Pharmacokinetics-pharmacodynamics of first-line antitubercular drugs: a comparative study in tuberculosis patients with and without concomitant diabetes mellitus.

PURPOSE: To observe the variability in the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profiles of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS: Newly diagnosed pulmonary TB patients aged 18-60 years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients with both TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. Improvements in clinical features, X-ray findings, sputum conversion, and adverse drug reactions (ADRs) were assessed after 2 months of therapy. RESULTS: Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentrations at 4, 8, and 12 h were significantly (P < 0.05) lower, and it displayed significantly (P < 0.05) lower area under the curve (AUC0-12 and AUC0-∞), shorter t1/2, higher clearance (Cl), and a lower AUC0-∞/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-∞, and t1/2 in diabetic patients. The improvements in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both groups. CONCLUSIONS: The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide, and ethambutol variably in the Indian population. Studies with a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM. TRIAL REGISTRATION: CTRI/2021/08/035578 dated 11/08/2021.

Pharmacoeconomics of medicines used for geriatric individuals in a tertiary care hospital in Delhi.

BACKGROUND OBJECTIVES: Expenditure on healthcare is a major concern in the geriatric age group. The current study was carried out to assess the expenditure patterns on medicines utilized in geriatric inpatients. METHODS: An observational study was conducted on 1000 geriatric inpatients, aged ≥60 yr, admitted to the medicine unit. Data were collected regarding demographic characteristics, prescribed medicines, expenditure incurred on medicines, appropriateness of medicines prescribed and adverse drug reactions (ADRs). Appropriateness of the prescribed medicines was determined using the American Geriatrics Society 2015 Updated Beers Criteria. RESULTS: Geriatric inpatients comprised 41.3 per cent of the total individuals admitted in the ward during the study period. A total of 8366 medicines were prescribed in 127 formulations. The total expenditure on prescribed medicines was INR 1,087,175 with a per capita expenditure of INR 1087.17. Parenteral medicines accounted for 91 per cent of the expenditure on medicines. Maximum expenditure (70%) was incurred on 11.9 per cent of the medicines prescribed. The per capita expenditure was significantly higher in individuals with comorbidities (P=0.03) and those who had a longer duration of hospital stay (P<0.0001). About 28.1 per cent prescriptions were inappropriate. ADRs (140) were observed in 139 (13.9%) inpatients. Individuals with inappropriate medicines prescriptions and ADRs had a longer duration of hospital stay and more number of medicines prescribed. INTERPRETATION CONCLUSIONS: Comorbidities, prolonged hospitalization, polypharmacy, inappropriate medicines and parenteral medicines being prescribed contribute to increased expenditure on medicines in geriatric inpatients. In view of the rising number of geriatric inpatients, there is a need to frame a drug policy for them along with surveillance of expenditure on prescribed medicines. This needs to be treated as a priority.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Pediatric prescribing in tertiary care teaching hospital of Delhi (India): fragmenting medicines for use.

Lack of availability of age-appropriate dosage forms for children often results in use of adult dosage forms, which are administered to children after crushing or breaking. This can result in inappropriate doses being given to the children. This study was done to assess the prescribing pattern of use of medicines that had to be fragmented or crushed for use in relation to the age of the child. A prescription audit of 1200 outpatients and 400 inpatient records was done in the pediatric department of Lok Nayak tertiary care teaching hospital in the National Capital New Delhi, India. A structured pro forma was used for collecting the data. The total medicines prescribed, use of adult formulations, and number of adult medicines that had to be fragmented or broken for administration to pediatric patients were assessed. A total of 880 medicines were prescribed among inpatients and 2701 in outpatients. In inpatients, 230 (26.1%) medicines and in outpatients, 1013 (37.5%) medicines were fragmented before use. Some of these medicines were available in liquid oral dosage forms in Delhi Essential Medicine List (DEML) and should be available in the hospital. Medicines for use for common conditions were fragmented. Maximum use of fragmented medicines was in the age group of 6-9 years, both among inpatients and outpatients. Association of fragmentation with age was significant (p value < 0.05).Conclusion: Children are being prescribed dosage forms, requiring manual fragmentation or crushing. Policy changes and measures to make available age-appropriate pediatric dosage formulations need to be taken to improve pediatric pharmacotherapy in the hospital and health system. What is Known: • The dosage formulation prescribed to a patient can impact the patient's compliance with the therapy, accuracy of dosing, and patient and care providers' safety. • Lack of availability of age-appropriate dosage forms is common for children and often results in administration of adult dosage forms after crushing or breaking. What is New: • Some regularly prescribed medicines (14) including amoxicillin, albendazole, chloroquine, carbamazepine, valproate, and phenytoin that had to be fragmented were available in liquid oral dosage forms in the Delhi Essential Medicine List (DEML). • Despite being included in the EML, the patient has been denied access to appropriate medicines. It indicates a lack of concern and sensitivity about what is required for rational prescribing to children.

