Aripiprazole versus olanzapine in the treatment of schizophrenia: a clinical study from India.

OBJECTIVE: The aim of the study was to compare efficacy and tolerability of aripiprazole with olanzapine in the short-term treatment of schizophrenia in an Indian population. METHOD: This was a randomized double-blind controlled study comparing aripiprazole and olanzapine in the treatment of individuals with schizophrenia in an inpatient clinical setting. Sixty subjects between 18 and 65 years of age, who fulfilled the ICD-10 criteria for schizophrenia, were enrolled. Patients' detailed demographic and clinical evaluation was conducted and they were administered efficacy assessment scales (BPRS, PANSS) and safety assessments scale (Simpson Angus Scale, UKU side effect rating scale) at regular intervals of 1 week each throughout the study. The laboratory tests (complete haemogram, electrocardiogram (ECG), lipid profile, liver and renal function tests) were conducted at baseline and after 1-week intervals until 6 weeks of treatment. The patients were randomly allocated to receive either aripiprazole or olanzapine. RESULTS: Both aripiprazole and olanzapine led to significant reductions on BPRS and PANSS total score over a period of 6 weeks. Weight gain was observed more frequently in the olanzapine-treated group (22.20%) as compared to aripiprazole (7.70%). More patients in the aripiprazole treatment group required comedications (trihexiphenidyl and lorazepam) than olanzapine recipients. CONCLUSION: This study demonstrates that aripiprazole is equally efficacious as olanzapine in the treatment of schizophrenia. Aripiprazole has a more benign side effect profile (weight gain, blood sugar level, lipid profile) as compared to olanzapine in the short-term treatment of schizophrenia. This study is the first in an Indian population to have compared aripiprazole and olanzapine.

Psychiatric morbidity among inmates of leprosy homes.

CONTEXT: Leprosy affected people are having high psychological distress and it in turn leads to psychiatric disorders. There is a paucity of literature from our country in this significant health problem. AIMS: The aim of this study was to find the prevalence of psychiatric morbidity and its association with sociodemographic and clinical factors among the inmates of leprosy homes. SETTINGS AND DESIGN: Study sample was obtained from individuals residing in two leprosy homes of malwa belt of Punjab. MATERIALS AND METHODS: In screening stage, the study subjects were administered sociodemographic proforma and general health questionnaire (GHQ-12). In the confirmation stage, the study subjects were interviewed in detail and disability assessment was done using World Health Organization disability scale. Final psychiatric diagnosis was made as per ICD-10 criteria's. STATISTICAL ANALYSIS: Statistical analysis was performed using the descriptive statistics, Chi-square test, analysis of variance, and correlation analysis. RESULTS: Majority of the subjects was in the age group 41-50 years, female, married, illiterate, Hindu and were from nuclear families. Nearly, 50.38% of subjects were having GHQ-12 score more than twelve. Nearly, 55.6% subjects were having psychiatric disorders out of which a large number of patients was diagnosed as having dysthymia. The other psychiatric disorders found in the study population were moderate depressive episode, generalized anxiety disorder, mixed anxiety and depressive disorder and schizophrenia unspecified. Psychiatric morbidity was found to be significantly related to age, family status, and duration of leprosy illness and presence of deformities among inmates. CONCLUSIONS: This study highlighted that psychiatric disorders were found in a large number among inmates of leprosy homes. Leprosy eradication program must place specific emphasis on psychiatric care of these patients.

LC-UV-PDA and LC-MS studies to characterize degradation products of glimepiride.

Degradation products of glimepiride formed under different forced conditions have been characterized through LC-UV-PDA and LC-MS studies. Glimepiride was subjected to forced decomposition under the conditions of hydrolysis, oxidation, dry heat and photolysis, in accordance with the ICH guideline Q1A(R2). The reaction solutions were chromatographed on reversed phase C8 (150 mm x 4.6mm i.d., 5 microm) analytical column. In total, five degradation products (I-V) were formed under various conditions. The drug degraded to products II and V under acid and neutral hydrolytic conditions while products I, III and IV were formed under the alkaline conditions. The products II and V were also observed on exposure of drug to peroxide. No additional degradation product was shown up under photolytic conditions. All the products, except I, could be characterized through LC-PDA analyses and study of MS fragmentation pattern in both +ESI and -ESI modes. Product I could not be identified, as it did not ionize under MS conditions. The products II, III and V matched, respectively, to impurity B (glimepiride sulfonamide), impurity J and impurity C (glimepiride urethane) listed in European Pharmacopoeia. The product IV was a new degradation product, characterized as [[4-[2-(N-carbamoyl)aminoethyl]phenyl]sulfonyl]-3-trans-(4-methylcyclohexyl) urea. The degradation pathway of the drug to products II-V is proposed, which is yet unreported.

LC and LC-MS study on establishment of degradation pathway of glipizide under forced decomposition conditions.

Forced degradation studies on glipizide are conducted under the conditions of hydrolysis, oxidation, photolysis, and dry heat. The solutions are subjected to liquid chromatographic (LC) investigations to establish the number of products formed in each condition. The degradation products are characterized through isolation and subsequent NMR, IR, and MS spectral analyses, or through LC-mass spectrometry (MS) fragmentation pattern study. The drug is shown to degrade in 0.1M HCl at 85 degrees C to two products: 5-methyl-N-[2-(4-sulphamoylphenyl)ethyl]pyrazine-2-carboxamide (II) and methyl N-[4-[2-{(5-methyl-2-pyrazinoyl)amino}ethyl] phenyl]sulfonyl carbamate (III). The latter, a methyl ester, is formed only in the presence of methanol (used as a solubilizer), and does not appear on use of acetonitrile. III is shown to convert to II on continued heating in acid. The drug degrades slowly in water at the same temperature, and both II and III could be seen in the chromatograms until the end of the study. The heating of the drug in alkali (0.1M NaOH) at 85 degrees C yields 5-methyl-2-pyrazinecarboxylic acid (IV), along with a small quantity of 4-(2-aminoethyl) benzenesulfonamide (I). On extended heating in the same condition, a new product, 4-(2-aminoethyl)-N,N-bis[(cyclohexylamino)carbonyl] benzenesulfonamide (VI) is formed in small quantities. At the lower temperature of 40 degrees C, the drug converts under each hydrolytic condition and in both the absence and presence of light to products II, III, or IV, along with a new product, 1-cyclohexyl-3-[[4-(2aminoethyl)phenyl] sulfonyl]urea (V). The light catalyzes formation of V, and it is formed until one or two weeks, after which its level decreases. The drug remains stable in 30% H2O2, except that products II and III appear as small peaks due to acidic character of the peroxide solution. Also, the drug remains unaffected in solid state under thermal and photolytic stress conditions. Based on the results, a more complete picture on degradation pathway of the drug is obtained, highlighting a clear advantage of the approach suggested by International Conference on Harmonization.

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method.

Isoniazid was subjected to different ICH prescribed stress conditions of thermal stress, hydrolysis, oxidation and photolysis. The drug was stable to dry heat (50 and 60 degrees C). It showed extensive decomposition under hydrolytic conditions, while it was only moderately sensitive to oxidation stress. The solid drug turned intense yellow on exposure to light under accelerated conditions of temperature (40 degrees C) and humidity (75% RH). In total, three major degradation products were detected by LC. For establishment of stability-indicating assay, the reaction solutions in which different degradation products were formed were mixed, and the separation was optimized by varying the LC conditions. An acceptable separation was achieved using a C-18 column and a mobile phase comprising of water:acetonitrile (96:4, v/v), with flow rate and detection wavelength being 0.5 ml min(-1) and 254 nm, respectively. The degradation products appeared at relative retention times (RR(T)) of 0.71, 1.34 and 4.22. The validation studies established a linear response of the drug at concentrations between 50 and 1000 microg ml(-1). The mean values (+/-R.S.D.) of slope, intercept and correlation coefficient were 35,199 (+/-0.88), 114,310 (+/-4.70) and 0.9998 (+/-0.01), respectively. The mean R.S.D. values for intra- and inter-day precision were 0.24 and 0.90, respectively. The recovery of the drug ranged between 99.42 and 100.58%, when it was spiked to a mixture of solutions in which sufficient degradation was observed. The specificity was established through peak purity testing using a photodiode array detector. The method worked well on application to marketed formulation of isoniazid, and a fixed-dose combination containing isoniazid and ethambutol HCl. It was even extendable to LC-MS studies, which were carried out to identify the three degradation products. The m/z values of the peaks at RR(T) 0.71 and RR(T) 1.34 matched with isonicotinic acid and isonicotinamide, respectively. The product appearing at RR(T) 4.22 was isolated using preparative LC-MS, and turned out to be a yellow compound that was identified as isonicotinic acid N'-(pyridyl-4-carbonyl)-hydrazide based on mass, FTIR and (1)H/(13)C NMR spectral data. The same was indicated to be responsible for discolouration of isoniazid bulk drug substance and formulations, which is a familiar problem. The mechanism of formation of the said compound is outlined.

Drug-drug interaction studies on first-line anti-tuberculosis drugs.

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.

Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs.

Rifampicin and isoniazid are known to interact with each other in solid formulation environment to yield isonicotinyl hydrazone (HYD). In earlier studies, this reaction was indicated to be catalyzed by pyrazinamide and ethambutol hydrochloride, the two other co-drugs present in oral anti-tuberculosis fixed-dose combination (FDC) formulations. Accordingly, the present study was carried out to understand the catalytic role of pyrazinamide and ethambutol hydrochloride on the reaction between rifampicin and isoniazid. For the purpose, organic bases and amides similar in structure to pyrazinamide and ethambutol hydrochloride were combined individually with rifampicin and isoniazid. The compounds employed were pyrazine, piperdine, pyrollidine, pyridine, triethylamine, diisopropylethylamine, picolinamide, benzamide, ethylenediamine, ethanolamine, diethanolamine, and triethanolamine. An additional study was also carried out in the presence of free base of ethambutol. The mixtures were exposed to accelerated stability test condition of 40 degrees C/75% RH for 15 d. The nature of the products formed and the changes in relative concentrations of the drugs and products were followed by HPLC. The drugs showed different extent of degradation, yielding HYD, and in some cases degradation products of rifampicin. The results confirmed the catalytic role of pyrazinamide and ethambutol hydrochloride. The catalysis is postulated to involve intra-molecular proton transfer during transhydrazone formation process, entailing a tetrahedral mechanism.

Overestimation of rifampicin during colorimetric analysis of anti-tuberculosis products containing isoniazid due to formation of isonicotinyl hydrazone.

When present together in fixed-dose combinations (FDC) of anti-tuberculosis drugs, rifampicin (R) and isoniazid (H) interact with each other to form isonicotinyl hydrazone (HYD). In a preliminary study, this product was found to possess similar colorimetric spectrum to that of rifampicin. Therefore, an investigation was undertaken to determine interference of HYD during analysis of rifampicin in FDC products by colorimetry. For the purpose, standard plots were constructed for rifampicin and HYD at 475 nm, the wavelength maximum for both the compounds. The plots were linear in the range of 10-100 microg/ml. Molar absorptivity values for rifampicin and HYD were 15279 and 5034, respectively. It indicated that HYD possessed one-third absorptivity to that of rifampicin. The analysis of combinations of rifampicin and HYD revealed that rifampicin could be overestimated to a maximum extent of 33%, while interference varied at other relative ratios of the two compounds. This was also confirmed by colorimetric and HPLC analysis of a degraded marketed product and samples from a dissolution study. Thus this investigation suggests that any method devoid of interference of HYD should be preferred for analysis of rifampicin, whenever it is present along with isoniazid.

Interference of isonicotinyl hydrazone in the microbiological analysis of rifampicin from anti-tuberculosis FDC products containing isoniazid.

Microbiological assay is a sensitive method for the estimation of rifampicin (R). In the present study, interference due to isonicotinyl hydrazone (HYD), an interaction product of R and isoniazid (H), was checked during microbiological analysis of R, employing Bacillus subtilis and Sarcina lutea. The assays were done by disc diffusion method. Both R and HYD showed linear log response curves in the range of 0.01-10microg. In the presence of HYD, R was overestimated when tested against S. lutea and underestimated in case of B. subtilis. The same extent and type of interference was observed on assay of a marketed anti-tuberculosis fixed-dose combination product, subjected to accelerated stability testing (40 degrees C/75% RH) for 1 month. This means that response of organisms used in microbiological assay of R might vary in the presence of HYD, with possibility of incorrect conclusions. Therefore, the study suggests that before a microbiological method involving a particular organism is extended to the determination of R in FDC formulations containing H, it should be tested for the influence of HYD and used only if non-interfering.

Dissolution test method for rifampicin-isoniazid fixed dose formulations.

A dissolution procedure for a rifampicin-isoniazid combination formulation was evaluated using 0.1 N hydrochloric acid solution and 0.4% (w/v) sodium lauryl sulphate solution as dissolution media. Rifampicin and isoniazid along with degradation components were chromatographed using reversed-phase liquid chromatography on a 10 microns octadecylsilica column using methanol-0.01 M disodium hydrogen phosphate (70:30, v/v; pH 4.6 +/- 0.1) as mobile phase. The detection was carried out at 254 nm. The data obtained indicate that the dissolution medium consisting of 0.4% (w/v) sodium lauryl sulphate solution is suitable for such a combination. The degradation observed in dissolution medium consisting of 0.1 N hydrochloric acid was 10-23%.

Determination of diltiazem hydrochloride in human serum by high-performance liquid chromatography.

A simple and sensitive reversed-phase high-performance liquid chromatographic method for the determination of diltiazem in human serum has been developed. The method involves a one-step deproteinization of serum for sample clean-up using acetonitrile. A LiChrosorb RP-8 column (30 cm x 4.1 mm I.D.) was eluted isocratically with acetonitrile-0.01 M dibasic sodium phosphate (40:60, v/v) containing 0.01% triethanolamine. Diltiazem was monitored at 237 nm and 0.1 a.u.f.s. The completion time for assay was less than 15 min, and the lower limit of quantitation was 10 ng/ml for a 100-microliters injection volume. Using this method, the pharmacokinetic parameters were calculated from a serum concentration versus time profile of diltiazem.

Reversed-phase high-performance liquid chromatography of ketorolac and its application to bioequivalence studies in human serum.

A reversed-phase high-performance liquid chromatographic assay was used to study the bioequivalence of the anti-inflammatory drug (+/-)-ketorolac in human volunteers. Following deproteinization of human serum with 5% zinc sulphate solution, ketorolac was chromatographed on a 10-microns octadecylsilica column using acetonitrile-water as mobile phase and ultraviolet detection at 313 nm. Under these conditions the method was reproducible with a coefficient of variation of less than 5%. The assay procedure was linear in the range 0.25-1.5 micrograms/ml, with a sensitivity of 0.01 micrograms/ml ketorolac. The recovery of ketorolac from serum ranged from 90 to 95%.

Drugs on a medical campus. III. Drug use among nursing and paramedical personnel.

Fifty nurses and 50 paramedical staff working in the Rajendra Hospital and Medical College, Patiala, were studied by means of a structured, self-report questionnaire. The life-time prevalence of drug use among nurses was comparatively low--55%, compared to 81% among the paramedical staff. Current use of drugs as shown by the 30-day prevalence rate was also very low among the nurses, a majority of whom restricted themselves to using tranquillizers and sedatives for the specific purpose of relaxation or inducing sleep; only a few had experimented with alcohol, cannabis, and tobacco. On the other hand, the most commonly used drug among the paramedical personnel was alcohol, followed by sedatives, tranquillizers, cannabis and tobacco, most of them taking the drug for social reasons or for the thrills from the effects of the drug. This is also reflected in the comparatively higher number of paramedicals who felt that they would probably continue to use these drugs in the future, as also the fact that there were a few dependent users of opium and narcotics in this group.

Drugs on a medical campus. II. Drug use among faculty members.

One hundred out of a total of 207 members of the faculty of Medical College, Patiala, selected by a process of random sampling were covered in the present survey. They were divided into two groups--the senior consultants and the junior doctors. The lifetime prevalence rate for drug use was 78.9 per cent, and the commonest drugs used were alcohol and tranquilizers, followed by sedatives, stimulants, tobacco and cannabis. However, current use as shown by the 30-day prevalence rate showed that only three drugs--alcohol, tobacco and tranquilizers--are commonly used. More of the senior doctors were single-drug users (44 per cent) compared to only 20 per cent among the junior doctors, who experimented with a larger variety of drugs and took them more frequently than the seniors. Enquiry into the reasons for drug use revealed further differences between the two groups; a majority of the senior physicians stated that they took drugs to help them obtain relief from their tensions, whereas among the younger group a considerable number took them for thrills or out of curiosity. A majority of the physicians felt they would continue to use alcohol, tobacco and tranquilizers in the future, whereas they would not take cannabis, opium or narcotics.