Evaluation of prescriptions from tertiary care hospitals across India for deviations from treatment guidelines & their potential consequences.

BACKGROUND OBJECTIVES: Irrational prescribing practices have major consequences on patient safety and also increase the economic burden. Real-life examples of impact of irrational prescription have potential to improve prescribing practices. In this context, the present study aimed to capture and evaluate the prevalence of deviations from treatment guidelines in the prescriptions, potential consequence/s of the deviations and corrective actions recommended by clinicians. METHODS: It was a cross-sectional observational study conducted in the outpatient departments of tertiary care hospitals in India wherein the 13 Indian Council of Medical Research Rational Use of Medicines Centres are located. Prescriptions not compliant with the standard treatment guidelines and incomplete prescriptions with respect to formulation, dose, duration and frequency were labelled as 'prescriptions having deviations'. A deviation that could result in a drug interaction, lack of response, increased cost, preventable adverse drug reaction (ADR) and/or antimicrobial resistance was labelled as an 'unacceptable deviation'. RESULTS: Against all the prescriptions assessed, about one tenth of them (475/4838; 9.8%) had unacceptable deviations. However, in 2667/4838 (55.1%) prescriptions, the clinicians had adhered to the treatment guidelines. Two thousand one hundred and seventy-one prescriptions had deviations, of which 475 (21.9%) had unacceptable deviations with pantoprazole (n=54), rabeprazole+domperidone (n=35) and oral enzyme preparations (n=24) as the most frequently prescribed drugs and upper respiratory tract infection (URTI) and hypertension as most common diseases with unacceptable deviations. The potential consequences of deviations were increase in cost (n=301), ADRs (n=254), drug interactions (n=81), lack of therapeutic response (n=77) and antimicrobial resistance (n=72). Major corrective actions proposed for consideration were issuance of an administrative order (n=196) and conducting online training programme (n=108). INTERPRETATION CONCLUSIONS: The overall prevalence of deviations found was 45 per cent of which unacceptable deviations was estimated to be 9.8 per cent. To minimize the deviations, clinicians recommended online training on rational prescribing and administrative directives as potential interventions.

Usage Pattern of Fixed-dose Combinations at ICMR Network of Rational Use of Medicine Centres across India: Recommendations for Policymakers and Prescribers.

AIM: Irrational use of medicines is a global problem. In India, one contributing factor is the availability of a large number of fixed-dose combinations (FDCs). To improve rational use and to strengthen policies, it is important to assess the usage patterns and rationality of FDCs. METHODS: This study was conducted as part of a 1-year prospective cross-sectional analysis of prescriptions in the outpatient clinics of broad specialities from 13 tertiary care hospitals across India. Five most commonly prescribed FDCs in each center were analyzed. In addition, all the prescribed FDCs were classified as per the Kokate Committee classification and it was noted whether any of the FDCs were irrational or banned as per the reference lists released by regulatory authorities. RESULTS: A total of 4,838 prescriptions were analyzed. Of these, 2,093 (43.3%) prescriptions had at least one FDC. These 2,093 prescriptions had 366 different FDCs. Of the 366 FDCs, 241 were rational; 10 were irrational; 14 required further data generation; and the remaining 96 FDCs could not be categorized into any of the above. Vitamins and minerals/supplements, antibacterial for systemic use, and drugs for gastroesophageal reflux disease (GERD) and peptic ulcer were the most used FDCs. CONCLUSION: Based on the finding that some prescriptions contained irrational FDCs, it is recommended that a rigorous, regular, and uniform method of evaluation be implemented to approve/ban FDCs and that prescribers be periodically notified about the status of the bans.

Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation.

