Anal Bioanal Chem. 2024 Aug 10. doi: 10.1007/s00216-024-05477-5. Online ahead of print.

ABSTRACT

Understanding the relationship between the concentration of a drug and its therapeutic efficacy or side effects is crucial in drug development, especially to understand therapeutic efficacy in central nervous system drug, quantifying drug-induced site-specific changes in the levels of endogenous metabolites, such as neurotransmitters. In recent times, evaluation of quantitative distribution of drugs and endogenous metabolites using matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry imaging (MSI) has attracted much attention in drug discovery research. However, MALDI-MSI quantification (quantitative mass spectrometry imaging, QMSI) is an emerging technique, and needs to be further developed for practicable and convenient use in drug discovery research. In this study, we developed a reliable QMSI method for quantification of clozapine (antipsychotic drug) and dopamine and its metabolites in the rat brain using MALDI-MSI. An improved mimetic tissue model using powdered frozen tissue for QMSI was established as an alternative method, enabling the accurate quantification of clozapine levels in the rat brain. Furthermore, we used the improved method to evaluate drug-induced fluctuations in the concentrations of dopamine and its metabolites. This method can quantitatively evaluate drug localization in the brain and drug-induced changes in the concentration of endogenous metabolites, demonstrating the usefulness of QMSI.

PMID:39126505 | DOI:10.1007/s00216-024-05477-5

J Am Heart Assoc. 2024 Aug 20;13(16):e033615. doi: 10.1161/JAHA.123.033615. Epub 2024 Aug 9.

ABSTRACT

BACKGROUND: Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline-directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication-related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication-related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action.

METHODS AND RESULTS: The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time-limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient-physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators.

CONCLUSIONS: This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.

PMID:39119934 | DOI:10.1161/JAHA.123.033615

Drug Ther Bull. 2024 Aug 8:dtb-2024-000049. doi: 10.1136/dtb.2024.000049. Online ahead of print.

NO ABSTRACT

PMID:39122358 | DOI:10.1136/dtb.2024.000049

Clin Transl Sci. 2024 Aug;17(8):e13896. doi: 10.1111/cts.13896.

ABSTRACT

Ruzotolimod (Toll-like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno-modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug-related adverse events of flu-like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu-like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC-suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu-like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu-like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN-α, neopterin, IP-10, and the transcriptional expression of ISG15, OAS-1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu-like symptoms occurrence increases with PD responses (IFN-α and IP-10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug-related flu-like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu-like symptoms.

PMID:39119977 | DOI:10.1111/cts.13896

Hum Vaccin Immunother. 2024 Dec 31;20(1):2383504. doi: 10.1080/21645515.2024.2383504. Epub 2024 Aug 8.

ABSTRACT

The Ad26.RSV.preF/RSV preF protein vaccine has previously demonstrated efficacyin protecting older adults against respiratory syncytial virus (RSV)-related lower respiratory tract disease in a phase 2b study. This study compared the immunogenicity of vaccine clinical trial material (CTM) representative of phase 2b clinical studies with CTM used in phase 3 clinical studies. A total of 248 adults aged 60-75 years, randomized in a 1:1 ratio, received one dose of either phase 3 CTM or phase 2b CTM. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-d, 28-d, and 6-month periods post-vaccination, respectively. RSV preF-ELISA antibody titers and RSV neutralizing titers were measured before and 14 d after vaccination. The phase 3 CTM-induced preF-ELISA response at Day 15, in terms of geometric mean titer, was shown to be non-inferior to that induced by phase 2b CTM. The RSV neutralizing antibody titers were also similar in the two groups at Day 15. The safety profile in terms of solicited AEs, unsolicited AEs, or SAEs was in general similar between the phase 3 CTM and phase 2b CTM groups, and solicited AEs were mostly mild to moderate in intensity. No related SAEs were reported, and no safety concerns were identified.

PMID:39118413 | DOI:10.1080/21645515.2024.2383504

Lancet Oncol. 2024 Aug 5:S1470-2045(24)00380-2. doi: 10.1016/S1470-2045(24)00380-2. Online ahead of print.

ABSTRACT

BACKGROUND: Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer.

METHODS: DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting).

FINDINGS: Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5).

INTERPRETATION: The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both.

FUNDING: Daiichi Sankyo and AstraZeneca.

PMID:39116902 | DOI:10.1016/S1470-2045(24)00380-2

Clin Case Rep. 2024 Aug 7;12(8):e9244. doi: 10.1002/ccr3.9244. eCollection 2024 Aug.

