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Volume XVI, Number 3, 2012 - Therapeutics Pharmacology and Clinical Toxicology

Review


The role of new adipokines in the pathogenic mechanisms of chronic hepatitis C

Radulescu Mihaela Andreea, Popescu Cristina, Arama Victoria, Streinu-Cercel A.
Abstract: Hepatitis C virus (HCV) infection is an important problem of public health in our country and worldwide. HCV infection leads to cirrhosis and in some cases to hepatocarcinoma. In the past years, HCV was associated with metabolic disturbances, including hepatic steatosis, dyslipidemia and insulin resistance, on the other hand these metabolic factors were identified to accelerate progression to cirrhosis and hepatocarcinoma. Also in patients with chronic hepatitis C (CHC), the endocrine activity of fat tissue is disturbed and a large number of adipokines seem to be involved in the pathogenic mechanisms of CHC progression, including liver inflammation, steatosis, fibrogenesis, insulin resistance and angiogenesis. In this paper we summarize published data regarding the role of two novel adipokines: Visfatin and Chemerin in the pathogenesis of HCV infection.

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Quantitative serum HBsAg in chronic hepatitis B: a never ending story

Gheorghita V., Caruntu F. A. , Curescu Manuela, Ion St., Coltan G., Olaru Ioana, Rascanu Aida, Streinu-Cercel A.
Abstract: Todays major concern in chronic HBV infections is quantitative serum HBsAg. Numerous data demonstrate its usefulness in determining the evolutionary stage of disease and the predictability of response to antiviral therapy. HBsAg production originates in two distinct viral DNA structures: intranuclear and extrachromosomal cccDNA and viral DNA sequences integrated in the host cell chromosome. At present, there are two tests available for commercial use in order to asses the HBsAg quantification: Architect QT assay (Abbott Laboratories) and Elecsys HBsAg II Quant assay (Roche Diagnostic). Serum HBV DNA levels and HBsAg decrease progressively during the natural evolution of chronic HBV infection, the lowest values being recorded in inactive carriers patients. Quantitative HBsAg decline at week 12 and 24 of Peg-IFN treatment can be used as a surrogate marker for predicting sustained response in patients with HBeAg-positive chronic HBV hepatitis. In general, a poor HBsAg decline at week 12 may predict lack of response, and a significant reduction in HBsAg at week 24 may predict response to peginterferon therapy. In conclusion, quantitative HBsAg is a topical issue in chronic HBV infections because seems to be a surrogate marker for immune control of disease. Perhaps, in the next therapeutic guidelines will be introduced the quantitative HBsAg kinetics with other established markers, especially when it is required for response-guided therapy.

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Original Papers


Recombination analysis for subtyping unclassified HIV-1 sequences from Romania

Paraschiv Simona, Batan Ionelia, Banica Leontina, Fratila Mihaela, Doana Angelica, Vizitiu I. Otelea D.
Abstract: The human immunodeficiency virus (HIV) has a high rate of evolution generated by mutations and recombinations in association with the high replication rate of this virus into the susceptible cells. The diversity of HIV can be easily observed in HIV-1 group M which comprises 9 subtypes, more that 50 inter-subtype circulating recombinant forms (CRFs) and several unique recombinant forms (URFs). Subtype distribution in Europe is geographically influenced; subtype B is highly prevalent in the Western part of the continent and subtype A is mainly responsible for the infections in the Eastern countries. From the beginning of the epidemic in Romania, a particular subtype has been reported as being highly prevalent, the F1subtype. Previous data suggested that the HIV-1 epidemiology in Romania has changed over time, other subtypes than F1 (subtype B, C and A1) being more and more encountered. 32 of 2132 sequences corresponding to HIV-1 strains isolated during 2003 and 2011 in the reference laboratory from the National Institute for Infectious Diseases ′Matei Bals were unassigned for the HIV-1 subtype. We have analysed these sequences using four different recombination algorithms. Half of them were classified as being CRFs (7 were CRF14_BG and 8 were CRF02_AG) and subtype F1 (1 sequence). The other 16 sequences were recombinants with more complex patterns of recombination. Therefore, we have improved the figure of HIV-1 subtype distribution in Romania, showing how using of more different bioinformatic tools can improve the subtype assignment.

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Inflammation biomarkers in HIV seropositive patients undergoing antiretroviral therapy

Mihailescu Raluca, Arama Victoria, Tiliscan C., Streinu-Cercel A., Ion Daniela, Arama S.S.
Abstract: Under combined antiretroviral therapy, HIV infection has become a chronic condition, still accompanied by a proinflammatory status with a consequent impact on multiple organs. We evaluated the levels of inflammatory biomarkers in HIV-infected patients undergoing specific therapy and their association with the presence of metabolic syndrome. Methods. A non-interventional study was conducted on HIV infected patients undergoing antiretroviral therapy in a tertiary care hospital in 2008. Besides routine laboratory assays, TNF alpha, IL 6 and MCP 1 were tested, by means of BioSource EASIA (Enzyme Amplified Sensitivity Immunoassay). Metabolic syndrome was defined according to International Diabetes Federation. Results. A total of 106 patients were included, with a M:F ratio =1.4; median age of 31 years, mode age of 20 years; mean CD4 cell count of 530/mmc; undetectable HIV viremia found in 69% of the subjects. In detectable versus undetectable HIV viremia samples, a pathological level of biomarkers was found in the following proportion: 53.1 % versus 39.1% for TNF alpha, 16.1% versus 13.2% for IL 6, and 9.7% versus 4.3% for MCP 1 respectively. Metabolic syndrome was identified in 10% of the cases (15.2% versus 8.2% in detectable versus undetectable HIV viremia samples). In multivariate analysis, patients with pathological values of MCP 1 are 11.7 times more likely to develop metabolic syndrome than those with normal values (CI 95% 2-71, p=0.008). Conclusions. In our young study population, MCP 1 is significantly associated with the presence of metabolic syndrome. Identifying key subclinical changes would help to anticipate the developing of metabolic syndrome in HIV infected patients. Once the practical utility of these biomarkers is well understood, it might also call for adequate therapy in order to reduce the incidence of polypathology associated with HIV infection.

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Pharmacological investigations regarding the nonselectivity of a newly synthetized compound, potentially B3 adrenergic receptors agonist

Stefanescu E., Cristea Aurelia Nicoleta, Putina Gabriela
Abstract: A newly synthesized compound by the Romanian National Institute of Chemical-Pharmaceutical Research and Development - Bucharest, conventionally named C1 and belonging to a larger group of substituted phenylethylamines with potential B3 adrenergic properties, was studied in order to determine its selectivity on B adrenergic receptors. Compounds in this class have shown in previous studies the capacity to induce hypoglycemia in normal rats [1] and to have a positive effect on the body mass evolution of normal mice without influencing significantly the food intake[2]. The studied compound has shown intense nervous stimulation, both in the acute toxicity tests as well as in the motor activity evaluation tests. Considering the hypothesis that the central nervous system (CNS) stimulation, observed on administrating compound C1 has a B1 adrenergic receptors agonist mechanism, we investigated whether an antagonism between C1 and propranolol (a well known nonselective B adrenergic receptors antagonist) can be established. For this purpose we used the Actometry test in order to determine the motor behavior and the single dose acute toxicity test in normal mice. Adrenaline and Ephedrine were used as reference substances as they are known to be nonselective a-B adrenergic receptors agonists. Results confirmed the hypothesis, showing a statistically significant decrees in the horizontal motor activity (-22.63%, p<0.001), as well as a significant reduction in mortality (-40%, p<0.0001), when C1 was associated with propranolol. A similar phenomenon was also observed when adrenaline was associated with propranolol. These first results encourage further research in this direction.

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The role of diabetes mellitus in periodontal disease and rheumatoid arthritis pathogenesis - the dentists point of view

Croitoru G. Al., Tiliscan C., Mihai Carmen Marina, Arama Victoria, Ion Daniela Adriana, Arama St. S.
Abstract: Periodontal disease requires the existence of particular periodontopathogens in the gingival sulcus, which determine the destruction of periodontal ligaments, gingival desinsertion and bone lysis. In diabetic patients the healing mechanisms are impaired as a result of increased levels of proinflammatory cytokines. Recent studies report that reduction of oral inflammatory processes in patients with diabetes mellitus determines a decrease of serum inflammatory mediators while the aggravation of periodontal disease may worsen diabetes mellitus evolution. Also, the prevalence of periodontal disease is known to be higher in rheumatoid arthritis patients. Periodontitis may be associated with a negative response to therapy in some rheumatoid arthritis patients.

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Comparative discontinuation rates in patients treated with antipsychotics

Dima Lorena, Vasile D., Voicu V.
Abstract: Continuity of antipsychotic treatment is a prerequisite for obtaining maximum benefit and favourable treatment outcome. However, there are considerable differences between studies in terms of the level of discontinuation rates and the estimated time to discontinuation for different antipsychotics. In order to clarify these aspects more information is needed on treatment discontinuation in routine clinical settings. The aim of this study was to compare the rate of treatment discontinuation among patients with schizophrenia or related disorders treated with antipsychotics. Material and methods. The study was a one-year follow-up, observational study of 131 patients with schizophrenia or related disorders treated with haloperidol, olanzapine, risperidone, quetiapine, or aripiprazole. The main outcome variable measured was time in months to treatment discontinuation. Reason of discontinuation was also registered. Results. Rate of discontinuation as resulted from Kaplan-Meier univariate analysis was significantly higher in patients treated with haloperidol compared to both atypical treated group and olanzapine treated group. In Cox proportional hazards regression analysis, the group of patients with at least one previous psychotic episode was associated with a 2.5-fold increased risk of treatment discontinuation, compared to first psychotic episode patients (HR=2.571 [CI 1.077-6.139], p 0.033). After adjustment for this covariate in the Cox model, resulted HR for discontinuation with haloperidol as the reference group confirmed the order of risk of discontinuation for any reason decreasing (highest for haloperidol, lowest for olanzapine), but differences between groups did not reach the level of statistical significance. When the same analysis was performed differentiated according to specific causes, the only difference between treatment groups confirmed as statistically significant was in case of non-adherence, for olanzapine compared to haloperidol: HR= 0.109 [CI 0.013-0.923], p 0.042. Conclusion. The results of this observational study suggest that the differences between typical and atypical antipsychotics and between atypicals cannot be excluded in what persistence to treatment is concerned and that the choice of antipsychotic may be an important factor in the long term evolution in patients with schizophrenia and related disorders.

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New methods for comparison of erythrocyte sedimentation curves in estimation of aggregant and antiaggregant effects of drugs

Borisova Stiliyana, Mormenschi Doina, Sarbu I., Mircioiu Ctin.
Abstract: Tests of erythrocyte sedimentation provide a measure of the acute phase response to inflammatory diseases, most infections, in cancer, cardiovascular and many other diseases. The term erythrocyte sedimentation rate (ESR) is retained because of traditional usage, although a single measurement after 60 minutes is not a rate Recommendations of International Council for Standardization in Haematology (ICSH) considers ESR as defined by the height of sedimented column of erythrocytes at a given time (usually one hour). Single parameter characterization of sedimentation of erythrocytes by ESR represents a course approach of complex phenomena. The simplicity of the sedimentation rate is only apparent. In practice, a lot of difficulties arises in definition of the -rate- since its estimation requires at least two points on the sedimentation curve. If the sedimentation does not start immediately, a positive lag-time appearing, ESR measured value at one hour is a rate lower than the real slope, estimated from sedimentation curve. If sedimentation is more rapid and curve reach saturation before one hour, the real rate, defined by sedimentation curve is greater than the rate defined by official ESR. A more in depth analysis of data started in the paper from -sedimentation curves- which characterise dynamic evolution in time of phenomena. Comparison of curves arises great difficulties even for mathematicians. Metrics in the spaces of curves implies a more advanced mathematics. Consequently, sedimentation curves where replaced by some of their global parameters such as initial slope or area under curve. Further for comparison of curves were introduced some specific methods from cancer research, biopharmacy and pharmacokinetics. It concerns the rate of sedimentation this was estimated from the initial slope of the curves. In fact the curve could be modelled for a longer time interval using a twophase linear regression. The slope of the first line could define better the ESR. If we consider evolution of height of sediment as a -survival curve-, the Kaplan Meyer method becomes immediately applicable. From dissolution studies in biopharmacy the official metric on the release curves space, based on the sum of squared differences between matched points of the sedimentation curves. A set of methods (linear regression in estimation of the slopes, of the similarity of curves using f2 metrics, of time-lag, of half-time etc.), as well as comparison of Areas Under Sedimentation Curves, were applied in evaluation of clopidogrel`s effect at concentrations between 1 and 8 µg/ml.

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Scores applied in toxicological practice. Prognostic assesment in intoxication by barbiturates and benzodiazepines

Oprita B., Gabor-Postole Dana Atena, Aignatoaie B.
Abstract: When determining whether to observe, admit, transfer, or discharge a person who has been poisoned, there are several factors to consider. For unstable patients, admission to an intensive care unit is appropriate, and transfer to a tertiary care facility should be considered, especially with children. For stable patients, the amount of observation time is based on the half-life of a medication, the amount ingested, and the formulation. Any patient who develops signs or symptoms of toxicity that do not reverse during the observation period should be admitted for further observation.[6] Triage is the initial assessment and sorting of patients in an emergency setting to determine clinical priority of need and, in some emergency departments (Eds), appropriate area for treatment. Overcrowding of EDs makes accurate triage category assignment a priority if patient safety and timeliness of care are to be assured.[29]. The purpose of this research consists in the formulation of a pre-therapeutic and prognostic score, correlating vital parameters of patients, toxicology and post-therapy scores, so we can decide whether to maintain the patient in the Emergency Department for treatment, to discharge him/her in safety conditions or to admit him/her in Toxicology Unit.

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Study of Lithium elimination in patients with chronic renal disease

Tudosie M.S., Paun S.C., M. Ionica, Luminita Ardelean, Viorica Bumbea, Ciupan R., Muresan A., Mladin C.
Abstract: Lithium belongs to the class of toxic elements. The maximum value permitted in blood is 3 µg/l, and 500 µg/l in urine [12]. Salt form is used as an antidepressant. There were analyzed blood samples collected from a sample of 50 subjects with normal renal function (creatinine <1.5 mg/dl), considered the control group, the average of creatinine being 0.99 mg/dl. The study group consisted of 50 patients with chronic renal disease. Blood samples were taken before and after dialysis and dialysis fluid samples, taken 0.5, 1, 2, 3, and 4 hours after, recorded with LD1 ... 5 . From samples taken from both groups, concentration of lithium was determined. The authors also present the analytical technique based on atomic absorption spectrometry for determination of lithium in the samples mentioned above. Control group average was 0.42 µg/dl with values raging from 0 to 2.7 µg/dl. Study group average was 3.29 µg / dl before and 1.58 µg/dl after dialysis. The averages of the five times of elimination of lithium in the dialysate were LD1 = 13.85, = 14.81 LD2, LD3 = 12.85, LD4 and LD5 = 15,308 = 13.46 µg/l. The study includes analysis of lithium concentration by gender. Average clearance of lithium elimination during dialysis was 10.78 µg/min and total elimination average during the dialysis session was 2.59 mg. Student Test applied to the two groups both at coupling and at return does not differ, statistically speaking, significantly from the average of the control group. Given the small amount of lithium removed during a dialysis session, special attention should be paid to the potential antidepressant treatment based on lithium due to risk of accumulation and hence occurrence of iatrogenic acute poisoning.

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The impact of Jet Lag on romanian travelers and its prevention

Niculescu Iulia, Hristea Adriana, Arama Victoria, Olaru Ioana, Jipa Raluca
Abstract: Jet lag (JL) develops as a consequence in the disruption of the circadian rhythm. This may occur when rapidly crossing more than 2 time zones. Travel medicine counseling can be very useful in minimizing JL effects by teaching the traveler how to plan the trip in advance, by using phototherapy and melatonin. Objective. The aim of our study was to investigate the knowledge and the impact of jet lag on Romanian international transmeridian travelers, as well as the risk factors related to the development of this syndrome. Methods. Retrospective study based on a questionnaire survey of international Romanian travelers who sought medical advice at the travel medicine department of the -Medicover- clinic in Bucharest between January 2010 and May 2012. Results. 110 international travelers, 66 men (M/F sex ratio 1,5/1), median age 30, with university education and a medium-to-high socioeconomic level; 64 (58%) traveled to Asia and 45 (70%) of them to India for professional purposes. The median travel duration was 30 days (range 4-365 days). Only 12 (10%) described themselves as cautious tourists, 67 (70%) practiced risky activities, 81 travelers (73%) stayed in a hotel. More than a half (63) experienced jet lag during their current trip, of whom 50 people traveled to the East (p < 0.001, 95%, OR=8.2, CI 3.4-19.4). The majority of this group (90) came for the first time to a pre-travel consultation and 60 of them were refferred by their employer, only 12 came by their own initiative. Only 5 subjects had taken melatonin before. Conclusion. Although JL develops almost universally factors like travels to the east, purpose of travel (involving physical and mental performance at destination- professional purpose, risky activities), young age, and frequent transmeridian flights are linked to a more severe form of this syndrome. An increase of awareness in the Romanian international traveler about travel medicine could prevent many health problems related to international travels.

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Antibiotherapy in the first year of life and atopic dermatitis

Panduru M., Panduru NM., Ion D.A.
Abstract: Atopic dermatitis is a disease whose incidence is continuously increasing. Administration of antibiotics in the first year of life is considered to be one of the factors which may influence the occurrence of the disease, but the studies are contradictory. This study aims to analyze the role of antibiotics in the occurrence of atopic dermatitis in a Romanian population group. Material and Method. We carried out a cross-sectional study on 1008 subjects regarding the administration of antibiotic in the first year of life and the occurrence of atopic dermatitis. All data were obtained by the distribution of questionnaires in schools and kindergartens. The analysis of data was made with MedCalc software, version 12.1.3.0. Results. Out of the patients diagnosed with atopic dermatitis, 47,4% received antibiotics in the first year of life, as compared to 39,5 % of those without atopic dermatitis. Antibiotherapy in the first year of life was not associated with atopic dermatitis in the simple logistic regression analysis (OR=1.38, P=0.13), nor yet after the adjustment for the other risk factors (OR=1.10, p=0.85). Conclusion. Antibiotherapy in the first year of life does not seem to be associated with a significant risk for developing atopic dermatitis.

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Endoscopic approach in residual common bile duct lithiasis

Marin I., Zaharia Roxana, Lupu L., Catrina E., Doran H., Brezean I., Patrascu T.
Abstract: Treatment of the common bile duct lithiasis is a current challenge, constantly evolving and improving. Between 2004 and 2010, 177 patients with jaundice of lithiasic ethiology were operated on in our department. Suspicion of common bile duct lithiasis was sustained by clinical, biological and imagistic criteria, and confirmed by endoscopic retrograde cholangiopancreatography or intraoperative transcystic cholangiography. By introducing in the current practice the endoscopic interventions we observed a reduction of complications, both specific and nonspecific, simultaneously decreasing overall rates of morbidity and mortality, a decrease of hospitalization and of the social-economical costs.

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Therapeutical Practice


Modifying factors of chronic pain perception in oncological patients

Bancila Ana Teodora, Ianovici N., Bancila S.C.
Abstract: Cancer patients are vulnerable to depression and anxiety for many reasons: metabolic or endocrine alterations, treatments with debilitating chemotherapy regimens, immune response modifiers, and chronic pain associated with their physical illness. Quite apart from the normal emotional impact of the diagnosis of a life-threatening illness, an estimated 20% to 25% of cancer patients meet diagnostic criteria for major depression or anxiety, treatable psychiatric conditions that have serious detrimental effects on their quality of life.

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