Obinutuzumab (also known as GA101, afutuzumab, Gazyva) is a humanized, glycoengineered type II monoclonal antibody targeted against CD20. The US Food and Drug Administration has approved obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first treatment to receive approval under the agency's breakthrough therapy designation, a program intended to facilitate and expedite the review and development of therapies for serious and life-threatening conditions. In preclinical studies, obinutuzumab has showed superior efficacy, as compared with rituximab, by inducing direct cell death and increased antibody-dependent cellular cytotoxicity activity with less complement-dependent cytotoxicity. Regulatory approval of obinutuzumab is based on a phase III (CLL11) study that demonstrated improved outcomes with a combination of obinutuzumab with chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities. Obinutuzumab plus chlorambucil induced deeper and longer remissions than rituximab plus chlorambucil combination as evidenced by prolongation of progression-free survival and higher complete response and molecular response rates. Marketing applications for obinutuzumab have also been submitted to other regulatory authorities including the European Medicines Agency.

Ellagic acid modulates sodium valproate induced reproductive toxicity in male Wistar rats.

This study evaluated the protective effect of ellagic acid on sodium valproate-induced sperm abnormalities in male Wistar rats. A total of 30 rats were grouped into five groups, each having 6 animals. Vehicle, sodium valproate (400 mg/kg) and ellagic acid (10, 25, 50 mg/kg) were given orally from day 1 to day 7, and ellagic acid was continued for 3 more days. On day fourteen, animals were sacrificed and the different parameters were recorded. There was a significant decrease in the sperm count and sperm motility after the exposure to sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. The histopathological examination revealed that sodium valproate had caused degeneration and desquamation of germinal cells in the epithelium and also showed a decrease in the Johnsen's scoring. Ellagic acid provided partial protection at the doses of 10 and 25 mg/kg and complete protection at 50 mg/kg, against sodium valproate induced testicular and spermatozoal damage.

An observational multi-centric COVID-19 sequelae study among health care workers.

Background: India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any. Methods: This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire. Finding: Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46-12.23) and lower among males (OR 0.55; 95% CI 0.39-0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19. Interpretation: Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae. Funding: This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Continued use of azithromycin for mild COVID-19 in India: Evidence and implications?

Azithromycin is an antibiotic commonly used for treating respiratory, gastrointestinal infections besides enteric fever, otitis media etc. It's convenient short duration oral dosing regimens and good tolerability make it a popular drug in routine outpatient settings in primary to tertiary care. Pre-clinical studies have shown immunomodulatory and in vitro activity of azithromycin against SARS CoV-2, which has led to its widespread usage in COVID-19. However, subsequent reviews of observational studies assessing its efficacy in different grades of COVID-19, as well as data from well conducted randomised clinical trials (RCTs) in mild - moderate COVID-19 have shown no or very low quality evidence of benefit of the drug on various clinical outcome parameters. Still, the drug continues to be used indiscriminately in many parts of India for treatment of home isolated patients of mild COVID-19. Such injudicious use in the community should be stopped, otherwise there will be serious adverse consequences of development of resistance to this very useful antibiotic during this pandemic.

Remogliflozin: the new low cost SGLT-2 inhibitor for type 2 diabetes mellitus.

SGLT-2 inhibitors have recently emerged as an important class of oral drugs for treatment of type 2 diabetes mellitus, especially in patients with cardiovascular or renal impairment, recommended in all recent treatment guidelines. They have additional advantages of weight and blood pressure reduction but also pose problems like genitourinary infections. These drugs generally have a high cost making affordability a major consideration in their prescription in developing countries like India. A new molecule remogliflozin has been approved in India in 2019 after a phase 3 trial proved its efficacy and safety in comparison to dapagliflozin. This drug has been priced substantially lower than other SGLT-2 inhibitors, and despite the disadvantage of twice daily administration, it potentially reduces treatment cost to less than half compared to other molecules of this class. With a good tolerability profile on the basis of available safety data till date, remogliflozin could be a useful alternative for providing SGLT-2 inhibitor therapy in a country like India where out of pocket expenses for drug acquisition matter significantly for the general population. However, long term safety and efficacy data especially on cardiovascular and renal outcomes are currently lacking for the drug.

Pattern of Disease and Therapy for Diabetes along with Impact of Generic Prescribing on Cost of Treatment among Outpatients at a Tertiary Care Facility.