ABSTRACT

CLINICAL KEY MESSAGE: In patients receiving anti-TNF-α drugs for ankylosing spondylitis, monitoring purpuric and ischemic skin lesions is crucial. This case underscores the significance of identifying and addressing drug-induced vasculitis while stressing the necessity for prompt evaluation and exploration of alternative treatment options to safeguard patient well-being.

ABSTRACT: The case discusses a 38-year-old female with a history of ankylosing spondylitis (AS) who presented with skin lesions, including purpuric skin lesions and ischemia of her right foot digits, after initiating treatment with adalimumab. After excluding other potential causes, such as infections and malignancies, the patient received a diagnosis of moderate-sized vascular vasculitis associated with adalimumab use. Discontinuation of adalimumab and treatment with high dose glucocorticoids and intravenous pulse of cyclophosphamide resulted in the resolution of her ischemic lesions. This case underscores the importance of considering drug-related side effects in patients with new skin lesions, particularly in the context of rheumatic diseases such as AS.

PMID:39114836 | PMC:PMC11305868 | DOI:10.1002/ccr3.9244

Psychiatry Investig. 2024 Aug 8. doi: 10.30773/pi.2023.0417. Online ahead of print.

ABSTRACT

OBJECTIVE: Extrapyramidal symptoms (EPS) are common side effects of antipsychotic drugs. Despite the growing interest in exploring objective biomarkers for EPS prevention and the potential use of voice in detecting clinical disorders, no studies have demonstrated the relationships between vocal changes and EPS. Therefore, we aimed to determine the associations between voice changes and antipsychotic dosage, and further investigated whether speech characteristics could be used as predictors of EPS.

METHODS: Forty-two patients receiving or expected to receive antipsychotic drugs were recruited. Drug-induced parkinsonism of EPS was evaluated using the Simpson-Angus Scale (SAS). Participants' voice data consisted of 16 neutral sentences and 2 second-long /Ah/utterances. Thirteen voice features were extracted from the obtained voice data. Each voice feature was compared between groups categorized based on SAS total score of below and above "0.6." The associations between antipsychotic dosage and voice characteristics were examined, and vocal trait variations according to the presence of EPS were explored.

RESULTS: Significant associations were observed between specific vocal characteristics and antipsychotic dosage across both datasets of 1-16 sentences and /Ah/utterances. Notably, Mel-Frequency Cepstral Coefficients (MFCC) exhibited noteworthy variations in response to the presence of EPS. Specifically, among the 13 MFCC coefficients, MFCC1 (t=-4.47, p<0.001), MFCC8 (t=-4.49, p<0.001), and MFCC12 (t=-2.21, p=0.029) showed significant group differences in the overall statistical values.

CONCLUSION: Our results suggest that MFCC may serve as a predictor of detecting drug-induced parkinsonism of EPS. Further research should address potential confounding factors impacting the relationship between MFCC and antipsychotic dosage, possibly improving EPS detection and reducing antipsychotic medication side effects.

PMID:39111750 | DOI:10.30773/pi.2023.0417

Heliyon. 2024 Jul 6;10(14):e34241. doi: 10.1016/j.heliyon.2024.e34241. eCollection 2024 Jul 30.

ABSTRACT

BACKGROUND: This report describes a case of bilateral transient myopia with a shallow anterior chamber and ciliochoroidal detachment following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and indapamide intake.

CASE PRESENTATION: A 37-year-old man with coronavirus disease 2019 (COVID-19) was referred to our department due to bilateral blurred vision. The patient had been treated with ibuprofen for fever and indapamide for uncontrolled blood pressure. After four days of indapamide intake, the patient complained of bilateral visual blurring. On ocular examination, his uncorrected visual acuity was 20/400 in both eyes. Slit-lamp examination revealed shallow anterior chambers. The following day, the patient experienced pain and redness in both eyes, which began the previous night. Ocular examination revealed a significant decrease in intraocular pressure (IOP) compared to the previous day: 11 mmHg and 12 mmHg in the right eye (OD) and left eye (OS), respectively. Slit-lamp examination revealed conjunctival injection and the presence of inflammatory cells (2+) in the shallow anterior chambers of both eyes. Ultrasound biomicroscopy revealed ciliary body detachment and B-scan ultrasonography showed peripheral shallow choroidal detachment in both eyes. Discontinuing indapamide and initiating treatment with oral prednisolone, topical tobramycin dexamethasone and tropicamide phenylephrine eye drops resulted in the rapid recovery of signs and symptoms after three days.

