BMC Public Health. 2023 Apr 3;23(1):640. doi: 10.1186/s12889-023-15474-5.

ABSTRACT

BACKGROUND: Despite the implementation and expansion of public health and harm reduction strategies aimed at preventing and reversing overdoses, rates of overdose-related events and fatalities continue to rise in British Columbia. The COVID-19 pandemic created a second, concurrent public health emergency that further exacerbated the illicit drug toxicity crisis, reinforced existing social inequities and vulnerabilities, and highlighted the precariousness of systems in place that are meant to protect the health of communities. By exploring the perspectives of people with recent experience of illicit substance use, this study sought to characterize how the COVID-19 pandemic and associated public health measures influenced risk and protective factors related to unintentional overdose by altering the environment in which people live and use substances, influencing the ability of people who use substances to be safe and well.

METHODS: One-on-one semi-structured interviews were conducted by phone or in-person with people who use illicit substances (n = 62) across the province. Thematic analysis was performed to identify factors shaping the overdose risk environment.

RESULTS: Participants pointed to factors that increased risk of overdose, including: [1] physical distancing measures that created social and physical isolation and led to more substance use alone without bystanders nearby able to respond in the event of an emergency; [2] early drug price spikes and supply chain issues that created inconsistencies in drug availability; [3] increasing toxicity and impurities in unregulated substances; [4] restriction of harm reduction services and supply distribution sites; and [5] additional burden placed on peer workers on the frontlines of the illicit drug toxicity crisis. Despite these challenges, participants highlighted factors that protected against overdose and substance-related harm, including the emergence of new programs, the resiliency of communities of people who use substances who expanded their outreach efforts, the existence of established social relationships, and the ways that individuals consistently prioritized overdose response over concerns about COVID-19 transmission to care for one another.

CONCLUSIONS: The findings from this study illustrate the complex contextual factors that shape overdose risk and highlight the importance of ensuring that the needs of people who use substances are addressed in future public health emergency responses.

PMID:37013524 | PMC:PMC10069735 | DOI:10.1186/s12889-023-15474-5

Cochrane Database Syst Rev. 2023 Apr 4;4:CD015179. doi: 10.1002/14651858.CD015179.pub2.

ABSTRACT

BACKGROUND: Neonates are an extremely vulnerable patient population, with 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU will undergo multiple painful procedures per day throughout their stay. There is increasing evidence that frequent and repetitive exposure to painful stimuli is associated with poorer outcomes later in life. To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. This review focused on non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and N-methyl-D-aspartate (NMDA) receptor antagonists, which alleviate pain through inhibiting cellular pathways to achieve analgesia. The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. We therefore sought to summarize the evidence on the level of pain experienced by neonates both during and following procedures; relevant drug-related adverse events, namely episodes of apnea, desaturation, bradycardia, and hypotension; and the effects of combinations of drugs. As the field of neonatal procedural pain management is constantly evolving, this review aimed to ascertain the scope of non-opioid analgesics for neonatal procedural pain to provide an overview of the options available to better inform evidence-based clinical practice. OBJECTIVES: To determine the effects of non-opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration.

SEARCH METHODS: We searched the Cochrane Library (CENTRAL), PubMed, Embase, and two trial registries in June 2022. We screened the reference lists of included studies for studies not identified by the database searches.

SELECTION CRITERIA: We included all randomized controlled trials (RCTs), quasi-RCTs, and cluster-RCTs in neonates (term or preterm) undergoing painful procedures comparing NSAIDs and NMDA receptor antagonists to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our main outcomes were pain assessed during the procedure and up to 10 minutes after the procedure with a validated scale; episodes of bradycardia; episodes of apnea; and hypotension requiring medical therapy.

