Therapeutic drug monitoring in India: A strength, weakness, opportunity and threats analysis.

Over the last three to four decades, Therapeutic Drug Monitoring (TDM) has shaped itself as therapeutic drug management, an integral component of precision medicine. The practice of TDM is not extensive in India, despite being one of the fastest-growing economies in the world. It is currently limited to a few academic medical centres and teaching hospitals. Apart from the immunosuppressive drugs, several other therapeutic areas, such as anticancer, antifungal, antibiotic and antitubercular, have demonstrated great potential to improve patient outcomes in Indian settings. Factors such as the higher prevalence of nutritional deficiencies, tropical diseases, widespread use of alternative medicines, unalike pharmacogenomics and sparse population-specific data available on therapeutic ranges of several drugs make the population of this subcontinent unique regarding the relevance of TDM. Despite the impact of TDM in clinical science and its widespread application, TDM has failed to receive the attention it deserves in India. This review intends to bring out a strength, weakness, opportunity and threats (SWOT) analysis for TDM in India so that appropriate steps for fostering the growth of TDM could be envisioned. The need of the hour is the creation of a cooperative group including all the stakeholders, such as TDM professionals, clinicians and the government and devising a National Action Plan to strengthen TDM. Nodal TDM centres should be established, and pilot programmes should be rolled out to identify the thrust areas for TDM in the country, capacity building and creating awareness to integrate TDM into mainstream clinical medicine.

Effectiveness of budesonide formoterol fixed-dose combination MDI in reducing cough symptoms in COVID-19 patients: A real-world evidence study.

Background: Cough is a wearisome and exasperating symptom affecting the daily life of the infected patient. Cough due to coronavirus disease 2019 (COVID-19) causes excessive morbidity in human populations globally. Apart from the morbidity associated with cough, it also enhances the transmission of this viral infection through droplets. Therefore, curbing cough is crucial to limit its spread. Patients often administer over-the-counter products and antitussive agents, which have no proven benefit. The present study was undertaken to find out if cough associated with COVID-19 and other indicative clinical outcomes is alleviated with a budesonide/formoterol fixed-dose combination (FDC) metered-dose inhaler (MDI). Materials and Methods: A prospective observational study was conducted in mild COVID-19 patients who presented with a cough score ≥8 at presentation. Patients who were initiated on ICS-LABA MDI were observed as group A and those who were not initiated on MDI were observed as Group B. Cough symptom score (at baseline and on day 3 and day 7), the incidence of hospital admission and/or death, and need for mechanical ventilation were documented. Prescribing patterns of anti-cough medications were also noted and analysed. Results: Compared to group B, a higher mean cough score reduction was noted for group A patients at day 3 and day 7 when compared to the baseline, and this was significant at P < 0.001. A significant negative correlation was also observed between mean latency of MDI initiation from the symptom onset and mean cough score reduction. Analysis of the proportion of patients prescribed medications to treat cough showed that overall, 10.78% did not require these, with a greater proportion in group A compared to group B. Conclusion: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 who were treated with ICS-LABA MDI along with usual care benefitted significantly in terms of symptom reduction compared to usual care.

Efficacy and safety of lobeglitazone, a new Thiazolidinedione, as compared to the standard of care in type 2 diabetes mellitus: A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of lobeglitazone as compared to the standard of care (SOC) in patients with type 2 diabetes mellitus (T2DM). METHODS: Databases were searched for relevant randomized controlled trials. The primary outcome was the comparison of the glycated hemoglobin (HbA1C) level after 24 weeks. Pooled mean differences and odds ratios were calculated using random-effects models. RESULTS: Of 267 studies that were screened, four were included. Treatment with adjunct lobeglitazone showed a reduction in the HbA1C level [mean difference: -0.23% (95% CI: -0.62 to 0.16); p = 0.24; i2: 87%; moderate GRADE (Grading of Recommendations Assessment, Development and. Evaluation) of evidence], fasting blood glucose level [mean difference: -7.12 mg/dl (95% CI: -20.09 to 5.85); p = 0.28; i2: 87%; moderate GRADE of evidence], and lipid profile as compared to those following treatment with the SOC; however, the changes were not statistically significant. The risk of hypoglycemia was significantly lower [odds ratio: 0.24 (95% CI: 0.08 to 0.70); p < 0.05; i2: 0%; moderate GRADE of evidence] without any significant difference in the risk of drug-related adverse events [odds ratio: 1.59 (95% CI: 0.87 to 2.93); p = 0.13; i2: 0%; moderate GRADE of evidence] following treatment with lobeglitazone as compared to those following treatment with the SOC. CONCLUSION: Treatment with adjunct lobeglitazone showed changes in the blood glycemic status and lipid profile similar to SOC in patients with T2DM, and the results were not statistically significant. Lobeglitazone was well tolerated; its safety profile was comparable to SOC.