DISCUSSION AND CONCLUSIONS: Indapamide intake may contribute to bilateral ciliochoroidal detachment, with SARS-CoV-2 infection possibly increasing susceptibility to drug-induced side effects. Timely drug withdrawal and symptomatic treatment can result in a good prognosis.

PMID:39108852 | PMC:PMC11301209 | DOI:10.1016/j.heliyon.2024.e34241

Front Pharmacol. 2024 Jul 23;15:1440681. doi: 10.3389/fphar.2024.1440681. eCollection 2024.

ABSTRACT

INTRODUCTION: Depressive spectrum disorders are common and can hinder breastfeeding success. While medications typically pose minimal risk, the concerns persist. This is the first study that investigates the prevalence and characteristics of drug-related problems among breastfeeding mothers with depressive spectrum disorders. We analyzed those problems to understand their nature, severity, and contributing factors. Additionally, we evaluated the outcomes of pharmacist-led interventions in reducing them. Understanding drug-related problems is crucial for informing evidence-based practices to optimize both maternal mental health and breastfeeding success.

MATERIALS AND METHODS: This prospective observational study was conducted at a specialized pharmacy office in Poznan, Poland, which focuses on lactation support and medication consultations. 47 breastfeeding patients were enrolled. Pharmaceutical consultations were conducted according to Joint Commission of Pharmacy Practitioners Pharmacists' Patient Care Process standards. Novel MILC Questionnaire was used for efficient and optimal pharmaceutical interview. Drug-related problems were assessed basing on PCNE Classification System version 9.1. For adverse events in lactation, MedDRA v27 nomenclature was used; for causality, Naranjo Scale and LCAT were utilized. CTCAE was used for grading.

RESULTS: Among the 47 patients, pharmacist identified 49 medication-related problems, with inadequate treatment effect due to underdosing or not taking the medication at all being the most common (57.1%). Pharmacist interventions focused on medication safety information and counseling. Overall, 78.7% of patients accepted these interventions, resulting in problem resolution for 71.4%. Twelve mothers (25.5%) reported adverse events in their infants, but after causality evaluation, only four (8.5%) might have been linked to maternal medication. None required medical intervention beyond one hospitalization for a serious adverse event possibly connected to maternal medication.

CONCLUSION: The study identified high rates of drug-related problems among breastfeeding mothers with depression, primarily due to non-adherence. Pharmacist interventions significantly improved DRP outcomes. Adverse events were reported, but most were mild and did not require intervention. Our findings suggest that lactating mothers with depressive spectrum disorders may benefit from pharmacist-led support to optimize treatment adherence and address medication safety concern.

PMID:39108757 | PMC:PMC11300373 | DOI:10.3389/fphar.2024.1440681

Kobe J Med Sci. 2024 Jul 25;70(3):E81-E88. doi: 10.24546/0100490464.

ABSTRACT

BACKGROUNDS: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization.

METHODS: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups.

RESULTS: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group (p < 0.05). However, discontinuations due to frailty increased (p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease (p = 0.273).

CONCLUSIONS: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

PMID:39107964 | DOI:10.24546/0100490464

Antimicrob Agents Chemother. 2024 Aug 6:e0045824. doi: 10.1128/aac.00458-24. Online ahead of print.

ABSTRACT

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t½ of 73 hours. The t½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t½, supporting further clinical investigation of islatravir administered at an extended dosing interval.

PMID:39105584 | DOI:10.1128/aac.00458-24

Toxicol Rep. 2024 Jul 8;13:101691. doi: 10.1016/j.toxrep.2024.101691. eCollection 2024 Dec.

ABSTRACT

Risperidone is useful for the treatment of schizophrenia symptoms; however, it also has side effects, and an overdose can be harmful. The metabolic effects of risperidone at high therapeutic doses and its metabolites have not been elucidated. Endogenous cellular metabolites may be comprehensively analyzed using untargeted metabolomics-based liquid chromatography-mass spectrometry (LC-MS), which can reveal changes in cell regulation and metabolic pathways. By identifying the metabolites and pathway changes using a nontargeted metabolomics-based LC-MS approach, we aimed to shed light on the potential toxicological effects of high-dose risperidone on brain microvascular endothelial cells (MVECs) associated with the human blood brain barrier. A total of 42 metabolites were selected as significant putative metabolites of the toxicological response of high-dose risperidone in MVECs. Six highly correlated pathways were identified, including those involving diacylglycerol, fatty acid, ceramide, glycerophospholipid, amino acid, and tricarboxylic acid metabolism. We demonstrated that methods focused on metabolomics are useful for identifying metabolites that may be used to clarify the mechanism of drug-induced toxicity.