MAIN RESULTS: We included two RCTs involving a total of 269 neonates conducted in Nigeria and India. NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention One RCT evaluated using oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision. The evidence is very uncertain about the effect of ketamine on pain score during the procedure, assessed with the Neonatal Infant Pain Scale (NIPS), compared with placebo (mean difference (MD) -0.95, 95% confidence interval (CI) -1.32 to -0.58; 1 RCT; 145 participants; very low-certainty evidence). No other outcomes of interest were reported on. Head-to-head comparison of different analgesics One RCT evaluated using intravenous fentanyl versus intravenous ketamine during laser photocoagulation for retinopathy of prematurity. Neonates receiving ketamine followed an initial regimen (0.5 mg/kg bolus 1 minute before procedure) or a revised regimen (additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg), while those receiving fentanyl followed either an initial regimen (2 μg/kg over 5 minutes, 15 minutes before the procedure, followed by 1 μg/kg/hour as a continuous infusion) or a revised regimen (titration of 0.5 μg/kg/hour every 15 minutes to a maximum of 3 μg/kg/hour). The evidence is very uncertain about the effect of ketamine compared with fentanyl on pain score assessed with the Premature Infant Pain Profile-Revised (PIPP-R) scores during the procedure (MD 0.98, 95% CI 0.75 to 1.20; 1 RCT; 124 participants; very low-certainty evidence); on episodes of apnea occurring during the procedure (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) -0.09, 95% CI -0.19 to 0.00; 1 study; 124 infants; very low-certainty evidence); and on hypotension requiring medical therapy occurring during the procedure (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI -0.03 to 0.10; 1 study; 124 infants; very low-certainty evidence). The included study did not report pain score assessed up to 10 minutes after the procedure or episodes of bradycardia occurring during the procedure. We did not identify any studies comparing NSAIDs versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention or different routes of administration of the same analgesics. We identified three studies awaiting classification. AUTHORS' CONCLUSIONS: The two small included studies comparing ketamine versus either placebo or fentanyl, with very low-certainty evidence, rendered us unable to draw meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on NSAIDs or studies comparing different routes of administration. Future research should prioritize large studies evaluating non-opioid analgesics in this population. As the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as we identified no studies on NSAIDs, which are widely used in older infants, or comparing different routes of administration, such studies should be a priority going forward.

PMID:37014033 | DOI:10.1002/14651858.CD015179.pub2

Int J Public Health. 2023 Apr 3;68:1605808. doi: 10.3389/ijph.2023.1605808. eCollection 2023.

ABSTRACT

Objective: The study aimed to investigate the pharmacist interventions in minimizing drug-related problems in diabetes with co-existing hypertension. Methods: Prospective observational study. Results: Overall, a total of 628 interventions were recommended for 1,914 patients during the 5-year period of study. Among all the interventions, the majority were suggested regarding "substituting the drug" (39%), change in frequency of administration (25%), and addition of drug (14%). Patient compliance status was found significant (p = 0.29 ± 0.07). Conclusion: Clinical pharmacists have a crucial role in minimizing drug related problems. Particularly, there should be a greater emphasis on patient counselling and patient follow-up.

PMID:37077511 | PMC:PMC10106567 | DOI:10.3389/ijph.2023.1605808

Front Immunol. 2023 Apr 3;14:1127935. doi: 10.3389/fimmu.2023.1127935. eCollection 2023.

ABSTRACT

BACKGROUND: Golidocitinib is an orally available, potent and highly selective JAK (Janus kinase)-1 inhibitor of JAK/STAT3 signaling under clinical development for the treatment of cancer and autoimmune diseases. The objectives of the two reported studies were to investigate the pharmacokinetics (PK), safety, and tolerability of golidocitinib in healthy Chinese participants as compared to those healthy Western participants, as well as the food effect exploration.

METHODS: Two phase I studies (JACKPOT2 and JACKPOT3) were conducted in USA and China, respectively. In JACKPOT2 study, participants were randomized into placebo or golidocitinib arm in single-ascending dose cohorts (5 - 150 mg) and multiple-ascending dose cohorts (25 - 100 mg, once daily) for 14 days. In the food effect cohort, golidocitinib (50 mg) was administrated shortly after a high-fat meal (fed conditions) as compared to under fasting conditions. In JACKPOT3 study conducted in China, participants were randomized to placebo or golidocitinib arm in single-ascending dose cohorts (25 - 150 mg).