Lithium Induced Amenorrhea: A First Case Report.

A 19-year-old female, known case of bipolar disorder had history of amenorrhea (absence of menstruation) for three years. While other causes of amenorrhea such as CNS, pregnancy, other medications, and thyroid issues were ruled out, she was found to have hyper-prolactinemia. Although antipsychotic medications are known to cause amenorrhea due to dopamine receptor blockade, which may result in hyperprolactinemia, the patient's symptoms began before she started these medications. Only drug that she was on for long period is lithium. Current literature shows mixed evidence about lithium's impact on prolactin levels, which can affect menstruation. This case may represent the first report of lithium causing amenorrhea through elevated prolactin levels. Clinicians should be aware of this potential side effect and monitor patients accordingly. Further studies are needed to confirm and understand this potential link.

Repurposing Drugs: An Empowering Approach to Drug Discovery and Development.

Drug discovery and development is a time-consuming and costly procedure that necessitates a substantial effort. Drug repurposing has been suggested as a method for developing medicines that takes less time than developing brand new medications and will be less expensive. Also known as drug repositioning or re-profiling, this strategy has been in use from the time of serendipitous drug discoveries to the modern computer aided drug designing and use of computational chemistry. In the light of the COVID-19 pandemic too, drug repurposing emerged as a ray of hope in the dearth of available medicines. Data availability by electronic recording, libraries, and improvements in computational techniques offer a vital substrate for systemic evaluation of repurposing candidates. In the not-too-distant future, it could be possible to create a global research archive for us to access, thus accelerating the process of drug development and repurposing. This review aims to present the evolution, benefits and drawbacks including current approaches, key players and the legal and regulatory hurdles in the field of drug repurposing. The vast quantities of available data secured in multiple drug databases, assisting in drug repurposing is also discussed.

Cost of medicines & their affordability in private pharmacies in Delhi (India).

BACKGROUND & OBJECTIVES: Medicines can account for up to 90 per cent of health care spending by poor people. High costs of medicines contribute to decreased access to healthcare. This study was conducted to assess the cost of medicines and their affordability in the private pharmacies in Delhi, India. METHODS: A survey was conducted to assess the costs of prescribed medicines and treatment of community acquired pneumonia (CAP), with medicines purchased from 27 private pharmacies, in Delhi. Affordability of medicines was assessed by comparing the costs of treatment (medicines) to the monthly per capita expenditure (MPCE) on food, minimum monthly and daily wages for different classes of workers. RESULTS: A large variability in the costs of prescriptions was observed (129.37 ± 217.99) The cost of treatment of CAP varied from Rs. 34.50- 244.75 with azithromycin and Rs.72.20- 277.30 with levofloxacin. The percentage of MPCE on food spent for a prescription was 17.64 per cent for urban and 23.4 per cent for rural population. The percentage of MPCE on food spent for treatment of CAP ranged from 10.11 to 13.42 per cent with azithromycin and 13.28 to 17.61 per cent with levofloxacin. The number of days a worker on minimum daily wages would have to work to enable him to purchase his prescription medicines ranged from 1-17 days, depending on the problem. The cost of treatment of CAP required 1-3 days of work by a daily wage earner, depending on the brand of medicine prescribed. INTERPRETATION & CONCLUSIONS: The findings of our study show that the costs of medicines are highly variable and not affordable for the economically poor in India. Modifications in National Pharmaceutical Policy need to be done urgently.

