HCA Healthc J Med. 2023 Oct 30;4(5):383-387. doi: 10.36518/2689-0216.1400. eCollection 2023.

ABSTRACT

INTRODUCTION: Fluoroquinolones, a class of antibiotics, are commonly employed in the treatment of a wide array of bacterial infections. Recognized for their effectiveness against a broad spectrum of pathogens, fluoroquinolones have played a pivotal role in managing conditions like urinary tract infections and respiratory diseases. Nevertheless, their usage is not without contention due to their association with a variety of adverse effects, including tendon rupture and the less frequently reported issue of peripheral neuropathy.

CASE PRESENTATION: We present the case of a 42-year-old male who developed peripheral neuropathy several days after completing a 10-day course of ciprofloxacin for gastroenteritis. The patient's presenting complaint was bilateral upper and lower extremity weakness for which inpatient treatment was initiated and workup for other causes was negative. Nerve conduction studies (NCS) and electromyography (EMG) demonstrated peripheral neuropathy. The patient was treated with intravenous immunoglobulin (IVIG), steroids, and physical therapy. Followup NCS and EMG showed continued neuropathy but with significant improvement.

CONCLUSION: The case aligns with existing research, demonstrating that fluoroquinolone use is linked to peripheral neuropathy, particularly axonal polyneuropathy, and emphasizes the importance of investigating the underlying mechanism for improved therapeutic strategies. The potential combination of intravenous immunoglobulin and physical therapy has exhibited promising results.

PMID:37969850 | PMC:PMC10635701 | DOI:10.36518/2689-0216.1400

J Res Pharm Pract. 2023 Aug 29;11(4):136-143. doi: 10.4103/jrpp.jrpp_42_22. eCollection 2022 Oct-Dec.

ABSTRACT

OBJECTIVE: The current study aims to investigate high- versus low-dose dexamethasone administration to control the disease with minor complications.

METHODS: The current multicentric randomized clinical trial was conducted on 119 patients with COVID-19 pneumonia and assigned into two groups of low-dose (8 mg daily intravenous dose for at least 7 days or until discharge) (n = 61) versus high-dose dexamethasone (24 mg for 3 days followed by daily 8 mg for the at least 4 days later or until discharge) (n = 58) during 2020-2021. Oxygen saturation, dyspnea severity based on the Borg scale, and laboratory indices were assessed at 3, 5, and 7 days of corticosteroid therapy. Patients were compared regarding the length of hospitalization, intensive care unit (ICU) admission requirement, and noninvasive or invasive ventilation. The other investigations included corticosteroid-related adverse effects and mortality rates within a month after the medications.

FINDINGS: Oxygen saturation, Borg scale, and C-reactive protein levels were significantly altered by the time in both the groups (P < 0.05). In contrast, the trend of improvements in Borg scale (P = 0.007) and lactate dehydrogenase levels (P = 0.034) were superior in high-dose treated cases. Drug-related adverse (P = 0.809), mortality rate (P = 0.612), hospitalization duration (P = 0.312), ICU admission requirement (P = 0.483), and noninvasive (P = 0.396) and invasive ventilation (P = 0.420) did not differ between the groups.

CONCLUSION: According to this study, low- versus high-dose dexamethasone therapy did not affect the outcomes, so low-dose dexamethasone is recommended for COVID-19 pneumonia to achieve optimal results and prevent potential adverse events.

PMID:37969616 | PMC:PMC10642588 | DOI:10.4103/jrpp.jrpp_42_22

J Korean Med Sci. 2023 Nov 13;38(44):e346. doi: 10.3346/jkms.2023.38.e346.

ABSTRACT

BACKGROUND: Remdesivir is a US Food and Drug Administration-approved drug for coronavirus disease 2019 (COVID-19). Clinical trials were conducted under strictly controlled situations for a selected population, and their reported adverse events may not fully represent conditions in real-world patients. We aimed to estimate the incidence of adverse drug events (ADEs) associated with remdesivir in hospitalized patients with COVID-19, including vulnerable subpopulations, such as those with impaired renal or hepatic function and pregnant women.

METHODS: This retrospective observational study included hospitalized patients with confirmed COVID-19 treated with remdesivir between January and December 2021 at ten hospitals. ADEs and severe ADEs (Common Toxicity Criteria for Adverse Events grade ≥ 3) were operationally defined and analyzed through laboratory investigations. The incidence of ADEs was compared with that of each matched control in subpopulations with renal or hepatic impairment and pregnant women.

RESULTS: Among 2,140 patients, 1,416 (66.2%) and 295 (13.8%) experienced at least one ADE and severe ADE, respectively. The most frequent ADE was 'hepatic injury' (42.9%), followed by anemia (27.6%). The most common severe ADEs were 'hypokalemia' (5.3%), 'hepatic injury' (2.9%), and 'anemia' (3.6%). There was no significant difference in the incidence of ADEs in patients relative to their respective matched-control groups, including those with renal impairment (80.0% vs. control 71.8%, P = 0.063), hepatic impairment (70.4% vs. control 75.0%, P = 0.623) and pregnant women (78.6% vs. control 63.7%, P = 0.067). However, severe ADE incidence was significantly higher in patients with renal impairment (40.8% vs. 16.0%, P < 0.001). The most common severe ADEs in those were 'anemia' (15.3%), 'hypokalemia' (10.5%), and 'thrombocytopenia' (8.9%). There was no statistically significant difference in the incidence of severe ADEs in patients with hepatic impairment or in pregnancy (P = 0.230; P = 0.085).

CONCLUSION: A significant proportion of patients with COVID-19 treated with remdesivir experienced ADEs and severe ADEs. Given the high incidence of severe ADEs, caution is required in patients with renal impairment. Further studies are needed to investigate ADEs in pregnant women and patients with hepatic impairment.

PMID:37967875 | PMC:PMC10643246 | DOI:10.3346/jkms.2023.38.e346

J Child Adolesc Psychopharmacol. 2023 Nov;33(9):344-355. doi: 10.1089/cap.2023.0054.

ABSTRACT

Objective: Attention-deficit/hyperactivity disorder (ADHD) treatment with stimulant products has been shown to be safe and effective; however, there are remaining concerns about their possible adverse effects on growth trajectories. We conducted a systematic review of the extant literature derived from ecologically valid databases and registries to assess the body of knowledge about the effects of stimulants on growth trajectories in naturalistic samples. Methods: Using PubMed and PsycINFO, we searched for articles published before February 8, 2023 that focused on growth findings associated with stimulant treatment in pediatric ADHD from comprehensive datasets derived from naturalistic population studies. Results: Of the 1070 articles initially identified, 12 met all inclusion criteria. Sample sizes ranged from 157 to 163,820 youths. Seven of 10 articles examining height found significant decreases in height associated with chronic stimulant treatment that normalized over time in 2 studies. Three articles found no significant association between stimulant treatment and height. No clear associations were identified between cumulative duration and dose of stimulant treatment and adult height. All articles examining weight and six of eight articles examining body mass index (BMI) found significant initial decreases that tended to normalize then increase over time. Longer duration of stimulant medication use was predominantly associated with significant weight and BMI reductions. The effects of stimulant dose on weight and BMI were mostly weak and clinically insignificant. Most studies found no significant association between age at start of stimulant treatment and change in height, weight, or BMI. Most studies did not find significant sex effects in relation to growth parameters. Conclusions: This review of ecologically informative samples revealed that the effects of stimulant treatment on growth trajectories are mainly small and transient. These effects seem to be clinically insignificant for most youth with ADHD who receive stimulant treatment from childhood onto adolescence and adulthood.

PMID:37966364 | DOI:10.1089/cap.2023.0054

EClinicalMedicine. 2023 Nov 1;65:102305. doi: 10.1016/j.eclinm.2023.102305. eCollection 2023 Nov.

ABSTRACT

BACKGROUND: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA).

METHODS: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18-74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4-25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0-2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants.

FINDINGS: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI -0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths.

INTERPRETATION: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns.

FUNDING: Southern Medical University and Nanfang Hospital.

PMID:37965431 | PMC:PMC10641480 | DOI:10.1016/j.eclinm.2023.102305

Int J Mol Sci. 2023 Nov 5;24(21):15976. doi: 10.3390/ijms242115976.

ABSTRACT

The use of natural compounds and, in general, the use of Complementary and Alternative Medicine (CAM), is growing steadily worldwide, both due to commercial pressure and the increasing use of self-medication and the desire to manage one's own personal health and well-being. Patients facing a cancer diagnosis are also strongly pressured to use these compounds, which are often added to standard therapeutic regimens, that should instead be based solely on diagnostic and therapeutic care pathways (DTCP) or evidence-based medicine (EBM). This study presents two clinical cases of cancer patients who presented to the pharmaceutical consultation service (PCD-Pharmacy Clinical Desk) established at the CRO Institute in Aviano, Italy. Both patients were using natural products along with prescribed chemotherapy. In the first case, a 55-year-old woman diagnosed with bilateral breast cancer with bone metastases, who was using natural compounds based on diosmin, escin (or aescin) and resveratrol in combination with ribociclib anticancer therapy, a severe ADR (neutropenia) was identified as a consequence of the drug-natural product interaction. In the second case, following a detailed medication review by the PCD, we avoided taking a therapeutic treatment (with natural compounds) that in itself could potentially render chemotherapy ineffective in a 57-year-old woman with multiple infiltrating ductal carcinoma of the left breast; the patient was planning to take a natural product containing St. John's Wort tincture and lemon balm tincture, in combination with paclitaxel and trastuzumab. In addition, we describe the corrective actions taken, thus outlining the main objectives of the activity of the PCD's pharmacy counseling service: first, to identify, report, and manage adverse drug reactions (ADRs), and second, to identify therapeutic combinations that present potential risks of toxicity or ineffectiveness of the drug therapy itself.

PMID:37958959 | DOI:10.3390/ijms242115976

Int J Mol Sci. 2023 Oct 31;24(21):15822. doi: 10.3390/ijms242115822.

ABSTRACT

The pervasive pollution caused by nano- and microplastics (N/MPLs) is a pressing concern, and was exacerbated during the COVID-19 pandemic due to the substantial release of disposable Personal Protective Equipment (PPE) into the environment [...].

PMID:37958802 | DOI:10.3390/ijms242115822

Int J Mol Sci. 2023 Oct 24;24(21):15547. doi: 10.3390/ijms242115547.

ABSTRACT

The high prevalence of kidney diseases and the low identification rate of drug nephrotoxicity in preclinical studies reinforce the need for representative yet feasible renal models. Although in vitro cell-based models utilizing renal proximal tubules are widely used for kidney research, many proximal tubule cell (PTC) lines have been indicated to be less sensitive to nephrotoxins, mainly due to altered expression of transporters under a two-dimensional culture (2D) environment. Here, we selected HK-2 cells to establish a simplified three-dimensional (3D) model using gelatin sponges as scaffolds. In addition to cell viability and morphology, we conducted a comprehensive transcriptome comparison and correlation analysis of 2D and 3D cultured HK-2 cells to native human PTCs. Our 3D model displayed stable and long-term growth with a tubule-like morphology and demonstrated a more comparable gene expression profile to native human PTCs compared to the 2D model. Many missing or low expressions of major genes involved in PTC transport and metabolic processes were restored, which is crucial for successful nephrotoxicity prediction. Consequently, we established a cost-effective yet more representative model for in vivo PTC studies and presented a comprehensive transcriptome analysis for the systematic characterization of PTC lines.

PMID:37958530 | DOI:10.3390/ijms242115547

Zhonghua Yi Xue Za Zhi. 2023 Nov 14;103(42):3416-3423. doi: 10.3760/cma.j.cn112137-20230911-00438.

ABSTRACT

Objective: To evaluate the hemostatic efficacy, safety and immunogenicity of recombinant human thrombin in the treatment of liver wounds that still ooze after conventional surgical hemostasis. Methods: A multicenter, stratified randomized, double-blind, placebo-controlled phase Ⅲ trial with a planned enrollment of 510 subjects at 33 centers, with a 2∶1 randomization to the thrombin group versus the placebo group. An interim analysis will be conducted after approximately 70% of the subjects have completed the observation period. The primary efficacy endpoint was the rate of hemostasis within 6 minutes at the point of bleeding that could be evaluated. Safety analysis was performed one month after surgery, and the positive rates of anti-drug antibody (ADA) and neutralizing antibody were evaluated. Results: At the interim analysis, a total of 348 subjects had been randomized and received the study drug (215 were male and 133 were female). They were aged 19-69 (52.9±10.9)years. Among them, 232 were in the thrombin group and 116 were in the placebo group, with balanced and comparable demographics and baseline characteristics between the two groups. The hemostasis rate at 6 minutes was 71.6% (95%CI:65.75%-77.36%) in the thrombin group and 44.0% (95%CI: 34.93%-53.00%) in the placebo group, respectively (P<0.001). No grade≥3 drug-related adverse events and no drug-related deaths were reported from the study.No recombinant human thrombin-induced immunologically-enhanced ADA or immunologically-induced ADA was detected after topical use in subjects. Conclusion: Recombinant human thrombin has shown significant hemostatic efficacy and good safety in controlling bleeding during liver resection surgery, while also demonstrating low immunogenicity characteristics.

PMID:37963740 | DOI:10.3760/cma.j.cn112137-20230911-00438

Cell. 2023 Nov 9:S0092-8674(23)01131-5. doi: 10.1016/j.cell.2023.10.014. Online ahead of print.

ABSTRACT

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

PMID:37963465 | DOI:10.1016/j.cell.2023.10.014

Int J Clin Oncol. 2023 Nov 14. doi: 10.1007/s10147-023-02422-x. Online ahead of print.

ABSTRACT

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas.

METHODS: This multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy's Law criteria, and all cases of overdose were reported on the case report forms.

RESULTS: A total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1).

CONCLUSION: This expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

PMID:37964066 | DOI:10.1007/s10147-023-02422-x

Sci Rep. 2023 Nov 14;13(1):19880. doi: 10.1038/s41598-023-46565-3.

ABSTRACT

Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD - 21.80; 95% CI - 33.80 to - 9.80) and total bilirubin (Tbil) compared with placebo (MD - 0.51; 95% CI - 0.76 to - 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.

PMID:37963954 | DOI:10.1038/s41598-023-46565-3

Daru. 2023 Nov 14. doi: 10.1007/s40199-023-00489-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Typical antipsychotics are known to produce extrapyramidal side effects such as drug induced parkinsonism, acute dystonia, akathisia, tardive dyskinesias and rabbit syndrome. Rabbit syndrome is characterized by vertical rhythmic motion of the mouth and lips, resembling chewing movements of a rabbit.

REASON FOR THE REPORT: Rabbit syndrome seen in patients on antidopaminergic therapies is characterized by vertical rhythmic movements of perioral region, has a late onset, and characteristically spares the tongue. The main aim of the report is to highlight atypical manifestation of antipsychotic associated Rabbit syndrome in the presence of a serotonergic antidepressant. An elderly patient presented with atypical rabbit syndrome with relatively acute onset, horizontal movements of jaw and marked tongue involvement after haloperidol-escitalopram initiation.

OUTCOME: The patient improved with discontinuation of antipsychotic. The tongue involvement was believed to be secondary to escitalopram use.

PMID:37962835 | DOI:10.1007/s40199-023-00489-5

Int J Clin Pharm. 2023 Nov 14. doi: 10.1007/s11096-023-01648-z. Online ahead of print.

ABSTRACT

BACKGROUND: A six year collaboration between academics, community pharmacists and informaticians, led to the development of nine guidelines for a clinical decision support system, enhancing community pharmacists' ability to address drug-related problems and improve care.

AIM: The objective of this study was to assess the effectiveness of clinical decision support system rules in enhancing medication management within the community pharmacy setting. This was achieved through retrospective monitoring of real-world usage and measuring the pharmacotherapeutic impact of the rules.

METHOD: In 2019, a retrospective observational evaluation appraised the acceptance rate of the clinical decision support system components in 490 Belgian pharmacies. Among these, 51 pharmacies underwent a longitudinal analysis involving (i) co-prescription of methotrexate and folic acid, (ii) gastroprotection with non-steroidal anti-inflammatory drugs, and (iii) drug combinations causing QT prolongation. The study period spanned one year pre-launch, one year post-launch, and two years post-launch.

RESULTS: Of the targeted pharmacies, 80% used 7 of the 9 rules. After four years, methotrexate-folic acid co-prescription increased 4%, reaching 79.8%. Gastroprotection improved by 3% among older patients and 7.47% in younger individuals (< 70 year) with multiple risk factors. The QT prolongation rules faced implementation difficulties.

CONCLUSION: Pharmacists' acceptance of the developed rules was high and coincided with a decline in drug-related problems, holding potential public health impact. This real-world data can inform the future implementation of such systems, as it demonstrated the need for more detailed data-gathering and more intensive training of pharmacists in the handling of more complex problems such as QT prolongation.

PMID:37962780 | DOI:10.1007/s11096-023-01648-z

PLoS Comput Biol. 2023 Nov 13;19(11):e1011597. doi: 10.1371/journal.pcbi.1011597. eCollection 2023 Nov.

ABSTRACT

The powerful combination of large-scale drug-related interaction networks and deep learning provides new opportunities for accelerating the process of drug discovery. However, chemical structures that play an important role in drug properties and high-order relations that involve a greater number of nodes are not tackled in current biomedical networks. In this study, we present a general hypergraph learning framework, which introduces Drug-Substructures relationship into Molecular interaction Networks to construct the micro-to-macro drug centric heterogeneous network (DSMN), and develop a multi-branches HyperGraph learning model, called HGDrug, for Drug multi-task predictions. HGDrug achieves highly accurate and robust predictions on 4 benchmark tasks (drug-drug, drug-target, drug-disease, and drug-side-effect interactions), outperforming 8 state-of-the-art task specific models and 6 general-purpose conventional models. Experiments analysis verifies the effectiveness and rationality of the HGDrug model architecture as well as the multi-branches setup, and demonstrates that HGDrug is able to capture the relations between drugs associated with the same functional groups. In addition, our proposed drug-substructure interaction networks can help improve the performance of existing network models for drug-related prediction tasks.

PMID:37956212 | PMC:PMC10681315 | DOI:10.1371/journal.pcbi.1011597

Therapie. 2023 Oct 31:S0040-5957(23)00169-5. doi: 10.1016/j.therap.2023.10.008. Online ahead of print.

ABSTRACT

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

PMID:37957054 | DOI:10.1016/j.therap.2023.10.008

J Acquir Immune Defic Syndr. 2023 Dec 15;94(5):468-473. doi: 10.1097/QAI.0000000000003301.

ABSTRACT

BACKGROUND: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP.

METHODS: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models.

RESULTS: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL).

CONCLUSIONS: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.

PMID:37955446 | DOI:10.1097/QAI.0000000000003301

Int Immunopharmacol. 2023 Dec;125(Pt B):111184. doi: 10.1016/j.intimp.2023.111184. Epub 2023 Nov 10.

ABSTRACT

BACKGROUND: To estimate the risk of facial nerve palsy (FP) associated with immune checkpoint inhibitors (ICIs), and to describe its clinical features.

METHODS: Data from randomized controlled trials (RCTs) and FDA Adverse Event Reporting System (FAERS) database were included. The primary outcome was the risk of FP events associated with ICIs. For data from RCTs, pooled analysis was performed by using risk ratios (RRs) with 95%CIs. In a separate retrospective pharmacovigilance study of FAERS, disproportionality was analyzed using the proportional reports reporting odds ratio (ROR) and information components (IC).

RESULTS: A total of 21 RCTs (193,05 patients) were included, ICIs were associated with increased risk of FP (OR = 3.07, 95%CI:1.43-6.58). Results of subgroup analysis indicated that OR of ICI-related FP did not vary significantly by tumor type, ICIs treatment schedule, case of events, study design, median PFS and publication status. FAERS pharmacovigilance data identified 274 cases of FP related to ICIs therapy. ICIs were significantly associated with over-reporting frequencies of FP (ROR = 3.03, 95%CI:2.69-3.42; IC = 1.56, 95%CI:1.38-1.76). The median onset time of FP was 5.5 weeks, drug interruption was recorded in 78.0% of cases, with a positive dechallenge in 82.8 % of cases, and 71.7% of cases were recovered or recovering.

CONCLUSIONS: These data suggest that ICIs were significantly associated with increased risk of FP in both trial settings and in clinical practice.

PMID:37952483 | DOI:10.1016/j.intimp.2023.111184

Dent Clin North Am. 2024 Jan;68(1):99-111. doi: 10.1016/j.cden.2023.07.004. Epub 2023 Sep 16.

ABSTRACT

Antibiotic prophylaxis is the use of antibiotics perioperatively to prevent infections at the surgical site or distant locations. The decision to provide prophylaxis must balance risks of antibiotic resistance, adverse drug reactions, and increased health care costs with the benefit of decreasing infection. This determination has been studied extensively in patients with specific cardiac conditions and prosthetic joints. Prophylactic antibiotics in healthy patients have been shown to reduce the frequency of alveolar osteitis and decrease the failure rates of dental implants.

PMID:37951640 | DOI:10.1016/j.cden.2023.07.004

Reg Anesth Pain Med. 2023 Nov 11:rapm-2023-104952. doi: 10.1136/rapm-2023-104952. Online ahead of print.

ABSTRACT

INTRODUCTION: Epidural steroid injections and epidural blood patches commonly involve the injection of a small amount of radiocontrast media under fluoroscopy to properly identify the target tissue or anatomic space and prevent off-target or intravascular delivery of therapeutic or diagnostic drugs. Iodinated low osmolar non-ionic contrast media is the standard preparation used as it is considered safe and cost-effective, but gadolinium-based preparations have been used as an alternative for patients with an 'iodine'-related or radiocontrast media allergy label to prevent hypersensitivity reactions. The risk of neurotoxic events when gadolinium is inadvertently injected into the intrathecal space has been reported in recent years, raising concerns when gadolinium-based contrast media is used in lieu of iodinated low osmolar non-ionic contrast media.

METHODS: A retrospective review was conducted of patients who received gadolinium-based contrast media for procedures with risk of inadvertent intrathecal access from January 1, 2019 to May 1, 2022. Information on patient demographics, allergy label information, and procedure description was documented for all patients who received gadolinium-based contrast media for axial spine procedures (including epidural steroid injections, epidural blood patch procedures, and selective nerve root blocks), and all side effects reported within 1 month of the procedure were recorded. Saved fluoroscopy images of all procedures for which there was concern for possible gadolinium-based contrast media-related side effect were reviewed for evidence of inadvertent intrathecal gadolinium-based contrast media administration. Descriptive statistical analysis was performed using REDCap and IBM SPSS Statistics V.28.

RESULTS: We identified 508 patients who received gadolinium-based contrast media during a fluoroscopically guided axial spine procedure. These patients underwent 697 epidural procedures and 23 patients were identified as experiencing an adverse event that could be consistent with possible, probable, or clear signs of exposure to intrathecal gadolinium. Our calculated adverse event rate was 3.3%. Ten patients required additional medical evaluation or treatment.

DISCUSSION: Almost all patients in our cohort had an allergy label on their chart that guided the provider to switch to gadolinium-based contrast media, but most were incomplete, ill-defined, or related to allergy to iodine but not iodinated contrast media. Such practice is not recommended based on current guidelines. The current study raises concern regarding the use of gadolinium-based contrast media in axial spine procedures, with the risk of potential severe adverse events, without evidence-based need for avoiding iodinated contrast media.

PMID:37951601 | DOI:10.1136/rapm-2023-104952