PMID:39104367 | PMC:PMC11299597 | DOI:10.1016/j.toxrep.2024.101691

JAMA Netw Open. 2024 Aug 1;7(8):e2425822. doi: 10.1001/jamanetworkopen.2024.25822.

ABSTRACT

IMPORTANCE: Use of herbal and dietary supplements (HDSs) accounts for an increasing proportion of drug hepatotoxicity cases. Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals, but their prevalence and reasons for use in the general population are unknown.

OBJECTIVE: To assess the prevalence and clinical characteristics of adult consumers of 6 potentially hepatoxic botanicals.

DESIGN, SETTING, AND PARTICIPANTS: This survey study analyzed nationally representative data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative, cross-sectional survey of the general US population. Prescription drug and HDS exposure data in the past 30 days were analyzed, and 2020 US Census data were used for population estimates. Data were analyzed July 1, 2023, to February 1, 2024.

EXPOSURES: Adult NHANES participants enrolled between January 2017 and March 2020.

MAIN OUTCOMES AND MEASURES: Baseline weighted characteristics of HDS users and users of 6 potentially hepatotoxic botanical products were compared with non-HDS users. Multivariable analysis was undertaken to identify factors associated with HDS use or at-risk botanical use.

RESULTS: Among 9685 adults enrolled in this NHANES cohort, the mean (SE) age was 47.5 (0.5) years, and 51.8% (95% CI, 50.2%-53.4%) were female. The overall prevalence of HDS product use was 57.6% (95% CI, 55.9%-59.4%), while the prevalence of using the 6 botanicals of interest was 4.7% (95% CI, 3.9%-5.7%). Turmeric-containing botanicals were most commonly used (n = 236), followed by products containing green tea (n = 92), ashwagandha (n = 28), Garcinia cambogia (n = 20), red yeast rice (n = 20), and black cohosh (n = 19). Consumers of these 6 botanicals were significantly older (adjusted odds ratio [AOR], 2.36 [95% CI, 1.06-5.25]; P = .04 for 40-59 years of age and AOR, 3.96 [95% CI, 1.93-8.11]; P = .001 for ≥60 years of age), had a higher educational level (AOR, 4.78 [95% CI, 2.62-8.75]; P < .001), and were more likely to have arthritis (AOR, 2.27 [95% CI, 1.62-3.29]; P < .001) compared with non-HDS users. An estimated 15 584 599 (95% CI, 13 047 571-18 648 801) US adults used at least 1 of the 6 botanical products within the past 30 days, which was similar to the estimated number of patients prescribed potentially hepatotoxic drugs, including simvastatin (14 036 024 [95% CI, 11 202 460-17 594 452]) and nonsteroidal anti-inflammatory drugs (14 793 837 [95% CI, 13 014 623-16 671 897]). The most common reason for consuming turmeric and green tea was to improve or maintain health.

CONCLUSIONS AND RELEVANCE: In this survey study, an estimated 15.6 million US adults consumed at least 1 botanical product with liver liability within the past 30 days, comparable with the number of people who consumed nonsteroidal anti-inflammatory drugs and a commonly prescribed hypolipidemic drug. Given a lack of regulatory oversight on the manufacturing and testing of botanical products, clinicians should be aware of possible adverse events from consumption of these largely unregulated products.

PMID:39102266 | DOI:10.1001/jamanetworkopen.2024.25822

Cureus. 2024 Jul 4;16(7):e63862. doi: 10.7759/cureus.63862. eCollection 2024 Jul.

ABSTRACT

Antineoplastic agents are often associated with a wide range of side effects, caused by either direct toxicity or indirect through their metabolism. Ifosfamide is a cytotoxic, antineoplastic medication that is known to cause a direct tubular injury with an associated normal anion gap metabolic acidosis due to type 1 or type 2 renal tubular acidosis (RTA). The manifestations and approach to its diagnosis have been well established. However, we present a case in which a patient presented with acute symptomatic hypokalemia in the setting of ongoing ifosfamide use for metastatic osteosarcoma but without the typical laboratory findings. The clinical- and laboratory-driven diagnosis of suspected type 3 renal tubular acidosis involving proximal and distal segments is suggested by this case report.

PMID:39100050 | PMC:PMC11297693 | DOI:10.7759/cureus.63862

Cureus. 2024 Jul 3;16(7):e63763. doi: 10.7759/cureus.63763. eCollection 2024 Jul.