RESULTS: Exposure of golidocitinib generally increased in a dose-proportional manner across a dose range of 5 mg to 150 mg (single dose) and 25 mg to 100 mg (once daily). High-fat food did not alter the PK of golidocitinib with statistical significance. Low plasma clearance and extensive volume of distribution characterizes PK of golidoctinib, and long half-life across the dose levels supported once daily dosing. The inter-ethnic difference in primary PK parameters was evaluated. The result suggested slightly higher peak plasma concentrations (Cmax) but comparable area under the plasma concentration-time curve (AUC) was observed in Asian (Chinese) subjects as compared to Caucasian and/or Black subjects, while it was not considered clinically relevant. Golidocitinib was well tolerated without Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher drug-related treatment emergent adverse events (TEAE) reported.

CONCLUSION: No noticeable inter-ethnic difference was observed among Asian, Black, and Caucasian healthy subjects in anticipation of the favorable PK properties of golidocitinib. The effect of food on the bioavailability of golidocitinib was minor following a single oral administration of 50 mg. These data guided to use the same dose and regimen for multinational clinical development.

CLINICAL TRIAL REGISTRATIONS: https://clinicaltrials.gov/ct2/show/NCT03728023?term=NCT03728023&draw=2&rank=1, identifier (NCT03728023); http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml, identifier (CTR20191011).

PMID:37077916 | PMC:PMC10108266 | DOI:10.3389/fimmu.2023.1127935

Front Immunol. 2023 Mar 16;14:1134436. doi: 10.3389/fimmu.2023.1134436. eCollection 2023.

ABSTRACT

Although the immunotherapy advent has revolutionized cancer treatment, it, unfortunately, does not spare cancer patients from possible immune-related adverse events (irAEs), which can also involve the peripheral nervous system. Immune checkpoint inhibitors (ICIs), blocking cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), can induce an immune imbalance and cause different peripheral neuropathies (PNs). Considering the wide range of PNs and their high impact on the safety and quality of life for cancer patients and the availability of large post-marketing surveillance databases, we chose to analyze the characteristics of ICI-related PNs reported as suspected drug reactions from 2010 to 2020 in the European real-world context. We analyzed data collected in the European pharmacovigilance database, Eudravigilance, and conducted a systematic and disproportionality analysis. In our study, we found 735 reports describing 766 PNs occurred in patients treated with ICIs. These PNs included Guillain-Barré syndrome, Miller-Fisher syndrome, neuritis, and chronic inflammatory demyelinating polyradiculoneuropathy. These ADRs were often serious, resulting in patient disability or hospitalization. Moreover, our disproportionality analysis revealed an increased reporting frequency of PNs with tezolizumab compared to other ICIs. Guillain-Barré syndrome is a notable potential PN related to ICIs, as it is associated with a significant impact on patient safety and has had unfavorable outcomes, including a fatal one. Continued monitoring of the safety profile of ICIs in real-life settings is necessary, especially considering the increased frequency of PNs associated with atezolizumab compared with other ICIs.

PMID:37006303 | PMC:PMC10060793 | DOI:10.3389/fimmu.2023.1134436

Am J Gastroenterol. 2023 Mar 31. doi: 10.14309/ajg.0000000000002275. Online ahead of print.

ABSTRACT

BACKGROUND: This study is to evaluate safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without FDA-approved therapies.

METHOD: This Phase 2a, multicenter, open-label, dose escalation study evaluated safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed AH subjects. Based on MELD (Model for End-stage Liver Disease) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous (IV) infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150mg, and were followed for 28 days. Efficacy signals from a subgroup of severe AH subjects were compared with two matched arms of severe AH subjects treated with standard of care (SOC), including corticosteroids (CS), from a contemporaneous study.

RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the severe AH subjects were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events (SAEs) nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to Day7 and Day28, and MELD scores were reduced at Day28. The efficacy signals compared favorably with two matched groups treated with SOC. Lille scores at Day7 were <0.45 in 16 of the 18 (89%) subjects with Day7 samples. Lille scores from 8 severe AH subjects who received 30 or 90mg larsucosterol (doses used in Phase 2b trial) were statistically significantly lower (p<0.01) than those severe AH subjects treated with SOC from the contemporaneous study.