In search for a panacea for coronavirus disease-19: Analysis of ongoing clinical trials for the management of coronavirus disease-19 pandemic in India.

OBJECTIVE: To analyze the clinical trials that are registered on the Clinical Trial Registry of India (CTRI) portal for a year, for the treatment, prevention, and supportive therapy of coronavirus disease-19 (COVID-19). MATERIALS AND METHODS: All the trials registered on CTRI (since January 2020 till January 2021) for therapeutic, preventive, and supportive interventions for COVID-19 were searched with the keywords "Coronavirus," "COVID-19," "SARS-COV-2," and "2019-nCoV". These registered studies were analyzed as follows: Trials under different systems of Medicine-Allopathy/Homeopathy/Ayurveda/Unani/Yoga/Naturopathy. The Allopathy trials were further analyzed in detail: Intervention, design, comparator, number of subjects, duration, and approvals taken. RESULTS: A total of 1597 records were found. After excluding the overlaps, behavioral and other studies conducted to understand the diagnosis, epidemiology, a total of 419 registered studies were included for further analysis. Out of these 419 studies, 166 (39.6%) were in Ayurveda, 154 (36.7%) in Allopathy, 33 (7.8%) in Homeopathy, 30 (7%) in Unani/Siddha, 18 (4.3%) in Yoga and Naturopathy and 18 (4.3%) in Nutraceuticals. A total of 264 interventions had been registered in 419 clinical trials. Sixty-seven interventions were being studied under allopathy in 154 studies. Same product was being evaluated in differently designed protocols with different endpoints. Maximum number of trials and subjects were for Hydroxychloroquine 25 (17,998), Ivermectin 11 (2820), Convalescent Plasma 11 (3982), Remdesivir 8 (3725), Tocilizumab 6 (884), and Azithromycin 6 (582). CONCLUSIONS: In response to the COVID-19 pandemic, Indian researchers came forward from all the systems of medicine to evaluate interventions for prophylaxis or treatment of the disease. The involvement of AYUSH systems of medicine was specifically more in this regard. A wide variation and heterogeneity in doses and outcomes were observed in trial designs which might make it difficult to generalize the study results when they are made available. Urgent analyses of studies involving interventions on the treatment advisory of the Government may help the healthcare providers take more informed decisions for managing COVID-19 patients in India.

Availability of Pediatric Formulations in Public Health Care System in India: A Case Study.

OBJECTIVES: To assess the availability of pediatric formulations in Essential Medicines Lists and public health care facility in India. METHODS: Availability of pediatric formulations in the public health sector was evaluated by assessing inclusion of pediatric formulations in the National List of Essential Medicines (NLEM), Delhi Essential Medicine List (DEML), Indian Academy of Pediatrics (IAP) Essential Medicines Lists (EML) and comparing it with the World Health Organization's list of essential medicines for children (WHO, EMLc). In addition, availability of 30 essential medicines in a public, tertiary care hospital was assessed over a period of 1 y. RESULTS: Many medicines present in WHO EMLc were not there in NLEM and DEML. The number of pediatric medicines formulations not available in pediatric doses as compared to WHO EMLc was 98,97 and 97 in NLEM, DEML and IAP respectively. Palliative care was the most neglected area in all the lists. In the public health care facility, only 53% of the tracer pediatric medicines were available. CONCLUSIONS: There is less availability of pediatric formulations in the Indian NEML and state DEML. Availability of key tracer pediatric medicine formulations in public health facility is poor. A separate pediatric EML is required in the country to improve focus on availability of child-specific formulations.

Drug utilization, rationality, and cost analysis of antimicrobial medicines in a tertiary care teaching hospital of Northern India: A prospective, observational study.

BACKGROUND: The burden of bacterial infections is huge and grossly under-represented in the current health-care system. Inappropriate use of antimicrobial medicines (AMMs) poses a potential hazard to patients by causing antibiotic resistance. This study was conducted to assess the: (i) AMM consumption and use patterns in patients attending the outpatients and inpatients of Medicine and Surgery departments of the hospital. (ii) Appropriateness of the AMM in the treatment prescribed, and (iii) cost incurred on their use in admitted patients. MATERIALS AND METHODS: An observational, prospective study was conducted among inpatients and outpatients of the Medicine and Surgery departments of a tertiary care hospital of northern India. Analysis of 2128 prescriptions and 200 inpatient records was performed using a predesigned format. The use of AMMs was reviewed using anatomical therapeutic chemical classification and defined daily doses (DDDs). To evaluate the expenditure incurred on AMMs, ABC analysis was performed. RESULTS: AMMs were prescribed to 37.9% outpatients and 73% of admitted patients. The percentage encounters with AMMs was 40.6% (medicine) and 25.6% (surgery) outpatients. The total DDDs/100 patient days of AMMs in medicine and surgery were 3369 and 2247. Bacteriological evidence of infection and AMM sensitivity was present in only 8.5% of cases. Over 90% of AMMs were prescribed from the hospital essential medicines list. Most of the AMMs were administered parenterally (64.9%). Multiple AMMs were prescribed more to inpatients (84.2% vs. 4.2% outpatients). Overall, expenditure on AMM was 33% of the total cost of treatment on medicine. ABC analysis showed that 74% of the expenditure was due to newer, expensive AMM, which constituted only 9% of the AMM used. The AMM therapy was found to be appropriate in 88% of cases as per Kunin's criteria for rationality. CONCLUSION: AMMs are being commonly prescribed without confirmation of AMM sensitivity in the hospital. A large proportion of expenditure is being incurred on expensive AMM used in a few number of patients. There is a need for developing a policy for rational use of AMM in the health facility.

Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Pyrazinamide is recommended in doses varying from 15 to 40 mg kg(-1). The most commonly used average daily dose is 25 mg kg(-1). Its use is associated with dose dependent hepatotoxicity. Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg(-1). WHAT THIS STUDY ADDS: This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg(-1) which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg(-1) in children suffering from tuberculosis. The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg(-1) doses. AIMS: To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg(-1) in children suffering from tuberculosis. METHODS: Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg(-1) (group I) and 15 mg kg(-1) (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 microg ml(-1) and 25 microg ml(-1) was studied. RESULTS: The mean peak serum concentration was 42.4 +/- 3.3 microg ml(-1) (95% CI +/- 6.5) and 38.6 +/- 3.9 microg ml(-1) (95% CI +/- 7.7) in groups I and II, respectively. The elimination half-life was 9.3 +/- 1.3 h and 10.5 +/- 2.3 h (P = 0.6) and clearance was 0.06 +/- 0.01 l h(-1) kg(-1) and 0.04 +/- 0.01 l h(-1) kg(-1) (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses. CONCLUSIONS: The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg(-1) and 15 mg kg(-1) doses in children. The elimination half-life was longer and volume of distribution greater in children than in the adult population.

Awareness, practice and views about integrating AYUSH in allopathic curriculum of allopathic doctors and interns in a tertiary care teaching hospital in New Delhi, India.

OBJECTIVE: To assess the knowledge, attitude, perception and practice of Ayurveda, yoga, Unani, Siddha, homeopathy and naturopathy (AYUSH) among allopathic doctors and interns and determine their opinion regarding integration of AYUSH education within the allopathic curriculum. METHODS: This prospective, cross sectional study was conducted in a tertiary care teaching Hospital, New Delhi, India, from March 2016 to March 2017. A survey of 500 allopathic doctors and 150 interns was performed using a structured questionnaire. RESULTS: A majority of doctors (95.2%) were aware of the term AYUSH and had knowledge of yoga (70.6%), homeopathy (55.6%), Ayurveda (50.3%), Siddha (47.8%), naturopathy (32.9%) and Unani (28.9%). Most of the participants (63.0%) felt that therapies under AYUSH are effective. A majority (84.0%) of the doctors were of the view that more research is required in the field of AYUSH. While homeopathy (44.0%) was the most common system used by doctors for themselves, yoga was the therapy most commonly (60.0%) recommended to patients. Nearly half of the doctors (46.7%) recommended AYUSH to their patients, mainly for chronic illness (74.0%). A majority (77.5%) of the respondents agreed that students of allopathic medicine should be familiarized with AYUSH. The modes of incorporation of AYUSH into the medical curriculum most commonly suggested by respondents were optional courses (54.5%) and introductory lectures (42.3%). CONCLUSION: Doctors and interns of allopathic medicine are aware of AYUSH systems. They use it for themselves and recommend it to patients. They believe that familiarization of Bachelor of Medicine and Bachelor of Surgery students with AYUSH therapies and their integration with allopathic medicine may help in improving patient care.