ABSTRACT

Atrial fibrillation (AF) is the most common long-term arrhythmia in adults. Rhythm control in patients with AF involves efforts to restore and maintain sinus rhythm and is accomplished by medication, catheter ablation, or electrical cardioversion. Amiodarone represents one of the most commonly used antiarrhythmic medications. Prolonged use of amiodarone can lead to many side effects. One of the most severe side effects is drug-induced long QT syndrome (LQTS), which can cause malignant arrhythmias and sudden cardiac death. We presented a case of a 52-year-old male who was admitted to the Coronary Unit due to first diagnosed AF with a rapid ventricular response. After amiodarone infusion was administrated the patient lost consciousness and the monitor displayed torsades de pointes (TdP) ventricular tachycardia with rapid conversion to ventricular fibrillation (VF). Cardiac resuscitation with two direct current (DC) shocks was performed. The patient was stabilized, and restoration of sinus rhythm with significant QT prolongation on the ECG was noted. This is a rare case of short-term amiodarone administration causing LQTS, TdP, and VF. The findings or observations emphasize the significance of diligent ECG monitoring during amiodarone treatment.

PMID:39099957 | PMC:PMC11296664 | DOI:10.7759/cureus.63763

Sex Transm Infect. 2024 Aug 3:sextrans-2024-056208. doi: 10.1136/sextrans-2024-056208. Online ahead of print.

ABSTRACT

OBJECTIVES: This systematic review aimed to identify the efficacy, adherence, safety and impact on antimicrobial resistance of postexposure prophylaxis with doxycycline (Doxy-PEP) in different populations.

METHODS: We searched MEDLINE (via PubMed), Embase and Cochrane CENTRAL databases from inception to 29 May 2024. Two reviewers independently screened the studies and extracted data. We included randomised clinical trials that evaluated the efficacy of Doxy-PEP within 72 hours after condomless sex. A random-effects meta-analysis was conducted to compare the risk of bacterial sexually transmitted infections (STIs) between Doxy-PEP and no prophylaxis. The risk of bias was assessed with the risk-of-bias tool for randomized trials (RoB 2) and the certainty of evidence (CoE) with Grading of Recommendations Assessment, Development and Evaluation (GRADE).

RESULTS: Four studies were included in the systematic review, totalling 1727 participants. Studies were conducted between 2015 and 2022. Most participants (73%) were men who have sex with men, and the median age of participants varied from 24 to 43 years. Doxy-PEP reduced the risk of having any bacterial STI in different populations by 46% (hazard ratio (HR) 0.54; 95% CI 0.39 to 0.75; CoE moderate), the risk of chlamydia by 65% (relative risk (RR) 0.35; 95% CI 0.15 to 0.82; CoE low) and syphilis by 77% (RR 0.23; 95% CI 0.13 to 0.41; CoE high), without significant effect for risk of gonorrhoea infection (RR 0.90; 95% CI 0.64 to 1.26; CoE very low). The self-reported adherence rate of Doxy-PEP was approximately 80% and one drug-related serious adverse event was reported.

CONCLUSION: Doxy-PEP reduced the incidence of chlamydia and syphilis infections. No significant reduction in gonorrhoea infection was observed. This strategy seems promising for some high-risk groups; however, there is still a lack of information on the induction of bacterial resistance and long-term adverse events. PROSPERO REGISTRATION NUMBER.

PMID:39097410 | DOI:10.1136/sextrans-2024-056208

Drug Ther Bull. 2024 Aug 3:dtb-2024-000044. doi: 10.1136/dtb.2024.000044. Online ahead of print.

NO ABSTRACT

PMID:39097399 | DOI:10.1136/dtb.2024.000044

Cell Stem Cell. 2024 Aug 1;31(8):1095-1096. doi: 10.1016/j.stem.2024.06.013.

ABSTRACT

Mitrofanova et al.1 engineer a human colonic in vitro model capable of producing an intestinal mucus barrier, with potential applications for predicting drug-induced gastrointestinal toxicity. This improved system paves the way for more accurate and efficient drug development processes.

PMID:39094538 | DOI:10.1016/j.stem.2024.06.013

J Antimicrob Chemother. 2024 Aug 2:dkae254. doi: 10.1093/jac/dkae254. Online ahead of print.

ABSTRACT

BACKGROUND: Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered.

METHODS: We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a β-lactam/β-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21-28), and late follow-up (LFU; Days 35-42).

RESULTS: A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality.

CONCLUSIONS: Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered.

PMID:39092963 | DOI:10.1093/jac/dkae254