CONCLUSION: Larsucosterol was well tolerated at all 3 doses in AH subjects without safety concerns. Data from this pilot study showed promising efficacy signals in AH subjects. Larsucosterol is being evaluated in a Phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

PMID:37011138 | DOI:10.14309/ajg.0000000000002275

Cureus. 2023 Mar 28;15(3):e36834. doi: 10.7759/cureus.36834. eCollection 2023 Mar.

ABSTRACT

Daptomycin is a canonical antibiotic used very commonly in practice for its bactericidal activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, bone infections, skin and soft tissue infections, meningitis, urinary tract infections, and endocarditis. Although daptomycin in conventional doses is usually well tolerated, it is paramount to be aware of the possible adverse effects. Daptomycin is reported to cause an elevation in creatine kinase levels, although frank rhabdomyolysis is rare. An even more infrequent occurrence is the simultaneous development of acute kidney injury and drug-induced liver injury with rhabdomyolysis. Daptomycin and rifampin combination are used for synergistic bactericidal action against MRSA. Still, data on the efficacy and safety of the combination is limited due to a lack of extensive studies. Herein, we present a clinical case of septic arthritis of a prosthetic knee, which resulted in bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) and subsequently led to infective endocarditis of the aortic valve. The patient was treated with a combination of daptomycin and rifampin, complicated by the development of rhabdomyolysis, acute kidney injury, and drug-induced liver injury. This case highlights the significance of timely recognizing adverse drug effects and identifying risk factors to ensure successful patient outcomes.

PMID:37009360 | PMC:PMC10050791 | DOI:10.7759/cureus.36834

J Assoc Med Microbiol Infect Dis Can. 2023 Mar 1;8(1):64-74. doi: 10.3138/jammi-2022-0029. eCollection 2023 Mar.

ABSTRACT

BACKGROUND: The treatment of tuberculosis (TB) is known to cause liver injury, however, there is limited data to guide optimal treatment for patients with chronic liver disease.

METHODS: We undertook a retrospective case series of patients with chronic liver disease and TB disease. The primary objective was to determine if there was a difference in the incidence of drug-induced liver injury (DILI) in patients with cirrhosis versus those with chronic hepatitis. Additionally, we sought to compare TB treatment outcomes, type and duration of therapy, and incidence of adverse events.

RESULTS: We included 56 patients (chronic hepatitis 40; cirrhosis 16). There were 33 patients (58.9%) who experienced DILI requiring treatment modification, with no significant difference between groups (65% versus 43.8%, p = 0.23). Patients with chronic hepatitis were more likely to receive treatment with standard first-line intensive phase therapy that included a combination of rifampin (RIF), isoniazid, and pyrazinamide (80.8% versus 19.2%, p = 0.03) and any regimen than included isoniazid (92.5% versus 68.8%, p = 0.04). The risk of DILI was higher when more hepatotoxic TB medications were used. Overall treatment success in this cohort was low (55.4%), with no significant difference between groups (62.5% versus 37.5%, p = 0.14). Most patients with treatment success (97%) were able to tolerate a rifamycin.

CONCLUSIONS: The risk of DILI is high, especially with the use of isoniazid, in patients with TB and chronic liver disease. This risk can be effectively mitigated with no difference in treatment outcomes in the presence of cirrhosis.

PMID:37008589 | PMC:PMC10052910 | DOI:10.3138/jammi-2022-0029

Cureus. 2023 Feb 27;15(2):e35554. doi: 10.7759/cureus.35554. eCollection 2023 Feb.

ABSTRACT

As a first-line immunosuppressant to maintain remission in Crohn's disease, 6-mercaptopurine (6-MP) has been commonly used. A rare, unpredictable, dose-independent and idiosyncratic reaction to this medication is acute pancreatitis. Unlike other side effects of this drug which have been well characterized and are often dose-dependent, acute pancreatitis is an uncommon adverse effect not frequently encountered in clinical practice. In this case report, we describe a 40-year-old man with Crohn's disease who developed acute pancreatitis within two weeks of starting 6-MP. Discontinuation of the drug followed by fluid resuscitation led to the overall improvement of symptoms within 72 hours. No complications were noted during the follow-up. It is our intention to raise awareness for this lesser-known side effect with this case report and to urge physicians to provide thorough counseling prior to starting on this medication, especially in patients with inflammatory bowel disease (IBD). Additionally, we hope to reinforce this disease entity as a differential for acute pancreatitis and aim to emphasize the importance of detailed medication reconciliations with this report, especially in the emergency department, to enable quick diagnoses and limit unnecessary treatments.

PMID:37007369 | PMC:PMC10060005 | DOI:10.7759/cureus.35554

Indian J Hematol Blood Transfus. 2023 Apr;39(2):344-346. doi: 10.1007/s12288-022-01585-3. Epub 2022 Oct 17.

ABSTRACT

The BCR-ABL mutation is the main cause of tyrosine kinase inhibitors(TKI) resistance. The second-generation TKI can overcome most of the mutations. However, both dasatinib and nilotinib have a unique set of mutants with reduced sensitivity. All TKIs are associated with adverse events, which lead to treatment discontinuation and affect the quality of life of patients. Flumatinib showed higher activity against BCR-ABL mutants in vitro. Drug-related adverse events of flumatinib were mainly grade 1 or grade 2 events. There is no study that reported the efficacy of flumatinib against F359V/C mutation.We report two cases of chronic myelocytic leukemia(CML) patients with F359V/C mutation resistance to Imatinib therapy. One patient with F359V mutation was shifted to Dasatinib. Repeated massive pleural effusion and anemia occurred after Dasatinib treatment, forcing drug dosage reduction or withdrawal, affecting drug efficacy and quality of life of patient. Two patients were shifted to Flumatinib. MR4 was achieved and F359V/C mutation was not detected after treatment with Flumatinib. There was no significant side effect. The patients had a high quality of life. Flumatinib is effective against F359V/C mutation, has less drugrelated adverse reactions. Flumatinib may be a better choice for patients with F359V/C mutation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-022-01585-3.

PMID:37006972 | PMC:PMC10064348 | DOI:10.1007/s12288-022-01585-3

Biol Pharm Bull. 2023;46(4):614-620. doi: 10.1248/bpb.b22-00823.

ABSTRACT

Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.

PMID:37005306 | DOI:10.1248/bpb.b22-00823

BMJ Open Diabetes Res Care. 2023 Apr;11(2):e003177. doi: 10.1136/bmjdrc-2022-003177.

ABSTRACT

INTRODUCTION: Hypoglycemia is listed as an adverse effect in the package inserts of not only hypoglycemic agents but also many other drugs. We aimed to clarify real-world factors related to an increased risk of hypoglycemia-related hospitalization (HRH) in Japanese patients with type 2 diabetes (T2D) on non-hypoglycemic agents that have been associated with hypoglycemia.

RESEARCH DESIGN AND METHODS: This cross-sectional study was performed using data from the Medical Data Vision administrative claims database. We identified patients with T2D who were enrolled in the database between April 2014 and October 2019. Logistic regression analyses were performed to identify clinical factors associated with HRH due to non-hypoglycemic agents.

RESULTS: Among 703 745 patients with T2D, 10 376 patients (1.47%) experienced HRH. The use of 332 non-hypoglycemic agents was associated with hypoglycemia. Multivariate analysis was performed to calculate OR for HRH. Seventy-five drugs had an OR greater than 1, and the values were significant. The OR was the highest for diazoxide (OR 15.5, 95% CI 4.87 to 49.3). The OR was higher than 2.0 for methylphenidate (OR 5.15, 95% CI 1.53 to 17.3), disulfiram (OR 4.21, 95% CI 2.05 to 8.62) and hydrocortisone (OR 2.89, 95% CI 1.11 to 7.51).

CONCLUSION: This large retrospective analysis revealed that the risk of HRH from some non-hypoglycemic agents in patients with T2D may be increased. The results of this study are expected to support treatment planning by physicians and healthcare professionals involved in diabetes care.

PMID:37085279 | DOI:10.1136/bmjdrc-2022-003177

Pediatr Infect Dis J. 2023 Mar 29. doi: 10.1097/INF.0000000000003911. Online ahead of print.

ABSTRACT

BACKGROUND: Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed.

METHODS: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points.

RESULTS: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol.

CONCLUSION: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious.

PMID:37000942 | DOI:10.1097/INF.0000000000003911

Chem Commun (Camb). 2023 Mar 31. doi: 10.1039/d3cc00220a. Online ahead of print.

ABSTRACT

L-Cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (H2S) in aqueous and cellular media. Considering the cytoprotective roles of H2S, the present adjuvant strategy would be helpful in minimizing the anti-cancer drug-induced side-effects.

PMID:37000594 | DOI:10.1039/d3cc00220a

Palliat Med. 2023 Mar 31:2692163231162889. doi: 10.1177/02692163231162889. Online ahead of print.

ABSTRACT

BACKGROUND: Older adults with advanced cancer are exposed to antibiotics but estimates of adverse drug events associated with antibiotic therapy are lacking.

AIM: Evaluate the association of antibiotic therapy with adverse drug events in older adults with advanced cancer.

DESIGN: Cohort study where the exposure was the ratio of days of therapy of an oral or intravenous antibiotic per patient-day and the outcome was an adverse drug event, defined as cardiotoxicity, hepatotoxicity, nephrotoxicity, Clostridioides difficile infection, or new detection of a multidrug-resistant organism.

SETTING/PARTICIPANTS: Patients aged ⩾65 years with solid tumors from a tertiary care center who received palliative chemotherapy (n = 914).

RESULTS: Mean age was 75 ± 6.6 years, and 52% were female. Common tumors were lung (31%, n = 284) and gastrointestinal (26%, n = 234). Mean time from first course of palliative chemotherapy to index admission was 128 days. Five-hundred thirty (58%) patients were exposed to antibiotics during the index admission; of these, 27% (n = 143) met standardized criteria for infection. Patients were commonly exposed to cephalosporins (33%, n = 298) and vancomycin (30%, n = 276). Among patients exposed to antibiotics, 35% (n = 183/530) developed an adverse drug event. In multivariable testing, antibiotic therapy was associated with development of an adverse drug event (>0 to <1 vs 0 days of therapy/patient-day: adjusted odds ratio [aOR] = 1.9; 95% confidence interval [CI], 1.2-2.8; ⩾1 vs 0 days of therapy/patient-day: aOR = 2.1, 95% CI, 1.4-3.0).

CONCLUSION: Antibiotic therapy was independently associated with adverse drug events in hospitalized older adults with advanced cancer. These findings may inform antibiotic decision-making among palliative care providers.

PMID:36999898 | DOI:10.1177/02692163231162889

Am J Health Syst Pharm. 2023 Mar 30:zxad060. doi: 10.1093/ajhp/zxad060. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: Costs of hospitalization due to severe adverse drug reactions (ADRs) were previously estimated within the Veterans Health Administration (VHA), but additional analyses are needed to infer potential interventions to mitigate these negative outcomes. The objective of the current study was to compare specific adverse reaction-related hospitalization costs between medications with similar indications.

METHODS: Mean hospitalization costs associated with the same ADR symptom were compared for different drugs with similar indications using adjusted generalized linear models with a Bonferroni correction for multiple comparisons as well as a gamma distribution.

RESULTS: Overall, hospitalization costs between medications with similar indications were not significantly different for specific adverse reactions. However, gastrointestinal hemorrhage-associated costs were higher for warfarin versus nonsteroidal anti-inflammatory drugs (model estimate of mean cost, $18,114 [range of lower and upper model estimates, $12,522-$26,202] vs $14,255 [estimate range, $9,710-$20,929]). Similarly, the estimated mean hospitalization cost associated with angioedema was higher for losartan versus lisinopril or lisinopril/hydrochlorothiazide: $14,591 (range, $9467-$22,488) versus $8,935 (range, $6,301-$12,669) and $8,022 (range, $5,424-$11,865), respectively.

