investigated at longer intervals of wearing orthodontic appliances.

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Clinical trial on different adjuvant treatment in unipolar depression

Lidia Nica Udangiu, Denise Buda
Abstract: Depressive disorders are considered to be clinical entities frequently seen in medical practice, causing a very high level of disease burden and are expected to show a rising trend during the coming 20 years. Simptoms of depressive episode in both recurrent depressive disorder and bipolar affective disorder are similar. Despite of theese similarities, recent studies show that depressive episode who appears in both disorders, is different regarding etiology, course and adjacent neurochemical processes. The therapeutic plan used for the treatment of depression usually combines an antidepressant with a benzodiazepine. The current study investigates the therapeutic efficiency of clonazepam versus diazepam in association with paroxetine used to treat the depressive episode - Major Depressive Disorder.

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Therapeutical Practice

Palliative care in AIDS cases

Carmen Manciuc, Cristina Nicolau, J.L. Prisacaru, Carmen Dorobat
Abstract: Terminal stages of AIDS must benefit from special attention and care for both patients and their relatives. Objectives. Establishing a team and protocols of palliative care for these patients. Material and method. The retrospective study of case report forms of patients who died of AIDS in the Infectious Diseases Clinic of Iasi. In the department of HIV-infected patients of the Infectious Diseases Hospital of Iasi, within an interval of 3 years (2007-2009), there were 28 deaths, with an average of 9 patients per year. Most of them died of multiple organ failure, in the final stage of AIDS (10 cases), meningeal coma (5 cases) or respiratory failure during the terminal pulmonary pneumocystosis TB (13 cases). The palliative therapy was conducted throughout the hospitalisation of the terminal stage. The patients who survived longer required psychological support from admission until they lost their state of consciousness - they were 23 in number, with a duration of psychological palliation from 2 to 32 days. Conclusions. Palliative care, in cases of terminal AIDS disease, must be conducted by a team including specialists in infectious diseases, intensive care, psychologists and it also addresses the patients families.

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Case Report

Dilated cardiomyopathy in HIV infected adolescent on HAART

Ana Maria Tudor, Ioana Anca, Monica Luminos, Mariana Mardarescu
Abstract: Even though cardiac disease is not frequent in HIV infected children, it is associated with poor prognosis. Dilated cardiomyopathy is the most frequent heart disease associated with HIV infection. In HIV children the most frequent cardiac lesion is dysfunction and/or enlarged dimensions of the left ventricle. The pathogenesis is complex, the most important factor is HIV itself. Human immunodeficiency virus can affect the heart directly or by secondary chronic inflammation and immune activation. We present a case of an HIV-infected teenager diagnosed with dilated cardiomyopathy and the evolution of heart disease during antiretroviral therapy.

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Acute generalized exanthematous pustulosis induced by simvastatin

Adina Dobritoiu, Gabriela Turcu, D.G. Forsea
Abstract: Acute generalized exanthematous pustulosis is an acute pustular eruption occurring most commonly after drug ingestion. It is a self-healing condition with spontaneous cure after discontinuation of the causative drug. We report the second case, as far as we know, of acute generalized exanthematous pustulosis induced by simvastatin intake. Conclusion: simvastatin can be included on the long list of AGEP inducing drugs.

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Ultrasound diagnosis of conotruncal heart defects

D. Albu, R. Vladareanu, D. Pelinescu-Onciul
Abstract: We present some cases of fetuses with conotruncal heart anomalies (CTA) diagnosed by four dimensional ultrasound (4D US). Improvement of detection and complete prenatal evaluation of conotruncal heart defects is possible if 4D US and STIC technique are available [1]. Fetal echocardiography was done with a 4D ultrasound system (Voluson E8, GE Healthcare, Kretztechnik, Zipf, Austria) equipped with a 4-8 MHz transabdominal transducer and STIC. All pregnant women underwent comprehensive evaluations with STIC, these views were stored and then shared for expert review, interdisciplinary consultation and parental counseling [2]. 4D-STIC echocardiography carried out by experts in fetal echocardiography can be used to accurately diagnose CTA.

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