Antigen loss following CAR-T cell therapy: Mechanisms, implications, and potential solutions.

Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR-T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%-70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T-cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR-T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR-T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem.

Smoking blunts sertraline response in depression: A prospective observational cohort study.

Background: Smoking is common in patients of depression and is known to affect response to antidepressants. This study was undertaken to evaluate the effect of smoking on the antidepressant effect of sertraline. Method: Patients with depression were divided into smoker and nonsmoker cohorts and followed up for 8 weeks. Serum sertraline levels were estimated using the high-performance liquid chromatography system. Response to treatment was evaluated with the Hamilton Depression Rating Scale (HAM-D). Results: Serum sertraline levels did not differ between smokers and nonsmokers at 4 and 8 weeks. Nonsmokers responded better to sertraline than smokers after 8 weeks. Adverse drug reaction profile did not vary between the two groups and was not impacted by serum sertraline levels. Nonsmokers showed a greater fall in the HAM-D score than smokers. Conclusion: This study found depression among smokers to be less responsive to sertraline. This was not explained by serum sertraline levels. Treatment of depression in smokers with sertraline might require higher doses and duration, with more frequent reviews.

Therapeutic drug monitoring of Amikacin in hospitalized patients: A pilot study.

Background: Amikacin, an aminoglycoside, is a widely used parenteral antibiotic. Therapeutic drug monitoring (TDM) is recommended for aminoglycosides to avoid toxicity. However, the lack of infrastructure at most places precludes it. This pilot and novel study attempt to estimate the real-world serum levels of Amikacin in hospitalised patients. Methods: Thirty admitted patients, given Amikacin injections, were included in the study. In addition, 15 clinical specimens isolated with gram-negative bacteria were tested for minimum inhibitory concentration (MIC) value of Amikacin. Trough and peak serum levels of Amikacin were estimated by high-pressure liquid chromatography (HPLC). Results: The average MIC value of Amikacin estimated in our laboratory was 3.92 mcg/mL. Peak and trough serum levels of Amikacin ranged from 12.1 to 66.4 mcg/ml and 1.1 to 20.7 mcg/ml, respectively. More than 83% of our patients achieved peak Amikacin levels of 15 mcg/mL, and 37% had trough levels above 5 mcg/mL. These levels are desirable watersheds as per available literature. Conclusion: Trough levels of Amikacin in all cases and a review of dosing according to MIC values are recommended to achieve drug safety and therapeutic efficacy.

Longitudinal study of the course and outcome of first-episode psychosis.

Background: Study of first episode psychosis (FEP), an episode of psychotic nature, which manifests for the first time in an individual in the longitudinal continuum of his/her illness, has been a matter of research interest in recent years, as this may give more insight to the overall phenomenology and course of psychotic illnesses. Methods: A study was undertaken to evaluate course and outcome of first episode psychosis. A total of 100 consecutive inpatients were selected for the study. Informed consent was obtained. Structured Proforma was used for recording psychosocial profiles and relevant medical history. Brief Psychiatric Rating Scale (BPRS) was given to assess the severity of psychopathology; Positive and Negative Symptom Scale (PANSS) to assess the severity of psychosis; Becks Suicidal Ideation Scale (BSI) to assess the extent of suicidality and Global Assessment of Functioning (GAF) to assess global functioning of the individual. The assessment was done at baseline, at six months, and at one year. Results: First episode psychosis constituted around a tenth of the caseload. It commonly affected people in the third decade of life. There was an improvement in 92% of the cases over a year of study. Schizophrenia constituted the majority of first episode psychosis. The history of smoking was relatively higher in acute and transient psychotic disorders. Age inversely correlated with the severity of psychopathology. There was no difference in improvement in psychopathology over time in patients of schizophrenia and related disorder vis--vis other psychotic disorders. Conclusion: Our study did not find any significantly varied sociodemographic factors in the course and outcome of the illness. It also refuted the schism between various types of psychosis based on the current classificatory system. It draws our attention toward the unitary concept of psychosis and is a call to re-think our strategies in the management of psychosis.

An experimental study of rosuvastatin's analgesic effect and its interaction with etoricoxib, tramadol, amlodipine, and amitriptytline in albino mice.