Association between Polypharmacy and Cardiovascular Autonomic Function among Elderly Patients in an Urban Municipality Area of Kolkata, India: A Record-Based Cross-Sectional Study.

We assessed the association between polypharmacy and cardiovascular autonomic function among community-dwelling elderly patients having chronic diseases. Three hundred and twenty-one patients from an urban municipality area of Kolkata, India were studied in August 2022. The anticholinergic burden and cardiac autonomic function (Valsalva ratio, orthostatic hypotension, change in diastolic blood pressure after an isometric exercise, and heart rate variability during expiration and inspiration) were evaluated. Binary logistic regression analysis was performed to find out the association of polypharmacy and total anticholinergic burden with cardiac autonomic neuropathy. A total of 305 patients (age, 68.9 ± 3.4; 65.9% male) were included. Of these patients, 81 (26.6%) were on polypharmacy. Out of these 81 patients, 42 patients were on ninety-eight potential inappropriate medications. The anticholinergic burden and the proportion of patients with cardiac autonomic neuropathy were significantly higher among patients who were on polypharmacy than those who were not (8.1 ± 2.3 vs. 2.3 ± 0.9; p = 0.03 and 56.8% vs. 44.6%; p = 0.01). The presence of polypharmacy and a total anticholinergic burden of > 3 was significantly associated with cardiac autonomic neuropathy (aOR, 2.66; 95% CI, 0.91−3.98 and aOR, 2.51; 95% CI, 0.99−3.52, respectively). Thus, polypharmacy was significantly associated with cardiac autonomic neuropathy among community-dwelling elderly patients.

Deprescribing for Better Patient Outcomes in Chronic Long Term Care and Role of Clinical Pharmacological Review.

Prescribing is always a risky proposition with a varied degree of vulnerability embedded in the act. It is therefore important to do a perfect balancing in favor of benefit against harm. Deprescribing is the planned and supervised process of dose reduction or stopping of prescribed medications, aimed at correcting inappropriate polypharmacy and improving patient outcomes. Informed reconciliation for potential deprescribing need should be a norm in all patients receiving many medications for multiple chronic comorbidities and is best done in partnership with the prescribing physician. Judicious deprescribing through clinical pharmacological review ensures better patient outcomes. We present here a case series from our experience in clinical pharmacology outpatients' department (OPD), highlighting how de-prescribing helps achieving better patient outcomes.

An Energy-Resolved Optical Non-invasive Device Detects Essential Electrolyte Balance in Humans at Point-of-Care.

Regular monitoring of electrolyte balance is essential for patients suffering from chronic kidney disease (CKD), particularly those undergoing dialysis. In the context of the recent COVID-19 pandemic, more severe forms of infection are observed in elderly individuals and patients having co-morbidities like CKD. The repeated blood tests for the monitoring of electrolyte balance predispose them not only to COVID-19 but also other to hospital-acquired infections (HAI). Therefore, a non-invasive method for easy detection of essential electrolyte (K+ and Na+) levels is urgently needed. In this study, we developed an optical emission spectroscopy-based non-invasive device for simultaneous monitoring of salivary Na+ and K+ levels in a fast and reliable way. The device consisted of a closed spark chamber, micro-spectrometer, high voltage spark generator, electronic circuits, optical fiber, and an indigenously developed software based on the LabVIEW platform. The optical emission originating from the biological sample (i.e., saliva) due to recombination of ions energized by impingement of electrons returning from high voltage spark provides necessary information about the concentration of electrolytes. A small-scale clinical trial on 30 healthy human subjects shows the potential of the indigenously developed device in determining salivary Na + and K+ concentration. The low-cost, portable, point-of-care device requires only 2 mL of sample, and can simultaneously measure 1.0-190.0 mM Na+, and 1.0-270.9 mM K+ . To our understanding, the present work will find its relevance in combating COVID-19 morbidities, along with regular CKD patient-care.

Materiovigilance Programme of India: A scheme to assure cardiovascular devices safety surveillance.

The Materiovigilance Programme of India (MvPI) has been implemented to ensure the safety of medical devices including cardiovascular devices (MD-CVD). This article describes the role of MvPI surveillance system that comprehensively collects, collates and analyses the adverse events associated with MD-CVD and also its supplementing role to the Central Drugs Standard Control Organization for taking regulatory decision to reduce the health burden on account of adverse events due to medical devices to the patients based on the evidence based data. This article is expected to stimulate ethical reporting of adverse events due to MD-CVD at MvPI.