BACKGROUND: India has become the diabetes capital of the world. Analyzing trends in drug prescribing helps in judging rationality of prescriptions in different settings. This study aimed to assess disease and prescribing trends with a special emphasis on evaluating use of metformin, insulin, fixed dose combinations (FDCs), concomitant medications, pill burden, and costs of drug therapy in diabetes. MATERIALS AND METHODS: This was a cross-sectional study in which patients of either sex who attended the diabetes clinic at a tertiary care center over 9 months were included consecutively. Basic demographic profile, clinical, and treatment details on the day of visit were collected from the prescription charts. Drug costs for prescriptions were calculated using generic and median brand prices of formulations using a recognized commercial drug directory and generic price list of the government, respectively. Data were analyzed by using Microsoft Excel and Open Epi online software to compare results with published studies. RESULTS: Average age of diabetics was 53.9 ± 11.8 years and disease duration was 8.13 ± 7.78 years in 336 prescriptions analyzed. Dual drug regimens were seen in 32.7% prescriptions, most commonly metformin and sulfonylureas, followed by triple drug regimens (25%) with inhibition of dipeptidyl peptidase IV (DPP IV) inhibitor. Metformin was prescribed in 95% prescriptions (mean dose 1511 ± 559.87 mg) and insulin in 22.6% prescriptions. Angiotensin receptor blocker (ARBs) and statins were the most commonly prescribed concomitant drugs. One FDC per prescription (median) each for diabetes and comorbidities were prescribed. Daily pill burden was 4.59 ± 2.65 pills. The median monthly cost of drug therapy with branded prescribing was INR 870.43 and INR 393.72 with the use of generics. Inferences drawn by comparison with published data showed variable results for different parameters analyzed. CONCLUSION: Disease pattern was as expected for the region and trends of therapy showed concurrence with rational prescribing. Pill burden and cost of therapy remain high with a significant contribution of comorbidities.

Approval of Itolizumab for COVID-19: A Premature Decision or Need of The Hour?

Itolizumab is a first-in-class anti-CD6 monoclonal antibody that was initially developed for various cancers and was later developed and approved in India for treatment of moderate to severe chronic plaque psoriasis in 2013. This drug is now being re-purposed for COVID-19. The potential utility of itolizumab in COVID-19, based on its unique mechanism of action in ameliorating cytokine release syndrome (CRS), was proposed first in Cuba with approval of a single-arm clinical trial and expanded access use. Subsequently, a phase II, open-label, randomized, placebo-controlled trial has been conducted in 30 COVID-19 patients in India after receiving regulatory permission. Based on the results, the Indian drug regulatory agency recently approved itolizumab in July 2020 for 'restricted emergency use' for the treatment of CRS in moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. This has drawn sharp criticism within the scientific community, with the approval being granted on the basis of a relatively small phase II trial, without conduct of a conventional phase III trial, and lacking availability of the claimed supportive real-world evidence in the public domain to date. In a global scenario where finding a successful treatment for COVID-19 is of utmost priority, a biologic agent has been re-purposed and approved with a successfully completed RCT, in a country where cases and mortality due to COVID-19 are growing exponentially. However, instead of welcoming the approval with open arms, many doubts are being raised. This is an issue that needs to be considered and dealt with sensitively, as well as scientifically.

Diabetes care during COVID-19 lockdown at a tertiary care centre in India.

Providing scheduled consultations to persons with diabetes during the COVID-19 induced lockdowns posed a major challenge. With the clinicians occupied in COVID management, a strategy of using telemedicine and engaging a team of para-clinical doctors was devised. Telephonic follow up consults were given and diabetes care was efficiently delivered.

Organoids: An invaluable tool in pharmacology.

Advances in stem cell cultures and human-induced pluripotent stem cells have inculcated interests in a rapidly evolving concept - "organoids." These are three-dimensional (3D) structures mimicking some of the phenomena of the real organs at anatomical, multicellular, and functional levels in vitro. Organoids have been proven to be better than two-dimensional cell culture in replicating the functionality, architectural, and geometrical features of tissues in vivo. Recent advancements have led to the generation of models for organ development and disease, finding applications in the drug discovery, screening of novel compounds, and personalized medicine. Since organoids follow the same natural pathway as the normal tissue or pathology, they can be used to study the expression of various genotypes and phenotypic variations across different species. In the light of these advancements, organoids are now being merged with bioengineering to come up with even better and reliable models to predict the disease progression and effectiveness of precision medicines, few of its important applications. This article discusses the various aspects of this emerging concept along with its uses, both in the present times and near future, with a special focus on pharmacological applications.

Involvement of the GABAergic system in the anxiolytic-like effect of the flavonoid ellagic acid in mice.

Anxiolytic-like effects of dietary flavonoids are relatively well known. Ellagic acid is a naturally occurring flavonoid compound which is abundant in many plants and fruits. The present study was designed to investigate the antianxiety-like effect of ellagic acid in mice using an elevated plus-maze test. The involvement of the GABAergic and serotonergic systems in the antianxiety-like activity of ellagic acid was also studied. Our results showed that ellagic acid treatment (25, 50 and 100 mg/kg, p.o.), produced a significant increase in the percentage of time spent and entry into the open arms, with a profile comparable to that of diazepam (1 mg/kg, p.o.). Unlike diazepam, the anxiolytic doses of ellagic acid did not prolong the duration of sodium thiopental-induced loss of righting reflex, indicating that this flavonoid is non-hypnotic. The anxiolytic effect observed with ellagic acid treatment (25 mg/kg, p.o.) was antagonized by pretreatment with picrotoxin (a non-competitive GABAA receptor antagonist, 1 mg/kg, i.p.) and flumazenil (a benzodiazepine site antagonist, 1 mg/kg, i.p.) but not with p-chlorophenylalanine (a serotonin synthesis inhibitor, 100 mg/kg, i.p.) and pindolol (a ß-adrenoceptors blocker/5-HT1A/1B receptor antagonist, 10 mg/kg, i.p.). Taken together, the data demonstrated that acute and chronic administration of ellagic acid to mice has produced antianxiety-like effect when tested in the elevated plus-maze. The experiments with different receptor blockers suggest an involvement of GABAergic system in the anxiolytic action of this bioflavonoid. However, this action is not seems to be mediated through serotonergic system.

Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice.

Dietary flavonoids possess a multiplicity of neuroprotective actions in various central nervous pathophysiological conditions including depression. Ellagic acid is a polyphenolic compound that occurs in plants such as raspberries, nuts and eucalyptus species. The present study was designed to investigate the antidepressant-like effect of ellagic acid in mice using forced swimming test (FST) and tail suspension test (TST). The involvement of the monoaminergic and opioid systems in the antidepressant-like activity of ellagic acid was also studied. Our results showed that ellagic acid when administered acutely or chronically to mice (25, 50 and 100mg/kg, p.o.), produced a significant reduction in the duration of immobility, with a profile comparable to that of fluoxetine (20mg/kg, p.o.). However, ellagic acid treatment had no effect on the locomotor activity of mice when tested in actophotometer. The reduction in immobility time observed with ellagic acid treatment (50mg/kg, p.o.) was prevented by pretreatment with p-chlorophenylalanine (100mg/kg, i.p., a serotonin synthesis inhibitor), pindolol (10mg/kg, i.p., a ß-adrenoceptors blocker/5HT(1A/1B) receptor antagonist), ketanserin (5mg/kg, i.p., a 5HT(2A/2B) receptor antagonist), ondansetron (1mg/kg, i.p., a 5HT(3) receptor antagonist), prazosin (1mg/kg, i.p., an α(1)-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist), but not with naloxone (1mg/kg, i.p., an opioid receptor antagonist). Our results suggest that ellagic acid produced an antidepressant-like effect which was unrelated to its locomotor activity. Furthermore, this anti-immobility effect seems most likely to be mediated through an interaction with the monoaminergic system (serotonergic and noradrenergic systems) and not through the opioid system.