Background: Statins are the mainstay for the treatment of dyslipidemia. Recently, rosuvastatin has also been demonstrated to possess analgesic properties in animal studies. The present study has been planned to further confirm the analgesic activity of rosuvastatin, etoricoxib, tramadol, amlodipine, and amitriptyline and study the interaction of rosuvastatin with the above-mentioned analgesics. The objective of the study was to confirm the analgesic activity of rosuvastatin and determine the minimum analgesic dose of rosuvastatin, etoricoxib, tramadol, amlodipine and amitriptyline and to study the analgesic effect of combination of subanalgesic doses of rosuvastatin with sub-analgesic doses of etoricoxib, tramadol, amlodipine, and amitriptyline. Method: After IAEC approval, the study was carried out in albino mice in two phases. In phase I, the analgesic effect of rosuvastatin, etoricoxib, tramadol, amlodipine, and amitriptyline was confirmed by using tail-flick and writhing methods. In phase II, analgesic effect of combinations of subanalgesic dose of rosuvastatin with subanalgesic dose of etoricoxib, tramadol, amlodipine, and amitriptyline was studied. Results: Minimal analgesic dose of rosuvastatin, etoricoxib, tramadol, amlodipine, and amitriptyline was observed as 5, 20, 10, 5, and 10 mg/kg, respectively. In phase II, combination of subanalgesic dose of rosuvastatin 2.5 mg/kg with subanalgesic doses of etoricoxib (10 mg/kg), tramadol (5 mg/kg), amlodipine (2.5 mg/kg), and amitriptyline (5 mg/kg), demonstrated synergistic analgesic activity. Conclusion: Rosuvastatin exerts dose-dependent analgesic activity that is synergistic to that of etoricoxib, tramadol, amlodipine, and amitriptyline. If established in clinical studies as well, this finding can lead to the reduction of analgesic dosing in patients already on statins.

A study to investigate the chemical potency, physical stability, and efficacy of analgesic agents over a period of two years post their expiry date.

Background: As per regulations, drugs have to be used within their shelf life and must be discarded after their expiry date. The present study was conducted in commonly used analgesic agents to investigate the change in the physical, chemical, and efficacy parameters of the drugs over a period of two years after their expiry date. Methods: The drugs studied were Tab Ibuprofen, Tab Diclofenac, Tab Piroxicam, Inj Diclofenac, and Inj Piroxicam. The parameters investigated were chemical potency, physical stability, and analgesic efficacy. Testing for these parameters was carried out once before expiry to establish the baseline followed by at expiry, and then every six months for two years post expiry date. Results: The active ingredient in all the drugs were within the accepted range as per IP during the study period indicating that they retained their potency up to a period of two years post expiry. The analgesic efficacy as determined by the "Radiant Heat Tail flick" and "Acetic acid-induced writhing" model also showed no significant difference in the Maximum Possible Efficacy and Percent protection, indicating that the drugs retained their efficacy. There was a slight difference in the dissolution times at expiry as compared to different time periods in the case of Ibuprofen and Diclofenac, while there are was no statistical difference in the disintegration times during the study period. Conclusion: The analgesic drugs in our study retained their chemical potency, physical stability and analgesic efficacy up to a period of two years after expiry. The expiry date of a drug, as estimated currently, is not an accurate reflection of its actual shelf life.

A cross-sectional questionnaire based study to assess and compare knowledge of drug schedules amongst healthcare professionals in a medical college.

Background: Ensuring quality, safety and efficacy of all pharmaceuticals is the responsibility of drug regulators. However, healthcare workers should be aware of the legal/regulatory provisions involved. This study was planned to assess and compare the knowledge of various drugs schedules under the Drugs and Cosmetics Act, 1940 amongst medical students, post graduate residents and pharmacists. Methods: A questionnaire was designed based on review of literature and was validated. After obtaining ethical clearance and consent from participants, questionnaire was administered to students undergoing internship/6 th semester/4 th semester, post graduate residents and pharmacy students. Participants' knowledge was assessed based on the percentage of correct responses and the intergroup comparison was done by applying ANOVA test. Results: Overall, nearly half of the participants had poor knowledge about schedule H1. Sixth semester MBBS students had maximum knowledge followed by interns whereas pharmacy students, 4 th semester MBBS students and PG residents had poor knowledge about drug schedules. Conclusion: The study clearly highlights the need for further knowledge dissemination about drug schedules. We recommend that a capsule course be developed especially for post graduate residents and final year pharmacy students.

Identification and quantification of prescription errors.

BACKGROUND: Prescription errors are commonly encountered in health care settings. They can lead to inefficient delivery of health care thus jeopardizing patient care. Knowing the quantum and the possible causes of such errors is the first step in trying to prevent them. We conducted a random audit of prescriptions received in service dispensary of a tertiary care hospital and analyzed them for prescription errors. METHODS: A total of 1000 prescriptions were randomly selected. These prescriptions were analyzed with the help of three qualified pharmacists and were stratified as per the errors encountered. RESULTS: Out of the total of 1000 prescriptions, 650 prescriptions (65%) were found to have a total of 1012 errors. Type B errors were found in 22.4% prescriptions, type C errors in 9.7% prescriptions and type D in 69.1% prescriptions. CONCLUSION: Prescription errors require proactive, continuous and meticulous monitoring so as to minimize them. It requires identification of preventable causes, increasing awareness and sensitizing the prescriber towards this important aspect of health care delivery.

Greater concern about hypoglycemia in Type 2 diabetics is the need of the hour-findings from a prospective, single-center, observational study.

CONTEXT: Hypoglycemia is a well-recognized adverse effect in the treatment of type 1 diabetes mellitus. For patients of type 2 diabetes mellitus (T2DM) on stabilized treatment with the current oral antidiabetic drugs, occurrence of hypoglycemia is considerably less well studied. The current study was undertaken to understand the extent of this problem in elderly Indian patients. OBJECTIVES PRIMARY OBJECTIVE: Assessment of incidence of hypoglycemia in patients of T2DM on stable treatment. SECONDARY OBJECTIVES: 1. Estimation of incidence of episodes of severe hypoglycemia in patients. 2. Correlation of presence of hypoglycemia with treatment modality. SETTINGS AND DESIGN: This study was conducted as an open label, single-center observational study at a multispecialty tertiary care hospital. MATERIALS AND METHODS: The study participants consisted of 50 elderly confirmed patients of either gender suffering from T2DM undergoing treatment and follow-up in the hospital for at least 12 weeks. After a brief training session and enrolment, the patients were asked to report to study site every month for next 2 months. Parameters recorded were plasma glucose levels, HbA1c levels, treatment regimen, body mass index, possible hypoglycemic episode based on symptoms and self-monitoring of blood glucose, and quality of life based on questionnaire score. STATISTICAL ANALYSIS: Descriptive and other statistics were used to analyze the hypoglycemic episodes experienced by the patients for correlation with medicines and the effect of hypoglycemia on their quality of life. RESULTS: Total of nine hypoglycemic episodes were recorded. Severe hypoglycemia did not occur in any patient. Patient on insulin reported significantly more hypoglycemia. Quality of life is not much different in patients using insulin in T2DM.

Difference in described indications of medicines among drug information sources in India: An issue urgently to be addressed.

BACKGROUND: Drug information can be obtained from various sources such as National Formularies, drug package inserts (PI), other sources such as Monthly Index of Medical Specialities (MIMS), Current Index of Medical Specialities, and the information available with the regulators. Any variation in the information available in different sources can promote irrational drug use. In this study, we assessed this variation in a sample of commonly used drugs. MATERIALS AND METHODS: Fifty commonly used drugs were analyzed for any variation (both quantitative and qualitative) in information on indications as mentioned in commonly used drug information sources such as Central Drugs and Standards Control Organization (CDSCO) website, National Formulary of India (NFI), MIMS, and PI of medicines. RESULTS: We observed a variation in average number of indications per drugs given in CDSCO (2.2 ± 0.25), NFI (3.51 ± 0.42), MIMS (2.98 ± 0.29), and PI (3.18 ± 3.52). The CDSCO and NFI did not contain information about indication for 10 and 17 drugs, respectively, while MIMS and PI contained information about all the selected drugs. A subset analysis was done for 24 such drugs which were mentioned in all the four sources and it was found that NFI had listed the maximum number of indications per drug (3.79 ± 0.53), followed by PI (3.08 ± 0.44), MIMS (3.04 ± 0.51), and CDSCO website (2.66 ± 0.37) and this difference was found to be statistically significant (P = 0.02). We also observed some gross qualitative variation regarding drug information given in different sources. CONCLUSION: Variation exists in the quantity and quality of information available on indications about drugs available in various sources. Necessary steps need to be taken to harmonize drug information available across various sources so as to provide reliable and uniform drug information thereby promoting rational drug use.

The Tamiflu fiasco and lessons learnt.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for seasonal flu by US Food and Drug Administration in 1999. A number of randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile. Majority of them were funded by Roche, which also first marketed and promoted this drug. In 2005 and 2009, the looming fear of pandemic flu led to recommendation by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in treatment and prophylaxis of influenza, and it's stockpiling as a measure to tide over the crisis. Serious Adverse Events, especially neuropsychiatric events associated with Tamiflu started getting reported leading to a cascade of questions on clinical utility of this drug. A recent Cochrane review and related articles have questioned the risk-benefit ratio of the drug, besides raising doubts about the regulatory decision of approving it. The recommendations for stockpiling the said drug as given by various international organizations viz WHO have also been put to scrutiny. Although many reviewers have labeled the Tamiflu saga as a "costly mistake," the episode leaves us with some important lessons. This article takes a comprehensive relook on the subject, and we proceed to suggest some ways and means to avoid a similar situation in the future.

Compensation for clinical trial-related injury and death in India: challenges and the way forward.

Clinical research, including clinical trials, is the bedrock of evidence-based medicine and is the most reliable method of generating credible data. Over the last decade, India has been one of the preferred destinations for clinical research activities. However, a couple of trials generated widespread media coverage due to alleged ethical transgressions, which generated debate among various stakeholders and dented the overall image of clinical research activities in the country. One of the major issues which has emerged is of compensation to research participants for clinical trial-related injury or death. To address this question, the Government of India has come up with regulations regarding compensation for research participants. While these rules provide a robust framework for compensation, some concerns have been raised regarding interpretation and implementation of these guidelines. In this article, we have tried to raise some debatable issues that need to be addressed to bring more clarity to this subject. These issues need to be handled in a balanced manner so that they are able to address the concerns of all stakeholders. It is envisaged that once clarity emerges, confidence in the clinical research process will be restored.