Combination Therapy Against Indian Visceral Leishmaniasis with Liposomal Amphotericin B (FungisomeTM) and Short-Course Miltefosine in Comparison to Miltefosine Monotherapy.

Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.

Leukocytoclastic vasculitis secondary to clozapine.

Leukocytoclastic vasculitis (LCV) may be secondary to drugs, underlying infection, collagen vascular disorders, or malignancy. Drug-induced vasculitis contributes to 10% of vasculitic skin lesions cases usually developing within 7-21 days of treatment initiation. The present case highlights a report of LCV in a 59-year-old male with a history of paranoid schizophrenia on clozapine therapy. The report upsurges the need to promote awareness and expedite diagnosis and treatment of drug-induced LCVs.

T11TS repress gliomagenic apoptosis of bone marrow hematopoietic stem cells.

Combating gliomagenic global immunosuppression is one of the emerging key for improving prognosis in malignant glioma. Apoptosis plays a pivotal role within the adult hematopoietic system particularly in regulating the cells of immune system. Gliomagenic regulation of apoptotic mediators within bone marrow milieu has not been elucidated. We previously demonstrated that administration of membrane glycopeptides T11 target structure (T11TS) not only rejuvenate bone marrow hematopoietic stem cells (BMHSCs) from glioma mediated hibernation by inhibiting gliomagenic overexpression of Ang-1/Tie-2 but also stimulate glioma mediated diminution of expression CD34, c-kit, and Sca-1 markers. In the present study, we investigated the impact of glioma on apoptotic signaling cascades of BMHSCs and consequences following T11TS therapy. Bone marrow smear and Annexin V staining confirm gliomagenic acceleration of apoptotic fate of BMHSCs whereas T11TS treatment in glioma-bearing rats disrupted apoptosis of BMHSCs. Flowcytometry, immunoblotting, and immunofluorescence imagining results revealed multi potent T11TS not only significantly downregulates gliomagenic overexpression of Fas, Fas L, Bid, and caspase-8, the pro-apoptotic extrinsic mediators but also strongly inhibits cytosolic release of cytochrome-c, Apf-1, and Bax to deactivate gliomagenic caspase-9, 3 the key intrinsic apoptotic mediators followed by up modulation of anti-apoptotic Bcl-2 in glioma associated HSCs. T11TS is also able to diminish the perforin-granzyme B mediated apoptotic verdict of BMHSCs during gliomagenesis. The anti-apoptotic action of T11TS on glioma associated BMHSCs provide a crucial insight into how T11TS exerts its immunomodulatory action against glioma mediated immune devastation.

A Rare Case of Fixed Drug Eruption due to Ondansetron.

Fixed drug eruption (FDE) is a unique type of cutaneous drug reaction that typically recurs in the identical locations on re-exposure to the attributed drug. FDE is characterized by the appearance of a single or multiple sharply demarcated violaceous erythematous plaques which heal with residual hyperpigmentation. A 27-year-old woman presented with multiple dark patches over her eyelids, mouth, lips, and shoulders of 1 week's duration. These lesions followed multiple erythematous plaques over the same areas which appeared within 4 hours of the intake of an ondansetron tablet, 12 days previously. The case was diagnosed as post-inflammatory hyperpigmentation following ondansetron-induced FDE. There was an identical episode 1 year earlier due to the intake of the same drug. The causality assessment pointed toward a probable/likely association as per the Naranjo algorithm and the WHO-UMC scale. There have been only a few cases of FDE due to ondansetron in the reported literature.

Adverse drug reaction monitoring in patients on antiretroviral therapy in a tertiary care hospital in Eastern India.

BACKGROUND: Besides unparalleled benefits, highly active antiretroviral therapy is also associated with wide range of potential adverse drug reactions (ADRs), which hinders treatment adherence. The present study was thus designed to monitor and explore the pattern of occurrence of ADRs to various antiretroviral therapy (ART) regimens in a tertiary care ART setup. MATERIALS AND METHODS: A prospective, observational clinical study was carried out in the outpatient setting of nodal ART center of Eastern India. A total of 610 patients on various ART regimens were studied for suspected ADRs over 12 months. Adverse event history, medication history, and other relevant details were captured. Causality and severity of each reported ADR were duly assessed. RESULTS: 32.45% patients of total study participants presented with a total of 330 ADRs. Patients from zidovudine-based regimens presented with majority of ADRs such as anemia (up to 36%), central nervous system (CNS), and gastrointestinal (GI) side effects. Tenofovir-based regimens were, however, found to be mildly safer. The combination with Efavirenz was associated with majorly CNS side effects while that of nevirapine was associated with rash and pigmentation of nails. Atazanavir boosted second-line regimens were notably associated with increased serum lipid levels followed by other GI and CNS adverse effects. Increased liver enzymes were found in atazanavir-based second-line ART. CONCLUSION: The study enables to obtain information on the incidence and pattern of ADRs associated with various antiretroviral regimens, thereby reducing its occurrence and protecting the patient population from avoidable harm. Need of intensive monitoring for ADRs in ARTs thus seems to be a mandate.

