J Psychopharmacol. 2024 Feb;38(2):127-136. doi: 10.1177/02698811231224171.

ABSTRACT

BACKGROUND: Medication adherence is a prerequisite to achieving beneficial treatment outcomes. In major depressive disorder, many patients fail to complete medication regimens, raising concern for poor treatment outcomes. It is usual to experience adverse drug reactions (ADRs) while taking antidepressants, and relative discomfort is reported by patients.

AIMS: The present review focuses on the presence of antidepressant-related side effects and the subsequent relationship with medication non-adherence.

METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Following the preliminary research, the research question and eligibility criteria were created based on the PICO framework. All articles retrieved from the selected databases were exported to Covidence, a Systematic Review managing software tool. Two reviewers assessed the papers to identify the risk of bias using the Joanna Briggs Institute critical appraisal tool for cross-sectional studies. Seven studies with a low-moderate risk of bias fulfilled the eligibility criteria and were conducted from 2013 to 2020 in Europe, Africa and Asia.

RESULTS: The results demonstrated high levels of suboptimal adherence ranging from 46% to 83% amongst the studied population. A variety of side effects were reported by a significant number of participants predominantly with moderate severity. A correlation between the presence of ADRs and suboptimal rates of adherence to antidepressants was found. Somnolence and headaches among other unspecified ADRs were found to increase the dropout rates for selective serotonin reuptake inhibitors.

CONCLUSIONS: The present study elucidates the need for effective interventions to facilitate antidepressant adherence and enhance doctor-patient communication, benefiting both the individuals and the healthcare system and leading to better clinical outcomes and reduction of relapse-related costs.

PMID:38344912 | PMC:PMC10863360 | DOI:10.1177/02698811231224171

Cureus. 2024 Jan 10;16(1):e52032. doi: 10.7759/cureus.52032. eCollection 2024 Jan.

ABSTRACT

Ocrelizumab is an anti-CD20 monoclonal antibody used to treat primary progressive and relapsing-remitting multiple sclerosis. Several prior case reports have demonstrated colitis in association with ocrelizumab infusion, and one case report has shown ocrelizumab-associated diverticulitis. We report on two cases in which ocrelizumab treatment of multiple sclerosis was complicated by acute diverticulitis. A 50-year-old woman and a 41-year-old man, both with relapsing-remitting multiple sclerosis, presented with acute abdominal pain. One patient had no known gastrointestinal history while the other had a history of laparoscopic sleeve gastrectomy. Both patients had received an ocrelizumab infusion one month prior to presentation. The woman underwent exploratory laparotomy, which revealed perforated sigmoid diverticulitis. The man was initially suspected of appendicitis and was treated with appendectomy, but a pathology review demonstrated diverticular disease in the appendix. In patients with multiple sclerosis on ocrelizumab, presentation with diverticulitis should include ocrelizumab-induced diverticulitis in the differential diagnosis.

PMID:38344628 | PMC:PMC10855644 | DOI:10.7759/cureus.52032

Ont Health Technol Assess Ser. 2024 Jan 11;24(2):1-162. eCollection 2024.

ABSTRACT

BACKGROUND: Pain is a common and very distressing symptom for adults and children with cancer. Compared with other routes of delivery, infusing pain medication directly into the intrathecal space around the spinal cord may reduce the incidence of systemic side effects and allow for more rapid and effective pain relief. We conducted a health technology assessment of intrathecal drug delivery systems (IDDSs) for adults and children with cancer pain, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding IDDSs, patient preferences and values, and ethical considerations.

METHODS: We performed a systematic literature search of the clinical evidence to retrieve systematic reviews, and we selected and reported results from 2 recent reviews that were relevant to our research questions. We complemented the chosen systematic reviews with a literature search to identify primary studies published after December 2020. We used the Risk of Bias in Systematic Reviews (ROBIS) tool to assess the risk of bias of each included systematic review. We assessed the quality of the body of evidence according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-effectiveness analysis comparing IDDSs with standard care (i.e., non-IDDS methods of pain management) from a public payer perspective. We also analyzed the budget impact of publicly funding IDDSs in Ontario. To contextualize the potential value of IDDSs, we spoke with patients with cancer pain and with caregivers of patients with cancer pain. We explored ethical considerations from a review of published literature on the use of IDDSs for the management of cancer pain in adults and children as well as a review of the other components of this health technology assessment to identify ethical considerations relevant to the Ontario context.

RESULTS: We included 2 systematic reviews (1 on adults and 1 on children) in the clinical evidence review. In adults with cancer pain who have a life expectancy greater than 6 months, intrathecal drug delivery was associated with a significant reduction in pain intensity compared with before implantation up to a 1-year follow-up (GRADE: Moderate to Low). Improved pain management appeared to be maintained beyond a 4-week follow-up. IDDSs likely decrease the use of systemic opioids (GRADE: Moderate to Low). They may also improve health-related quality of life (GRADE: Low), functional outcomes (GRADE: Low), and survival (GRADE: Low to Very low). In children with cancer pain, IDDSs may reduce pain intensity, improve functional outcomes, and improve survival, but the evidence is very uncertain (all GRADEs: Very low). IDDS implantation carries certain rare risks related to mechanical errors, drug-related side effects, and surgical complications. There are inherent limitations in conducting research in patients with refractory cancer pain; therefore, it is unlikely that higher-quality evidence will emerge in the next few years. Our primary economic evaluation found that IDDSs are more effective and more costly than standard care. The incremental cost-effectiveness ratio of IDDSs compared with standard care is $57,314 per quality-adjusted life-year (QALY) gained. The probability of IDDSs being cost-effective versus standard care is 43.46% at a willingness-to-pay of $50,000 per QALY gained and 72.54% at a willingness-to-pay of $100,000 per QALY gained. Publicly funding IDDSs in Ontario would cost an additional $0.27 million per year, for a total of $1.34 million over the next 5 years. The patients with cancer pain and caregivers with whom we spoke described the debilitating nature of cancer pain and the difficulty of finding effective pain management options. Patients with experience of an IDDS spoke of its effectiveness and its positive impact on their quality of life and mental health. Implementing IDDSs for patients with cancer pain raises several ethical and equity considerations related to the experiences and management of cancer pain, how limitations in evidence may entail uncertainties in clinical and health system decision-making, as well as clinical, geographic, and health system access barriers.

CONCLUSIONS: Intrathecal drug delivery likely reduces pain intensity and decreases the use of systemic opioids in adults with cancer pain who have a life expectancy greater than 6 months. It may also improve health-related quality of life, functional outcomes, and survival, although the evidence for survival is very uncertain. The clinical evidence in children with cancer pain is very uncertain. IDDS implantation is reasonably safe. Intrathecal drug delivery is more effective and more costly than standard care. We estimate that funding IDDSs in Ontario will result in additional costs of $0.27 million per year, for a total of $1.34 million over the next 5 years. Considerations related to funding and implementing IDDSs for patients with cancer pain in Ontario will require explicit and focused attention to considerations of equity and access in the diagnosis and management of cancer pain and in the use, clinical uptake, and delivery of IDDS pain management.

PMID:38344326 | PMC:PMC10855886

Am J Hematol. 2024 Feb 11. doi: 10.1002/ajh.27245. Online ahead of print.

ABSTRACT

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.

PMID:38343062 | DOI:10.1002/ajh.27245

J Coll Physicians Surg Pak. 2024 Feb;34(2):151-155. doi: 10.29271/jcpsp.2024.02.151.

ABSTRACT

OBJECTIVE: To determine the frequency of parenteral Acyclovir-induced Acute Kidney Injury (AKI) in patients with viral encephalitis.

STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Neurology, Liaquat National Hospital, Karachi, from January to December 2021.

METHODOLOGY: A total of 89 suspected and proven cases of encephalitis receiving IV Acyclovir were collated. All had extensive medical histories and underwent CSF studies with +/- brain imaging. CSF routine and viral PCR were done. Acyclovir-induced AKI was defined as a rise in serum creatinine of >0.3 mg/dl in 48 h or by ≥1.5 times the baseline value, and its severity was staged into 1 (risk), 2 (injury), and 3 (failure) according to the KDIGO guidelines (Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group, 2012). Patients' variables, including age, gender, presenting features, comorbid conditions, and CSF findings, were divided into two groups, i.e. with and without AKI.

RESULTS: This research included 89 patients with a mean age of 48 years. AKI occurred in 34 patients (38.2%). The frequency of AKI with Stage 1 was 24%, Stage 2 was 44%, and Stage 3 was 32%; approximately two-thirds of cases were in Stage 2 and 3 (p >0.05). Five patients (5.6%) from Stage 3, required dialysis.

CONCLUSION: AKI is an important adverse effect of parenteral acyclovir, which necessitates its early identification and timely management. Renal function monitoring is essential for patients on Acyclovir treatment as they are at risk for AKI.

KEY WORDS: Acyclovir, Acute kidney injury, Viral encephalitis, Creatinine, Kidney Disease Improving Global Outcomes.

PMID:38342863 | DOI:10.29271/jcpsp.2024.02.151

J Dig Dis. 2024 Feb 11. doi: 10.1111/1751-2980.13251. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions.

METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia.

RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed.

CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

PMID:38342693 | DOI:10.1111/1751-2980.13251

Lancet Oncol. 2024 Feb 8:S1470-2045(24)00004-4. doi: 10.1016/S1470-2045(24)00004-4. Online ahead of print.

ABSTRACT

BACKGROUND: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease.

METHODS: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032).

FINDINGS: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug.

INTERPRETATION: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer.

FUNDING: GTx.

PMID:38342115 | DOI:10.1016/S1470-2045(24)00004-4

Int J Mol Sci. 2024 Feb 2;25(3):1811. doi: 10.3390/ijms25031811.

ABSTRACT

Three-dimensional (3D) bioprinting is one of the most promising methodologies that are currently in development for the replacement of animal experiments. Bioprinting and most alternative technologies rely on animal-derived materials, which compromises the intent of animal welfare and results in the generation of chimeric systems of limited value. The current study therefore presents the first bioprinted liver model that is entirely void of animal-derived constituents. Initially, HuH-7 cells underwent adaptation to a chemically defined medium (CDM). The adapted cells exhibited high survival rates (85-92%) after cryopreservation in chemically defined freezing media, comparable to those preserved in standard medium (86-92%). Xeno-free bioink for 3D bioprinting yielded liver models with high relative cell viability (97-101%), akin to a Matrigel-based liver model (83-102%) after 15 days of culture. The established xeno-free model was used for toxicity testing of a marine biotoxin, okadaic acid (OA). In 2D culture, OA toxicity was virtually identical for cells cultured under standard conditions and in CDM. In the xeno-free bioprinted liver model, 3-fold higher concentrations of OA than in the respective monolayer culture were needed to induce cytotoxicity. In conclusion, this study describes for the first time the development of a xeno-free 3D bioprinted liver model and its applicability for research purposes.

PMID:38339088 | PMC:PMC10855587 | DOI:10.3390/ijms25031811

Sci Rep. 2024 Feb 8;14(1):3255. doi: 10.1038/s41598-024-53561-8.

ABSTRACT

Apart from the inequality in vaccination, war zones and areas where communication is disrupted are affected by myths and misconceptions about COVID-19 vaccines, heightening vaccine hesitancy. Local data on adverse events of the vaccines and their mildness can increase confidence and acceptance of the vaccines in the respective population. In areas of conflict and communication blackouts, the perception of the vaccines by health workers is of paramount importance as public health recommendations may not reach the public. Therefore, the scientific evaluation of adverse events following COVID-19 vaccination in such areas is invaluable. This cross-sectional, facility-based study was conducted using a structured, interviewer-administered questionnaire to assess the adverse events experienced by healthcare workers who received the Janssen COVID-19 vaccine. The sample was divided proportionally to the number of vaccinated healthcare workers for the different healthcare professions, and participants were then randomly selected from each profession. Prior to data collection, a pilot test was conducted with 5% of the sample size outside the selected hospital. The study was conducted using a structured questionnaire completed by an interviewer to assess adverse events in 442 healthcare workers who had received the Janssen COVID-19 vaccine between July 11 and 25, 2022. The study period was from August 15 to September 15, 2022. A significant number of healthcare workers [366 (83.3%); 95% CI 79.5%, 86.5%] experienced at least one adverse event. Nearly 90% of participants reported that the adverse events were mild to moderate. Pain at the injection site [307 (69.5%); 95% CI 65.0%, 73.6%] and headache [247 (55.9%); 95% CI 51.2%, 60.4%] were the most common local and systemic adverse events, respectively. Two HCWs experienced anaphylactic reaction. Younger age was significantly associated with the occurrence of adverse events. We deciphered that the adverse events reported by the study participants were not different from the typically occurring vaccine-related adverse reactions, and therefore concluded that post-vaccination reactions in healthcare workers were minor. Although vaccination in Tigray is currently stalled due to the siege, responsible stakeholders should develop a mechanism to track population-wide adverse events once the vaccines start to rollout.

PMID:38332047 | PMC:PMC10853211 | DOI:10.1038/s41598-024-53561-8

Altern Ther Health Med. 2024 Jan 31:AT10092. Online ahead of print.

ABSTRACT

OBJECTIVE: Acute pancreatitis (AP) is a process of acute inflammation and cell damage of the pancreas. Gallstones and alcohol abuse are the most common cause for AP. Drug-induced pancreatitis (DIP), accounting for less than 3% of the AP, has become increasingly recognized as an additional and vitally important etiology of acute pancreatitis. Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI)class that has a range of side effects even when used at the recommended dose. A recognized but rare association in teenagers is acute pancreatitis. The report is of a 15-year-old male teenager with a history of depression who developed acute pancreatitis following self-overdose of his sertraline prescription.

CASE REPORT: A 15-year-old teenager with an overdose of sertraline, which was the only medication he took, presented abdominal pain, nausea, and vomiting. The common causes of alcohol consumption, gallstones, biliary duct obstruction, malignancy, trauma, hypertriglyceridemia, and hypercalcemia were eliminated. The increased level of amylase and parenchymal edema of the pancreas revealed in computed tomography supported the diagnosis of acute pancreatitis. After discontinuation of the drug and conventional acute pancreatitis treatment, he recovered evenly.

CONCLUSION: With the increasing use of antidepressant medications in patients of teenagers, this report is a reminder that clinicians should be aware of the association between SSRIs such as sertraline, particularly in cases of overdose, and the development of acute pancreatitis.

PMID:38330584

Cureus. 2024 Feb 7;16(2):e53754. doi: 10.7759/cureus.53754. eCollection 2024 Feb.

ABSTRACT

Restless leg syndrome (RLS) is a chronic disorder characterized by a compulsive urge to move the legs, accompanied by various subjective symptoms and a distinctive nyctimeral pattern. A negligent entity is drug-induced RLS, which may be challenging to recognize by practitioners due to its rarity. Among various drugs that can induce or exacerbate RLS, metoclopramide is notable; however, the literature primarily describes cases related to its intravenous forms. In this case presentation, a 33-year-old male experienced drug-related gastrointestinal (GI) symptoms after starting semaglutide for weight loss. Semaglutide was discontinued, and oral metoclopramide was administered to manage the GI symptoms. Subsequently, he developed RLS-like symptoms, which resolved within 48 hours of stopping metoclopramide. His family history included chronic RLS. Laboratory tests were normal. The case highlights a potential link between drug administration and transient RLS symptoms. This case suggests that RLS can be a rare, reversible side effect of oral metoclopramide. It emphasizes the need for careful monitoring of RLS symptoms in patients using this drug and highlights the variability of side effects depending on the method of drug administration. The case serves as a reminder of the unpredictable nature of drug reactions and the importance of vigilance in pharmacotherapy.

PMID:38327722 | PMC:PMC10848601 | DOI:10.7759/cureus.53754

Drug Ther Bull. 2024 Feb 7:dtb-2024-000010. doi: 10.1136/dtb.2024.000010. Online ahead of print.

ABSTRACT

Overview of: Medicines and Healthcare products Regulatory Agency. Omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000 mg capsules): dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors. Drug Safety Update 2024;17(6):3.

PMID:38326011 | DOI:10.1136/dtb.2024.000010

Drug Ther Bull. 2024 Feb 7:dtb-2024-000011. doi: 10.1136/dtb.2024.000011. Online ahead of print.

ABSTRACT

Overview of: Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial [correction appears in Lancet 2023;402:850]. Lancet 2023;402:851-8.

PMID:38326010 | DOI:10.1136/dtb.2024.000011

Expert Opin Drug Saf. 2024 Feb 7. doi: 10.1080/14740338.2024.2315113. Online ahead of print.

ABSTRACT

Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations for the evaluation, treatment, and monitoring of anticancer DIILD were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared to analyze the consistency among documents. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements. The quality of AGREE II assessments differed greatly, both between domains of documents and between documents across domains. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents regarding specific recommendations for evaluation, treatment and, monitoring of anticancer DIILD, and further discussions among multidisciplinary experts are needed to reach an agreement. In particular, we have focused our concerns on the differences in steroid regimens, and future research is still needed on the risks of adverse events related to hormone therapy and discovery of precise biomarkers.

PMID:38323333 | DOI:10.1080/14740338.2024.2315113

Nature. 2024 Feb;626(7998):261. doi: 10.1038/d41586-024-00301-7.

NO ABSTRACT

PMID:38321136 | DOI:10.1038/d41586-024-00301-7

Elife. 2024 Feb 6;12:RP87318. doi: 10.7554/eLife.87318.

ABSTRACT

BACKGROUND: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused.

METHODS: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15-20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given.

RESULTS: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1-5.9; relative decline of 26% [range: 15-40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9-4.1; relative fall of 12% [range: 7-30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline.

CONCLUSIONS: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen.

FUNDING: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z).

CLINICAL TRIAL NUMBER: Thai Clinical Trial Registry: TCTR20170830002 and TCTR20220317004.

PMID:38319064 | DOI:10.7554/eLife.87318

Lab Chip. 2024 Feb 6. doi: 10.1039/d3lc00829k. Online ahead of print.

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death worldwide, casting a substantial economic footprint and burdening the global healthcare system. Historically, pre-clinical CVD modeling and therapeutic screening have been performed using animal models. Unfortunately, animal models oftentimes fail to adequately mimic human physiology, leading to a poor translation of therapeutics from pre-clinical trials to consumers. Even those that make it to market can be removed due to unforeseen side effects. As such, there exists a clinical, technological, and economical need for systems that faithfully capture human (patho)physiology for modeling CVD, assessing cardiotoxicity, and evaluating drug efficacy. Heart-on-a-chip (HoC) systems are a part of the broader organ-on-a-chip paradigm that leverages microfluidics, tissue engineering, microfabrication, electronics, and gene editing to create human-relevant models for studying disease, drug-induced side effects, and therapeutic efficacy. These compact systems can be capable of real-time measurements and on-demand characterization of tissue behavior and could revolutionize the drug development process. In this review, we highlight the key components that comprise a HoC system followed by a review of contemporary reports of their use in disease modeling, drug toxicity and efficacy assessment, and as part of multi-organ-on-a-chip platforms. We also discuss future perspectives and challenges facing the field, including a discussion on the role that standardization is expected to play in accelerating the widespread adoption of these platforms.

PMID:38318723 | DOI:10.1039/d3lc00829k

BMJ Case Rep. 2024 Feb 5;17(2):e256956. doi: 10.1136/bcr-2023-256956.

ABSTRACT

A large percentage of the US population is either receiving or should be considered for statin therapy. Whether through primary or secondary prevention for atherosclerotic disease, statins remain one of the mainstay options available to physicians. Myalgias are the most commonly reported side effects, though largely self-limited and subjective in nature. Here, we report a case of drug-related myonecrosis following long-term use of atorvastatin. Prompt recognition of the condition and initiation of treatment is paramount to control the disease's progression. While high-dose steroids are first line, quick escalation to methotrexate, IVIG or rituximab should be considered in refractory cases. This decision is guided by monitoring of serum markers such as CK and transaminases. The goal is quick normalisation of these enzymes, signalling cessation of underlying muscle necrosis. Patients may never regain full function and treatment can last months to years.

PMID:38316487 | PMC:PMC10859973 | DOI:10.1136/bcr-2023-256956

Int J Clin Pharm. 2024 Feb 5. doi: 10.1007/s11096-023-01697-4. Online ahead of print.

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is a multifactorial condition often induced by drugs commonly used in hospitals. Identifying and staging AKI necessitates frequent monitoring of renal function.

AIM: To assess the impact of real-world hospital practices regarding serum creatinine (SCr) testing on the identification and staging of AKI, and its implications for adjusting drug doses.

METHOD: A historical cohort study utilizing hospital records from all adult patients admitted between 01/06/2018 and 31/12/2020 was conducted. Patients with no SCr assessment during their stay or those with an SCr at admission ≥ 2 mg/dL were excluded. AKI was determined using two criteria, namely AKIN and KDIGO, considering the time intervals between two SCr tests as outlined in the criteria. Additionally, patients with SCr increases exceeding AKI limits, regardless the time interval, were also identified. The estimated glomerular filtration rate (eGFR) and kinetic eGFR (KeGFR) were calculated.

RESULTS: During the study period, 17,269 hospitalizations and 62,255 SCr tests were recorded. Among the 17,032 hospitalizations with a length of stay > 48 h, 46.8% experienced periods with no SCr tests performed for more than 48 h. Any stage of AKI was identified in 7.0% of patients and in 9.1% using AKI and KDIGO criteria, respectively. Ignoring time limits in both criteria revealed potential AKI in 1942 patients (11.2%), indicating a potential underdiagnosis of AKI by 37.5% or 19.1%, depending on the criteria used. A total of 76 drugs requiring dose adjustment in patients with eGFR ≤ 50 ml/min were prescribed in 78.5% admissions. These drugs were prescribed in 87.9% of patients potentially underdiagnosed with AKIN and in 88.9% with KDIGO.

CONCLUSION: There is a need for changes in the established hospital procedures to ensure more frequent testing of SCr levels. Implementing an advanced scope of practice for clinical pharmacists could support these changes.

PMID:38315304 | DOI:10.1007/s11096-023-01697-4

Drug Des Devel Ther. 2024 Jan 30;18:165-192. doi: 10.2147/DDDT.S445555. eCollection 2024.

ABSTRACT

Cardiovascular diseases (CVDs) are the most common cause of death worldwide and has been the focus of research in the medical community. Curcumin is a polyphenolic compound extracted from the root of turmeric. Curcumin has been shown to have a variety of pharmacological properties over the past decades. Curcumin can significantly protect cardiomyocyte injury after ischemia and hypoxia, inhibit myocardial hypertrophy and fibrosis, improve ventricular remodeling, reduce drug-induced myocardial injury, improve diabetic cardiomyopathy(DCM), alleviate vascular endothelial dysfunction, inhibit foam cell formation, and reduce vascular smooth muscle cells(VSMCs) proliferation. Clinical studies have shown that curcumin has a protective effect on blood vessels. Toxicological studies have shown that curcumin is safe. But high doses of curcumin also have some side effects, such as liver damage and defects in embryonic heart development. This article reviews the mechanism of curcumin intervention on CVDs in recent years, in order to provide reference for the development of new drugs in the future.

PMID:38312990 | PMC:PMC10838105 | DOI:10.2147/DDDT.S445555