Drug-induced optic neuropathy in a case of extensively drug-resistant pulmonary tuberculosis.

We report a 26-year-old male patient diagnosed with extensively drug-resistant pulmonary tuberculosis presenting with reversible bilateral toxic optic neuropathy induced by the use of linezolid along with high-dose isoniazid. The case emphasizes the importance of recognizing toxic optic neuritis in patients on antitubercular therapy. Prompt recognition and treatment of such adverse drug reactions will reduce the associated morbidity.

Gaussian Elimination-Based Novel Canonical Correlation Analysis Method for EEG Motion Artifact Removal.

The motion generated at the capturing time of electro-encephalography (EEG) signal leads to the artifacts, which may reduce the quality of obtained information. Existing artifact removal methods use canonical correlation analysis (CCA) for removing artifacts along with ensemble empirical mode decomposition (EEMD) and wavelet transform (WT). A new approach is proposed to further analyse and improve the filtering performance and reduce the filter computation time under highly noisy environment. This new approach of CCA is based on Gaussian elimination method which is used for calculating the correlation coefficients using backslash operation and is designed for EEG signal motion artifact removal. Gaussian elimination is used for solving linear equation to calculate Eigen values which reduces the computation cost of the CCA method. This novel proposed method is tested against currently available artifact removal techniques using EEMD-CCA and wavelet transform. The performance is tested on synthetic and real EEG signal data. The proposed artifact removal technique is evaluated using efficiency matrices such as del signal to noise ratio (DSNR), lambda (λ), root mean square error (RMSE), elapsed time, and ROC parameters. The results indicate suitablity of the proposed algorithm for use as a supplement to algorithms currently in use.

Generic medicines: issues and relevance for global health.

Generic medicine is a pharmaceutical product which is bioequivalent to the innovator product in terms of dosage form, strength, route of administration, quality, safety, performance characteristics, and intended use. Generic medicines are a cornerstone for providing affordable medicines to patients. The major generic markets in the world include United States of America followed by European Union, Canada, Japan, and Australia. The major suppliers of generic medicines China and India are showing tremendous growth in the generic medicine sector. There are many legal and regulatory issues along with quality concerns associated with the use of the generic products. Lately, bilateral international agreements called free trade agreements, delaying tactics by originator companies like strategic patenting and litigations on generic manufacturers, have been a major setback for the generic medicine industry. These issues need to be addressed to optimize the use of generic medicines. The sustainability of generic medicine sector is crucial for improving access to essential medicines for the worldwide.

Perception, attitude and usage of complementary and alternative medicine among doctors and patients in a tertiary care hospital in India.

AIM: Complementary and alternative medicine (CAM) has been practiced in India for thousands of years. The aim of this study was to determine the extent of use, perception and attitude of doctors and patients utilizing the same healthcare facility. METHODS: This study was conducted among 200 doctors working at a tertiary care teaching Hospital, India and 403 patients attending the same, to determine the extent of usage, attitude and perception toward CAM. RESULTS: The use of CAM was more among doctors (58%) when compared with the patients (28%). Among doctors, those who had utilized CAM themselves, recommended CAM as a therapy to their patients (52%) and enquired about its use from patients (37%) to a greater extent. CAM was used concomitantly with allopathic medicine by 60% patients. Very few patients (7%) were asked by their doctors about CAM use, and only 19% patients voluntarily informed their doctors about the CAM they were using. Most patients who used CAM felt it to be more effective, safer, less costly and easily available in comparison to allopathic medicines. CONCLUSION: CAM is used commonly by both doctors and patients. There is a lack of communication between doctors and patients regarding CAM, which may be improved by sensitization of doctors and inclusion of CAM in the medical curriculum.