Effects of co-treatment with pioglitazone and methotrexate on experimentally induced rheumatoid arthritis in Wistar albino rats.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the synovial joints of the body. Methotrexate (MTX) is considered as a mainstay in the management of RA. However, monotherapy with MTX in RA is often limited by potential long-term toxicity. The present study was conducted to evaluate if MTX-pioglitazone combination therapy has an add-on benefit over monotherapy with MTX or pioglitazone on disease activity in male Wistar rats in adjuvant-induced arthritis model. MATERIALS AND METHODS: Arthritis was induced by single subcutaneous injection of complete Freund's adjuvant (CFA) in thirty male Wistar albino rats. They were then divided into five equal groups, which included two control groups (arthritic and nonarthritic), pioglitazone-treated (1.35 mg/kg daily), MTX-treated (0.225 mg/kg daily), and MTX + pioglitazone-treated. The disease-modifying action of the drugs was assessed by various physiological, hematological, and biochemical parameters along with histopathological and radiological analysis of affected joints. The experimental data were statistically assessed by one-way ANOVA. RESULTS: There was a significant reduction of disease activity in the MTX monotherapy group when compared with disease control. However, pioglitazone monotherapy group failed to demonstrate any significant effect on disease activity. The MTX-pioglitazone combination group demonstrated greater suppression of disease activity as compared to MTX and pioglitazone monotherapy and disease control group (P < 0.05). CONCLUSION: The present study demonstrates that the combination therapy of MTX with pioglitazone offers better control of disease activities in RA as compared to MTX or pioglitazone monotherapy.

Fatal Nevirapine-Induced Toxic Epidermal Necrolysis in a HIV Infected Patient.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are the most Severe Cutaneous Adverse Reactions (SCARs) which mainly caused by exposure to drugs and having significant morbidity and mortality. TEN represents an immunologic reaction to a foreign antigen and is most often caused by drugs. Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI) is an important component of Highly Active Antiretroviral Therapy (HAART). It is sometimes associated with life-threatening adverse reactions. Here, we report the fatal case of 72-year-old male who developed TEN secondary to intake of nevirapine. This fatal case report will increase awareness among treating physicians for careful monitoring of patients on NNRTI-based antiretroviral therapy and better counseling of the patient on NVP regimen for early identification and reporting of SCARs so that fatalities due to adverse drug reactions can be prevented with timely intervention.

A Comparative Study of Lipid-Lowering Effects of Guggul and Atorvastatin Monotherapy in Comparison to Their Combination in High Cholesterol Diet-Induced Hyperlipidemia in Rabbits.

BACKGROUND: Hypolipidemic activity of gugulipid has been widely described in traditional literature. OBJECTIVE: This study was done to evaluate hypolipidemic activity of guggul and atorvaststin monotherapy in comparison to their combination in rabbits. MATERIALS AND METHODS: Male New Zealand White rabbits (body weight 1.3-1.8 kg and age 8-10 weeks) were made hyperlipidemic by feeding cholesterol (0.5 g/kg) for three weeks and randomly divided into a control and three treatment groups receiving: atorvastatin (3.7 mg/kg), guggul (3.5 mg/kg) and their combination (same dose) for the next three weeks. Body weight measurements, estimation of serum lipid profile were done at the beginning, after three and six weeks, respectively. Histopathological examination of liver, heart and aorta was done after six weeks. Statistical analysis was done with SPSS version 16.0 using one-way and repeated measures analysis of variance (ANOVA) followed by post-hoc multiple comparison test with two tailed P value < 0.05 as significant. RESULTS: All treated groups had significant reduction in cholesterol, triglyceride, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) in comparison to pre-treatment values and control group, and had significant increase in high-density lipoprotein (HDL) in comparison to pre-treatment values. CONCLUSION: Combination of atorvastatin and guggul was comparable to their monotherapies in improving lipid profile.

Specific allergen immunotherapy attenuates allergic airway inflammation in a rat model of Alstonia scholaris pollen induced airway allergy.

Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcɛRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcɛRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities.