Efficacy and Safety of Asenapine Versus Olanzapine in Combination With Divalproex for Acute Mania: A Randomized Controlled Trial.

BACKGROUND: Atypical antipsychotics are used for the treatment of acute mania, either as monotherapy or in combination with lithium or divalproex, which have a better tolerability profile as compared with typical antipsychotics. Asenapine, a newer atypical antipsychotic, has been found to be effective for the treatment of mania, with efficacy similar to olanzapine. The objective of the study was to compare the efficacy and safety of asenapine and olanzapine when used in combination with divalproex in patients with acute mania. METHODS: One hundred twenty patients aged 18 to 55 years, diagnosed with manic episode, were randomized to receive either flexible dose of sublingual asenapine (10-20 mg/d) or tablet olanzapine (10-20 mg/d), in combination with valproate 20 mg/kg per day for a period of 6 weeks. Efficacy was measured as change in Young Mania Rating Scale and Clinical Global Impression-Bipolar using intention-to-treat analysis with last observation carried forward, and safety was measured using Udvalg for Kliniske Undersøgelser scale and Modified Simpson-Angus Extrapyramidal Side Effects Scale. RESULTS: There was a significant reduction in Young Mania Rating Scale and Clinical Global Impression-Bipolar scores over time in both groups, with a significantly higher reduction in the olanzapine group as shown by the group × time interaction effect. Higher weight gain, increased sleep and appetite, and tremors were seen in the olanzapine-treated patients as compared with asenapine-treated patients; however, tongue hypesthesia was seen in the asenapine group only. CONCLUSIONS: This study found that asenapine was an effective and well-tolerated atypical antipsychotic alternative to olanzapine in combination with divalproex for the short-term management of acute mania.

Drug-induced diseases (DIDs): An experience of a tertiary care teaching hospital from India.

BACKGROUND & OBJECTIVES: Drug-induced diseases (DIDs) are well known but least studied. Data on DIDs from India are not available. Hence, this retrospective cross-sectional study was undertaken using suspected adverse drug reaction (ADR) data collected form Pharmacovigilance Programme of India (PvPI) to evaluate profile of DIDs over two years, in a tertiary care teaching hospital from north India. METHODS: The suspected ADRs in the form of DID were evaluated for drug and disease related variables and were classified in terms of causality. RESULTS: DID rate was 38.80 per cent. Mean duration of developing DIDs was 26.05 ± 9.6 days; 25.16 per cent had more than one co-morbid condition. Geriatric population (53.99%) accounted for maximum DIDs followed by adult (37.79%) and paediatric (8.21%). Maximum events were probable (93.98%) followed by possible (6.04%). All DIDs required intervention. Gastritis (7.43%), diarrhoea (5.92%), anaemia (4.79%), hypotension (2.77%), hepatic dysfunction (2.69%), hypertension (1.51%), myalgia (1.05%), and renal dysfunction (1.01%) were some of the DIDs. Anti tubercular treatment (ATT), anti retroviral treatment (ART), ceftriaxone injection, steroids, non-steroidal anti-inflammatory drugs, antimicrobials and anticancer drugs were found as commonly offending drugs. INTERPRETATION & CONCLUSIONS: Our findings show that DIDs are a significant health problem in our country, which need more attention.

Fatal adverse drug reactions: Experience of adverse drug reactions in a tertiary care teaching hospital of North India - A case series.

Medical burden of fatal adverse drug reactions (FADRs) is significant. The epidemiological data on FADR do exist from the western world, but there is scanty from India. We hereby report a case series of FADRs recorded in a 2 years period. Point prevalence of FADRs was 0.223%. Point prevalence of all cause death in the hospital was 1.20%. The drugs causing FADRs were injection bupivacaine, amphotericin B, directly observed treatment short-course Category-1, injection streptokinase, and tablet ferrous sulfate. All these FADR were labeled as possible expect one case as probable. All FADR were labeled as type A. In three out of five the central nervous system was involved, while the hepatic system and multiorgan failure accounted for one case each. Two cases each were acute and subacute, while one was latent in nature. Reporting of FADRs shall go a long way in patient safety.

Zidovudine-induced nail hyper-pigmentation in 45-year-old women prescribed for HIV/tuberculosis co-infection.

Zidovudine is an important component of first-line antiretroviral treatment regimens used to manage HIV and tuberculosis (TB) co-infection. Nail pigmentation is documented both in adult as well as pediatric HIV patients, but to the best of our knowledge, it has not been reported in 45-year-old women of HIV/TB co-infection. Such an adverse drugs reactions (ADR), although is harmless and reversible, psychological aspects of such ADR may be immense to the extent that it can negatively affect the compliance and result in therapeutic failure. Thus, it is worth reporting.

Under-reporting of adverse drug reactions: a challenge for pharmacovigilance in India.

AIM: The aim was to evaluate the extent and factors responsible for underreporting (UR) of adverse drug reactions (ADRs) in India. MATERIALS AND METHODS: A retrospective observational, cross-sectional prospective questionnaire-based analysis was undertaken to evaluate the extent and factors for UR of ADRs in pharmacovigilance. RESULTS: At the time, this report was prepared, 90 ADR Monitoring Centers (AMC) were operational in India. Indian AMC functional rate was 56.45%. The average number of Individual Case Safety Reports reported by our center via VigiFlow per month was 48.038. In a period of the 3 years the total number of ADRs reported was 3024. The average number of reports per month was 80.08. Active surveillance versus spontaneous reporting contributed 66.13% versus 33.86% of the total ADRs (P < 0.0001). Outpatient Department (OPD) contribution was 76.05% and indoor contribution was 23.94% of total reports (P < 0.0001). Department of Medicine (33%), followed by oncology (19.27%) and chest disease (13.49%) contributed maximally. The contribution of Pharmacology ADR monitoring OPD was 16.20%. Eye, ear, nose and throat and surgery, private Medical Colleges, hospitals in periphery, sub-district and district contributed no ADRs. ADR detection rates by clinical presentation, biochemical investigation and diagnostic tools were 84.33%, 14.57%, and 1.09% respectively (P < 0.0001). Reporting by postgraduate, registrars, consultants and nurses were 72.65%, 6.58%, 16.56% and 4.19% respectively (P < 0.0001). PG students in Pharmacology contributed an average number of 5.61 ADR reports/month. The lack of knowledge and awareness about Pharmacovigilance Programme of India (PvPI), lethargy, indifference, insecurity, complacency, workload, lack of training were the common factors responsible for UR. Major academic activity, exams, thesis and synopsis submission time influenced reporting of ADRs by postgraduate students. CONCLUSION: UR is a matter of concern PvPI. Multiple interventions are needed to improve ADR reporting.

Upper gastrointestinal bleed in a post menopausal woman due to combination of high first dose aspirin and clopidogrel prescribed for acute coronary syndrome.

Combination of aspirin, clopidogrel and enoxaparin remains the standard treatment for acute coronary syndrome (ACS) but is known to increase the incidence of upper gastrointestinal bleed (UGIB). We hereby report an unusual case of gastrointestinal bleed (GIB) as it resulted inspite of proton pump inhibitor (PPI) prophylaxis within the second day of treatment in a post-menopausal woman (PMW) with high first dose of aspirin clopidogrel dual combination in a patient of ACS.

Comparative evaluation of efficacy and safety of combination of metformin-vidagliptin versus metfromin-glimepiride in most frequently used doses in patients of type 2 diabetes mellitus with inadequately controlled metformin monotherapy-A randomised open label study.

AIM AND OBJECTIVE: The aim was to evaluate and compare the efficacy and safety of combinations of metformin-vidagliptin (MF-VG) and metfromin-glimepiride (MF-GP) in type 2 diabetes mellitus (T2DM) patients. MATERIALS AND METHODS: A comparative randomized open-label trial was conducted on patients with uncomplicated T2DM, on treatment with MF for 4 months out of which on maximum tolerated dose of MF (1000-2500 mg/day) for 4 weeks, glycosylated Haemoglobin [HbA1c]) ≥6.5%, fasting blood glucose (FBG) ≥126 mg/dl and post prandial glucose (PPG) ≥200 mg/dl were included in the study. Patients were randomized to receive MF (500 mg BD) + VG (50 mg BD) or MF (500 mg BD) + GP (2 mg BD). RESULTS: Both the groups caused significant decline in blood glucose levels both FBG as well as PPG levels (P < 0.01). HbA1c was also reduced significantly in both groups at 12 weeks (P < 0.01). Total serum cholesterol, triglycerides, low-density lipoprotein and very low-density lipoprotein decreased significantly, whereas high-density lipoprotein levels increased significantly from baseline levels in both the groups (P < 0.01). Intergroup comparison failed to demonstrate any statistical difference on all of above parameters. Both weight and body mass index did not alter statistically from baseline in either of the groups as well as demonstrated no difference statistically on comparison (P > 0.05). At the end of the study, both liver functions tests and renal functions tests remained unaltered statistically and within normal clinical range in both the groups (P > 0.05). However, hypoglycemia and other adverse events were numerically more in MF + GP group. CONCLUSION: Both the regimens on comparison revealed similar efficacy and safety thereby failing to prove superiority over each other.

To evaluate efficacy and safety of Caralluma fimbriata in overweight and obese patients: A randomized, single blinded, placebo control trial.

AIM: The aim of the following study is to evaluate the efficacy and safety of Caralluma fimbriata extract (CFE) in overweight and obese individuals in a prospective, randomized, placebo controlled trial. MATERIALS AND METHODS: Commercially available CFE was assessed in overweight and obese individuals. A total of 89 patients were randomized into a treatment group (n = 47) and placebo group (n = 42) to receive either CFE in the form capsules/oral 500 mg b.d. for 12 weeks or matching placebo in similar way. Patients were evaluated clinically and biochemically at 4, 8 and 12 weeks for anthropometric measurements, appetite, biochemical investigations and other safety parameters. RESULTS: At the end of study period both CFE and placebo for 12 weeks caused only numerical reduction in weight, body mass index, waist circumference, hip circumference and waist hip ratio in overweight and obese individuals. However, these parameters failed to attain significant statistical levels (P ≥ 0.05). CFE and placebo both failed to elucidate any modification of the appetite. There were no significant changes in the biochemical and clinical parameters in both the test and placebo group. However, CFE was well-tolerated and adverse events noted were mild and transient in nature. CONCLUSION: A commercially available extract of CFE in an oral dose of 1 g/day claimed to have anti-obesity effect failed to yield any positive results on anthropometry and appetite in overweight and obese individuals beyond placebo. There were also no significant differences in the clinical and biochemical parameters. However, CFE was well tolerated. Thereby, underscoring the need to carry more research before CFE is recommended as an anti-obesity drug.

Gastrointestinal bleed induced by a fixed dose combination of rabeprazole and diclofenac sodium.

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause gastrointestinal (GI) bleed. Co-administration of proton pump inhibitors (PPIs) has been widely suggested as one of the strategies to prevent these GI complications among NSAIDs users. Herein, we present a case of severe GI bleeding in a patient taking fixed dose combination (FDC) of rabeprazole (20 mg) and diclofenac sodium (100 SR).

Angioedema due to fixed dose combination of telmisartan plus ramipril.

The risk for angioedema has been suggested lower with angiotensin receptor blockers (ARBs) than with angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren. Many isolated reports do exist, reporting angioedema with ARBs such as olmesartan, valsartan, losartan and telmisartan. To the best of our knowledge this is the first case report of telmisartan plus ramipril fixed dose combination leading to angioedema from India questioning the rationality of ARBs plus ACEIs combination in the treatment of hypertension.

Cilnidipine induced ankle edema.

Cilnidipine is a 4(th) generation dihydropyridine calcium channel blocker approved recently for the treatment of essential hypertension. It is not known to present with ankle edema like amlodipine. Moreover, it has been proposed as an alternative anti-hypertensive for patients with amlodipine-induced edema. We report a case of cilnidipine induced ankle edema.

First Indian study evaluating role of biochemical investigations and diagnostic tools in detection of adverse drug reactions.

AIM OF STUDY: To evaluate the role of biochemical investigations (BI) and diagnostic tools (DT) in ADR detection. MATERIALS AND METHODS: An observational prospective cross-sectional study was done using suspected ADR data collection form. RESULTS: A total of 2381 ADR related events were recorded in two years. Total number/percentage of biochemical abnormalities (BA) related ADR detection rate was 14.57% and of DT was 1.091% in contrast to 84.33% recorded with clinical presentation. Maximum cases were inward patients (87.13%), 67.02% were recorded by active surveillance. ADR detection rate at one point & detection on follow up was 56.31% Vs 46.38%. ADR detection rate of ECG, endoscopy, X-ray were 0.57%, 0.22%, 0.22% and of CT scan, MRI, DEXA scan, USG and biopsy was 0.04% each. Maximum ADRs were severe/serious, latent and Type-A in nature. Anemia (4.6%), followed by liver dysfunction (2.8%), renal dysfunction, electrolyte imbalance, hyperglycemia (1.1% each), abnormal coagulation profile (1%), decrease platelet count (0.8%), hypoglycemia (0.7%) were the most common BAs. Anti retroviral drugs (ART), tirofiban and methotrexate accounted for anemia, ART and anti tubercular drugs for liver & renal dysfunction, insulin for hypoglycemia, tirofiban, paclitaxel, capecipabine and ifosfamide for thrombocytopenia, hematuria by enoxaparin & dyslipidemia with ART were common ADRs. CONCLUSION: BI and DT can play very important role in ADR detection.

Prevalence of vitamin d deficiency among Indian menopausal women and its correlation with diabetes: A first Indian cross sectional data.

AIM AND OBJECTIVE: To evaluate prevalence of Vitamin D deficiency and establish any correlation between diabetes and vitamin D deficiency among postmenopausal women. MATERIALS AND METHODS: The 25-hydroxy vitamin D [25 (OH) D] concentrations were measured by competitive in-vitro quantitative immunoassay. The subjects were classified as vitamin D-deficient, insufficient or sufficient on the basis of 25 (OH) D concentrations of < 20 ng/mL, 20-30 ng/mL or > 30 ng/mL respectively. The apparently normal postmenopausal women (PMW) were subjected to fasting blood sugar levels to analyse any correlation between vitamin D deficiency and diabetes. RESULTS: Vitamin D deficiency was observed in 53.35% of the population, 19.48% had insufficiency and 26.83% had adequate Vitamin D levels. In 12.14% of the study population fasting blood glucose was > 110 mg/dl and rest of the subjects were between the normal range which is 70-110mg/dl. Correlation between raised blood sugar levels and Vitamin D deficiency among PMW was non-significant (P = 0.324). CONCLUSION: High prevalence of vitamin D deficiency exists among apparently healthy Indian PMW. However, the current study failed to show any statistical correlation between vitamin D deficiency and existence of diabetes, which may be due to small sample size.

Comparative evaluation of efficacy, safety and haemostatic parameters of enoxaparin and fondaparinux in unstable coronary artery disease.

AIM: To compare the safety and efficacy of Enoxaparin (EX) and Fondaparinux (FD) in patients with Unstable Coronary Artery Disease (UCAD). MATERIALS AND METHODS: A prospective, open label, randomized comparative study was designed to study the comparative efficacy and safety of EX and FD in UCAD patients. Recovery, recurrence, major and minor bleeding and biochemical investigations were evaluated and compared among two arms. RESULTS: The baseline demographic characteristics were similar in both groups, with mean age of 56.05 and 56.05 years in EX and FD group respectively. Recovery was equal in two arms. Recurrent MI or angina was seen numerically more in EX group, but it did not statistically vary from that in the FD group. Incidence of haemorrhage was similar in both groups at 9 days, but at 30 days, EX showed a higher incidence (p<0.05). Deaths were prevented in both the treatment arms. Bleeding parameters such as BT, CT and platelet count were not altered in both groups. CONCLUSION: FD appeared to be better than EX in efficacy, as was indicated by a numerically more decrease in recurrence of angina or MI. FD regimen group also had better safety profile, as there was no incidence of haemorrhage at 30 days Therefore, we conclude that FD is an attractive option than EX in UCAD patients.

First Indian prospective randomized comparative study evaluating adherence and compliance of postmenopausal osteoporotic patients for daily alendronate, weekly risedronate and monthly ibandronate regimens of bisphosphonates.

AIM: The aim of the following study is to evaluate adherence and compliance of postmenopausal osteoporotic patients for different regimens of bisphosphonates (BP). MATERIALS AND METHODS: A prospective observational randomized comparative 1 year study was undertaken to evaluate the adherence/compliance rates of most commonly prescribed daily alendronate (ALN), weekly risedronate (RIS) and monthly ibandronate (IBN) BP regimens. RESULTS: Nearly 40% was the 1 year adherence rate with BP and 41.33% of non-compliance. Whereas, 8.66% was interrupted compliance rate and 6% switched over to other anti-osteoporotic treatment. The three treatment arm did not vary significantly. However, numerically maximum adherence rate of 56% was recorded in monthly BP regimen followed by weekly (36%) and daily regimen (32%). Medication possession rate confirmed on a follow-up visit was maximum with monthly regimen as 84.61% followed by daily (62.5%) and weekly (61.11%) respectively. Average time in days for non-adherence was 48, 56 and 92 day with daily ALN, weekly RIS and monthly IBN regimen respectively. Age, mean age at menopause, demographical profile failed to influence the adherence. Concomitant treatment for co-morbid condition (57.14%), unawareness about osteoporosis (OP) (50%), cost of treatment (45.33%), belief that drugs is for their general disability (39.28%), physician's failure to stress the need and necessary calcium + vitamin D daily requirement (23.80%) each were the most prevalent factors responsible for non-adherence. Intolerance and adverse drug reactions were responsible for only 13.09% and 11.90% of non-adherence. CONCLUSION: Treatment compliance is poor with daily ALN, weekly RIS and monthly IBN regimen along with calcium and vitamin D3 in Indian paramedical workers suffering OP.

Effect of Carum carvi, a herbal bioenhancer on pharmacokinetics of antitubercular drugs: A study in healthy human volunteers.

AIM AND OBJECTIVES: The present study was undertaken in 20 healthy human volunteers to evaluate the effect of a herbal bioenhancer, Carum carvi on pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in fixed dose combination (FDC). MATERIALS AND METHODS: It was a prospective, two-period, open-label, cross-over experiment on 20 healthy human male volunteers. The volunteers were administered a single dose of FDC containing rifampicin (450 mg), isoniazid (300 mg), and pyrazinamide (1000 mg) and after 10 days washout period the same FDC along with C. carvi extract (100 mg) was administered. Blood samples were collected at different time-points and analyzed by high-performance liquid chromatography (HPLC). Detailed pharmacokinetic parameters were calculated, which included C max, area under curve (AUC), time to reach maximum plasma concentration (T max), clearance (Cl), volume of distribution (V d), and half-life (t ½). RESULTS: Additions of C. carvi extract lead to increase in plasma levels of rifampicin, isoniazid, and pyrazinamide. The bioavailability indices C max of rifampicin increased from 4.57 ± 0.19 to 5.95 ± 0.19 (P = 0.000) and AUC increased from 40.11 ± 1.69 to 53.01 ± 1.88 (P = 0.000). Similarly, C max of isoniazid increased from 2.66 ± 0.16 to 3.62 ± 0.16 (P = 0.000) and AUC from 17.72 ± 0.78 to 22.87 ± 0.94 (P = 0.000). The bioavailability indices of pyrazinamide also revealed an increase in C max from 18.81 ± 0.79 to 25.06 ± 1.14 (P = 0.000) and AUC from 107.65 ± 4.42 to 137.71 ± 5.92 (P = 0.000), respectively. CONCLUSION: C. carvi acts as a bioenhancer and modifies the kinetics of antitubercular treatment (ATT) favorably.

Pregabalin-induced self-harm behavior.

Antiepileptic Drugs (AEDs) such as lamotrigine, gabapentin, and oxcarbazepine may have the potential to increase the risk of self-harm or suicidal behavior. We report a case of pregabalin-induced self-inflicted multiple injuries on forearm after its continuous use. This is an interesting adverse drug reaction (ADR) that is rare, unusual, and potentially serious.