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A great number of drugs affect thyroid function by different mechanisms. A wide range of mechanisms include modifications to the hypopthlamo-pituitary axis, synthesis and secretion of thyroid homone by thyroid and change in thyroid hormone metabolism as well as their acitivities in tissue. A small subset of drugs including glucocorticoids, dopamine and dopamine agonists, somatostatine analogs and rexinoids cause suppression of TSH and central hypothyreoidism.This central hypothyroidism usually is not cllinically evident and its medical treatment is not necessery. Non-thyroidal illness syndrome (NTIS) also causes TSH suppression and central hypothyreoidism by complex mechanisms. It becomes clinically apparent if the treatment of NTIS is associated with using glucocorticoids and dopamine and then possibilities possibilities of treatment this hypothreoidism should be considered. Different mechanisams by which these drugs cause central hypothyreoidism and their clinial relevance were analysed in this review. [ABSTRACT FROM AUTHOR]

Background/Aim. There is a high rate of schizophrenic patients who do not adhere to their prescribed therapy, despite the implementation of antipsychotic long-acting injections and the introduction of atypical antipsychotics. The aim of this study was to investigate the differences in sociodemo-graphic, clinical and medication adherence variables between the two groups of schizophrenic patients on maintenance therapy with depot antipsychotic fluphenazine decanoate and oral antipsychotics only as well as a correlation between the medication adherence and other examined variables. Methods. A total of 56 patients of both genders, aged < 60 years, with the diagnosis of schizophrenia (F20) (ICD-10, 1992) clinically stable for at least 6 months were introduced in this cross-sectional study. The patients from the depot group (n = 19) were on classical depot antipsychotic fluphenazine decanoate administering intramuscularly every 4 weeks (with or without oral antipsychotic augmentation) and the patients from the oral group (n = 37) were on oral therapy alone with classical or Atypical antipsychotics, either as monotherapy or combined. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Item G12 of the PANSS was used to assess insight into the illness. The patients completed the Medical Adherence Rating Scale (MARS) was used to assess adherence to the therapy. A higher MARS score indicates behavior [Medical Adherence Questionnaire (MAQ subscale)] and attitudes toward medication [Drug Attitude Inventory (DAI subscale)] that are more consistent with treatment adherence. The exclusion criteria were determined. The Pearson's χ² test was used to compare categorical variables, Student's t-test to compare continuous variables and Pearson's correlation to test the correlation significance; p = 0.05. Results. Significant between-group differences in age, illness duration, chlorpromazine equivalents, PANSS score and DAI subscore were found. Item G12 of the PANSS subscore and MARS score correlated significantly negatively. A significant positive correlation between receiving depot antipsychotic and DAI subscore as well as between illness duration and both DAI subscore and MARS score were also found. Conclusion. Schizophrenic patients on classical depot antipsychotic maintenance therapy might present subpopulation of patients with significantly longer illness duration, more favorable medication attitude and outcome in relation to those on oral antipsychotics alone. [ABSTRACT FROM AUTHOR]

Background/Aim. Hydrophilic matrix tablets represent the most commonly used oral dosage form. Carbomers used in the concentration of 10%-30% for preparation of matrix tablets, may significantly affect the profile of drug release due to the formation of hydrogel matrix tablets. The aim of this study was to compare the influence of different types of Carbopol® (carbomers in the pharmacopoeia) on the release rate of lithiumcarbonate and other pharmaceutical, technological, physical and chemical properties of the prepared formulations of matrix tablets. Methods. Three different formulations of matrix tablets were made according to direct compression method. The tablets were of the following composition: carbomer, lactose monohydrate, magnesium-stearate, lithium-carbonate in the proportion 75 : 120 : 5 : 300. The first formulation was made with Carbopol® 971P NF, the second one with Carbopol® 974 P NF and the third one with Carbopol® 71G NF. The quantity of lithium-carbonate was determined according to the BP 2009, pharmaceutical and tecnological properties were examined in accordance with the regulations of Ph. Jug. V, whereas the release rate of lithium-carbonate from the formulations was examined by the application of dissolution test, prescribed in the monography 'Lithium Carbonate Extended-Release Tablets' in USP 26. Results. The profile of lithium-carbonate release from matrix tablets with Carbopol® 974P NF entirely complies with the regulations of USP 26, whereas the values obtained from the analysis of matrix tablets with Carbopol® 971P NF and Carbopol® 71G NF were considerably lower than the prescribed ones. In all the investigated formulations the content of the drug, mass variation and tablet hardness comply with the regulations set in pharmacopoeia. Conclusion. In the formulation of matrix tablets with lithium-carbonate, by the application of carbomers in the concentration of 15%, with Carbopol ® 974 P NF a favourable lithium-carbonate release profile was achieved, whereas in the formulations with Carbopol® 971P NF and Carbopol® 71G NF, the release rate was significantly lower than that given in the USP 26 monography. [ABSTRACT FROM AUTHOR]

One titrimetric and two spectrophotometric methods are described for the determination of cyproheptadine hydrochloride (CPH) in bulk drug and tablets employing N-bromosuccinimide (NBS) as a brominating agent and two dyes, erioglaucine (EG) and meta-cresol purple (MCP) as auxiliary reagents. In titrimetry, a measured excess of NBS is added to an acidified solution of CPH and the unreacted NBS is determined iodometrically. Spectrophotometry involves the addition of a known excess of NBS to CPH in acid medium followed by estimation of residual NBS by reacting with a fixed amount of either erioglaucin and measuring the absorbance at 630 nm (method A) or meta-cresol purple and measuring the absorbance at 540 nm (method B). The titrimetric procedure is applicable over the range of 1.5-15 mg of CPH, and the reaction stoichiometry is found to be 1:2 (CPH: NBS). The spectrophotometric methods are applicable over the ranges of 0.1-2.0 μg mL-1 (method A) and 0.4-12 μg mL-1 (method B). The molar absorptivities are calculated to be 1.4x105 and 2.2x104 L mol-1 cm-1 for methods A and B, respectively, and the corresponding Sandell sensitivity values are 0.0023 and 0.0141 μg cm-2 . The limits of detection are calculated and found to be 0.03 and 0.24 μg mL-1 for methods A and B, respectively with corresponding limits of quantification 0.09 and 0.71. The methods were applied to the assay of CPH in tablets, and the results were compared statistically with those of a reference method. [ABSTRACT FROM AUTHOR]

Introduction. Nitrofurantoin, a furan derivative, introduced in the fifties has widely been used as an effective agent for the treatment and prevention of urinary tract infections (UTI). Spectrum of adverse reactions to nitrofurantoin is wide, ranging from eosinophilic interstitial lung disease, acute hepatitis and granulomatous reaction, to the chronic active hepatitis, a very rare adverse effect, that can lead to cirrhosis and death. Case report. We presented a 55-year- old female patient with eosinophilic interstitial lung disease, severe chronic active hepatitis and several other immune- mediated multisystemic manifestations of prolonged exposure to nitrofurantoin because of the recurrent UTI caused by Escherichia coli. We estimated typical radiographic and laboratory disturbances, also restrictive ventilatory changes, severe reduction of carbon monoxide diffusion capacity and abnormal liver function tests. Lymphocytic-eosinophylic alveolitis was consistent with drug-induced reaction. Hepatitis was confirmed by liver biopsy. After withdrawal of nitrofurantoin and application of high dose of glicocorticosteroids, prompt clinical and laboratory recovery was achieved. Conclusion. Adverse drug reactions should be considered in patients with concomitant lung and liver disease. The mainstay of treatment is drug withdrawal and the use of immunosuppressive drugs in severe cases. Consideration should be given to monitor lung and liver function tests during long term nitrofurantoin therapy. [ABSTRACT FROM AUTHOR]

Background/Aim. Antidepressants are a widely used class of drugs. The aim of this study was to investigate different aspects of antidepressant prescribing practice at University Psychiatric Clinic in Belgrade. Methods. This cross-sectional study was carried out by retrospective analysis of the patient's medical charts. The study included all patients with antidepressant prescribed at discharge during 2009 (n = 296). The evaluation was focused on patient- related factors (socio-demographic and illness related), psychiatrist-related factors (sex and duration of working experience) and drug related factors (type of antidepressant, dose, polypharmacy and reimbursement by national health insurance). Results. Antidepressants were prescribed for unipolar depression (F32-34, ICD X) either without comorbidity (46.2%) or with comorbidity (24.7%), mostly as a monotherapy (91% had one antidepressant), to the patients who were 65% female, aged 50.1 ± 8.9, most of them with 12 years of education (52.6%), married (69.3%) and employed (55.9%). The majority of patients had a history of two hospitalizations (Med 2; 25th--75th perc. 1--4) during nine years (Med 9; 25th--75th perc. 2--15) after the first episode of depression. Among them, 19% were found to be suicidal in a lifetime. The single most prescribed antidepressant was sertraline (20.4%), followed by fluoxetine (13.3%) and maprotiline (11.7%). Utilization of antidepressants was positively correlated with the rate of reimbursement (p < 0.01). The most prescribed antidepressant group was selective serotonin reuptake inhibitors (SSRI) (47.8%), followed by tricyclic antidepresants (TCA) (25.3%) and new antidepressants -- venlafaxine, tianeptine, mirtazapine, bupropion, trazodone (15.1%). Most of the drugs were prescribed in doses which are at the lower end of the recommended dose-range. Regarding severity of the actual depressive episode, TCA were prescribed for severe depression with psychotic features, while SSRI were choice for episodes with moderate symptom severity (p = 0.01). Psychiatrists with longer working age (20--30 years) hesitated to prescribe new antidepressants in comparison to younger colleagues (p = 0.01). Conclusion. Economic issues in Serbia as developing country influence the choice of antidepressants, as well as a psychiatrist's working age and severity of depression. However, SSRI are the drugs of the first choice, as it was shown in most of the developed countries nowadays. [ABSTRACT FROM AUTHOR]

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One titrimetric and two indirect spectrophotometric methods are described for the determination of doxycycline hyclate (DCH) in bulk drug and in its formulations. The methods use bromate-bromide, methyl orange and indigo carmine as reagents. In titrimetry (method A), DCH is treated with a known excess of bromate- -bromide mixture in acid medium and the residual bromine is back titrated iodometrically after the reaction between DCH and in situ bromine is ensured to be complete. In spectrophotometric methods, the excess of bromine is estimated by treating with a fixed amount of either methyl orange (method B) or indigo carmine (method C) and measuring the change in absorbance either at 520 or 610 nm. Titrimetric method is applicable over 1-8 mg range and the calculations are based on a 1:2 (DCH:bromate) stoichiometric ratio. In spectrophotometry, the calibration graphs were found to be linear over 0.25-1.25 and 1.0-5.0 μg mL-1 for method B and C, respectively, with corresponding molar absorptivity values of 2.62×105 and 6.97×104 L mol-1 cm-1. The accuracy and precision of the assays were determined by computing the intra-day and inter-day variations at three different levels of DCH. [ABSTRACT FROM AUTHOR]

Two simple titrimetric methods have been developed for the determination of hydroxyzine dihydrochloride (HDH) in pure form and in tablets. The principle of the methods are simple acid-base reactions in which the hydrochloride content of the drug was determined by titrating with an aqueous standardized NaOH solution either visually using phenolphthalein as indicator (method A) or potentiometrically using glass-calomel electrode system (method B). The methods were applicable over the range of 2-20 mg HDH. The procedures were also applied for the determination of HDH in its dosage forms and the results were found to be in good agreement with those obtained by the reference method. The precision, expressed by intra-day and inter-day relative standard deviation values, was satisfactory (RSD = 2.76%). The accuracy was satisfactory as well (RE = 2.67%). Excipients used as additives in pharmaceutical formulations did not interfere in the proposed procedures as shown by the recovery study via a standard addition technique with recovery percentage in the range 97.48-106.3% with a standard deviation of 1.76-3.42 %. [ABSTRACT FROM AUTHOR]

Background/Aim. Urgent psychiatric help and effective psychotherapeutic treatments are required soon after revival of a person after suicide attempt by self-poisoning. The aim of this article was to define an assessment of actual psychological characteristics of a person after suicide attempt by self-poisoning in order to apply psychotherapeutic crisis intervention after suicide attempt, as well as to show an approach to the treatment guided by the assessment that uses a psychodynamic model of suicidal crisis intervention based on our clinical experience. Methods. Hamilton Depression Rating Scale (HAMD), Center for Epidemiological Studies- Depression Scale (CES-D), Defensive Questionnaire Scale (DSQ-40), Scaling of Life Events (Paykel), and Pierce Suicide Intent Scale (SIS) were applied in 30 hospitalized persons following suicide attempt by self-poisoning and in 30 patients who had asked for psychiatric examination at the outpatient clinic due to various life crises not resulting in suicide attempt. The examinees of both groups were matched by sex, age, and education, professional and marital status. Comparison of the patient groups was done by the ttest. Logistic regression analysis was used for suicidal risk assessment. Results. The suicide attempters were depressed (HAMD = 22.60 ± 5.93, CES-D = 29.67 ± 7.99), with medium suicide risk factor (SIS = 4.5 ± 4.17), using immature (projection, dissociation, devaluation, acting-out) and neurotic (altruism) defense mechanisms. The most important motives for suicide attempt were separation problems, problems with parents and a problem of loneliness. The commonest feelings and thoughts of a subject preceding suicide attempt were a wish to escape an unbearable situation, loss of control, desire to show love for a partner and wish to be helped. After a suicide attempt, 90% of the persons felt relief because the attempt failed, although almost half of them intend to repeat it. The risk of repeated suicide attempt was 1.8 (90% CI = 0.09-37.70, p < 0.001) times higher if values on the SIS Total Score were increased and 1.62 (90% CI = 0.03-81.39, p < 0.001) times higher if values on the SIS 1 (Circumstances Score) subscale were increased, too. Conclusion. Before starting with psychotherapy for persons after suicide attempt by self-poisoning it is very important to define psychological assessment of a person, choose the treatment (out-patient clinic or inpatient/ hospital), assess indications for pharmacotherapy and psychotherapy that also must include a selection of patients for application of this therapeutic method. Assessment of conscientious and unconscientious conflicts leading to a suicide attempt represents initial basis for a therapist's work with a patient after suicide attempt and for application of psychotherapeutic crisis intervention. [ABSTRACT FROM AUTHOR]

Background/Aim. Sometimes resistance of Pseudomonas aeruginosa (Ps. aeruginosa) is developed during antibiotic treatment, in spite of the initial susceptibility in vitro. The aim of this study was to use an in vitro model for the study of the development of resistant strains of Ps. aeruginosa after a short exposure to ceftazidime, and to study the hydrolysing capacity of β-lactamases produced by the resistant strains. Methods. Among 563 clinical strains of Ps. aeruginosa, 37 multisensitive strains were collected for the study. After being identified, strains with simultaneous sensitivity to 5 expanded spectrum cephalosporins were chosen. For each strain, the minimal inhibitory concentration (MIC) of the 5 expanded spectrum cephalosporins was determined, and the production of extended spectrum β-lactamases (ESBL) was excluded by the double-disc synergy diffusion test. Strains non producing ESBL were cultivated in concentrations of ceftazidime equal to MICx2 and MICx4. After 24 hours of culture, the development of resistant strains was estimated and the cephalosporinase. The hydrolyzing capacity of the enzymes was expressed as the percentage of the antibiotic, which was hydrolysed in 10 sec. Results. A total of 60% and 50% of strains developed resistant strains after exposure to ceftazidime in concentration MICx2 and MICx4, respectively. The hydrolyzing capacity of the original strains was 15-36% while the hydrolyzing capacity of the resistant strains was 10-73%. Totally 64% of the resistant strains expressed higher hydrolyzing capacity than the original strains. Conclusion. Regardless of the susceptibility test results, Ps. aeruginosa presented a high tendency to develop resistant strains after a short exposure to ceftazidime in vitro. In most cases the resistant strains expressed higher cephalosporinase activity than the original strains, suggesting derepression of chromosomal β-lactamases. Our model offers a simple, inexpensive and rapid method for detecting resistance of Ps. aeruginosa developed due to derepression of β-lactamases, and for discriminating resistant strains with derepressed β-lactamases from strains that developed other mechanisms of resistance. activity of the produced β-lactamases was determined by their ability to hydrolyse cefazolin. Hydrolysis of cefazolin was studied by measuring the change of its absorbance on 272 nm using a Shimadzu 160A spectrophotometer. [ABSTRACT FROM AUTHOR]

Background/Aim. A single nucleotide polymorphism c.- 1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Methods. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Results. Out of 43 low dose patients, 40 (93 %) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of an- ticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). Conclusion. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5 % of our patients - carriers of AA genotype, before anticoagulation therapy initiation. [ABSTRACT FROM AUTHOR]

Background/Aim. Medicamentous abortion was first introduced in Serbia and Montenegro in September 2001. The aim of this study was to assess the efficiency, side effects, and acceptability of medicamentous abortion using mifeprostone orally (600 mg), and 48 hours later, misoprostol both orally and vaginally in different regiments in our population (400 mcg, 600 mcg, 800 mcg). Methods. A total of 235 consecutive women with pregnancies up to 49 days of gestational age were assigned to 4 groups according to the different misoprostol regiment (group I 400 mcg, group II 600 mcg, group III 800 mcg orally, and group IV 800 mcg both orally and vaginally). The principal outcome measure was a successful abortion defined as a complete expulsion of intrauterine contents without a need for surgical intervention 14 days after the procedure. Other outcome measures were the following: drug related effects, and adverse effects related to the abortion process. Results. In general, the success rate was 50%, 89.48%, 75% and 92.11% in the groups I, II, III, and IV, respectively, as judged by the complete expulsion of the intrauterine contents without surgical intervention (t1:4 = 7.005; t2:4 = 0.3872, t3:4 = 2.9784, p < 0.01). The incidence of adverse effects (vomiting, abdominal pain, bleeding, and fever) was low in general, but among our groups it occurred mostly with the higher doses of orally applied misoprostol (800 and 600 mcg). Only one case required urgent curettage for heavy vaginal bleeding, and two blood transfusions, as well. No cases of intact pregnancies were recorded in the study. Conclusion. Our study showed that a mifepristone dose of 600 mg orally, and misoprostol 400 mcg orally and 400 mcg vaginally were most effective. Thus, a combination of mifepristone and misoprostol for medicamentous abortion should take a higher proportion in the termination of early pregnancy in our population. [ABSTRACT FROM AUTHOR]

Background/Aim. A comprehensive reform strategy in drug management has been applying for a few years in Montenegro in order to promote a rational use of drugs. The reform strategy covered: an information system named ”The Control of Distribution and Use of Drugs“, a new List of Essential Drugs (that are reimbursed by the Republic Fund for Health), legislative and regulatory measures in order to establish a better control of drug prescribing and more efficient processing of the prescriptions. The aim of this study was to evaluate the effects of the reform strategy on the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting of Montenegro. Methods. A retrospective-prospective pharmacoepidemiologic study included a sample of 100% of cardiovascular drugs that were taken with prescription from state pharmacies during 2000 and 2004. The results were presented by the number of defined daily doses (DDD) per 1000 inhabitants per day. All the drugs were classified according to the uniform anatomical-therapeutic-chemical (ATC) classification of the drugs. The Wilcoxon test for matched pairs was used in order to calculate the significance of difference in cardiovascular drugs utilization before and after the introduction of new measures. Results. Although prescribing and the resulting outpatient use of cardiovascular drugs (ATC group C) that were reimbursed by the Republic Fund for Health was increased approximately by 13% in 2004 in comparison with 2000 (67.98 vs. 60.17 DDD/1000 inh./day), we did not find a statistically significant difference (p > 0.05). Prescribing of ACE inhibitors (C09A) increased approximately by 45% during the investigated period (15.30 vs. 22.17 DDD/1000 inh./day). The selection of drugs was also altered: cilazapril, ramipril and quinapril were left out, captopril and enalapril were more prescribed, and a newly-included fosinopril was prescribed mostly (31.5%). Calcium-channel blockers (C08) were prescribed 33.7% more (7.12 vs. 9.52 DDD/1000 inh./day), mostly because of seven times higher prescribing of amlodipine in 2004. Pentaerythritol tetranitrate was left out, but isosorbide dinitrate and isosorbide mononitrate were prescribed more frequently. High-priced atorvastatin was replaced with the older simvastatin, that was prescribed three times more. Conclusion. The reform strategy in drug management mostly improved the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting. For the most part, the noticed changes were in accordance with the actual recommendations, but some cases need additional measures. Regulatory policy, however, could not compensate for the continual education of doctors that prescribe drugs. [ABSTRACT FROM AUTHOR]

Background/Aim. The analysis of drug prescribing in general practice in Serbia showed that the use of benzodiazepines is most frequently associated with hypertension. The aim of this study was to establish the correlation of the characteristics of patients with hypertension to antihypertensive drug therapy, and the intake of benzodiazepines. Methods. A special questionnaire was used for interviewing the patients (n = 171) chronically treated for hypertenson. Statistical tests used were χ²-test and Student's t-test. Results. No differences were noted in terms of age, gender, education, body weight, smoking habits and blood pressure (155±4.9/100±2.7 mmHg vs. 160±2.2/105±3.7 mmHg), between the group I (antihypertensive drugs+benzodiazepines: n = 79), and the group II (antihypertensives only: n = 92). The patients taking benzodiazepines received a lower number of different antihypertensive drugs (2.3±0.09 vs. 2.7±0.10; p < 0.01), but the total antihypertensive drug load was significantly greater than in the group II (2.6±0.10 vs. 1.9±0.15 defined daily doses (DDD)/patient/day; p < 0.01). Benzodiazepines were taken for anxiety (62%) and hypertension (21%), rarely for insomnia, mostly once a day, at bedtime. About half the patients took benzodiazepines regularly for months or years aware of the risk for addiction. Diazepam was used by 82% of the patients. The average daily exposure to benzodiazepines was 0.45±0.05 DDD/patient/day. The drug was bought without prescription in 25% of the patients, and without consulting a physician in 12% of them. Conclusion. The study confirmed a close association of hypertension with the use of benzodiazepines. The frequent use of benzodiazepines in the patients with hypertension might be caused by an inadequate response to antihypertensive drug therapy, besides anxiety and insomnia. The therapeutic efficacy of a long-term use of low doses of benzodiazepines in hypertension requires further investigation. [ABSTRACT FROM AUTHOR]