CONCLUSION: Although we found few differences in the cost of hospitalization when comparing drugs with similar indications and the same adverse reaction, there were specific drug-ADR pairs that merit attention and consideration of interventions to improve safe and appropriate medication use. Evaluation of the effect of those interventions on the incidence of ADRs is an area for future study.

PMID:36994836 | DOI:10.1093/ajhp/zxad060

JTO Clin Res Rep. 2023 Feb 24;4(4):100491. doi: 10.1016/j.jtocrr.2023.100491. eCollection 2023 Apr.

ABSTRACT

Treatment with drugs can cause lung disorders. Immune checkpoint inhibitors are often associated with organizing pneumonia. Capillary leak syndrome is a clinical form of drug-induced lung injury, a rare condition characterized by hemoconcentration, hypoalbuminemia, and hypovolemic shock. There have been no reports of multiple lung injury with immune checkpoint inhibitors, and although capillary leak syndrome alone has been reported in the past, there have been no reports of pulmonary edema as a complication. We report a 68-year-old woman who died of respiratory and circulatory failure owing to pulmonary edema caused by capillary leak syndrome, preceded by organizing pneumonia induced by combination therapy with nivolumab and ipilimumab for postoperative recurrence of lung adenocarcinoma. Residual inflammation and immune abnormalities from previous immune-related pulmonary adverse events may have increased pulmonary capillary permeability, leading to marked pulmonary edema.

PMID:36994310 | PMC:PMC10040893 | DOI:10.1016/j.jtocrr.2023.100491

Ther Adv Neurol Disord. 2023 Mar 23;16:17562864231162420. doi: 10.1177/17562864231162420. eCollection 2023.

ABSTRACT

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a devastating autoimmune disorder with cycles of escalating relapse. Rates of diagnosis in the elderly are increasing. Therapeutic decision-making is more challenging in elderly patients due to multiple comorbidities and high risk of drug-induced side effects.

OBJECTIVE: This retrospective study assessed the efficacy and safety of standard plasma exchange (PLEX) treatment in an elderly population with NMOSD.

DESIGN: Seventy-six patients with NMOSD who received PLEX were apportioned to two groups as either elderly (⩾60 years, n = 26) or young (<60 years) at the time of the first procedure.

METHODS: Therapeutic response was judged according to functional recovery at 6 months, as reflected by Expanded Disability Status Scale (EDSS) and visual outcome scale (VOS) scores.

RESULTS: The mean age of the 26 elderly patients was 67.7 ± 7.9 years (range 60-87 years); the population was predominantly female (88.5%). PLEX sessions were generally well tolerated among the elderly. Compared with the young patients, the elderly had significantly more comorbidities and concomitant medications. Twenty-four (96.0%) elderly patients showed functional improvement at 6 months after PLEX, of which 15 (60.0%) experienced moderate-to-marked improvement. Six months after the initial PLEX treatment, the patients overall experienced a significant improvement in EDSS and VOS scores. Logistic regression showed that severe optic neuritis attack was a significant independent prognostic factor associated with poor PLEX response. The groups were comparable regarding overall or serious adverse events. The rate of transient hypotension was significantly higher in the elderly compared with the young.

CONCLUSION: PLEX is an effective and safe therapy for elderly patients with NMOSD and should be considered a treatment option during NMOSD attacks. In the elderly, preventive measures against hypotension are recommended before PLEX.

PMID:36993936 | PMC:PMC10041617 | DOI:10.1177/17562864231162420

medRxiv. 2023 Mar 14:2023.03.13.23287215. doi: 10.1101/2023.03.13.23287215. Preprint.

ABSTRACT

OBJECTIVES: Xylazine is an alpha-2 agonist increasingly prevalent in the illicit drug supply. Our objectives were to curate information about xylazine through social media from People Who Use Drugs (PWUDs). Specifically, we sought to answer the following: 1) what are the demographics of Reddit subscribers reporting exposure to xylazine? 2) is xylazine a desired additive? and 3) what adverse effects of xylazine are PWUDs experiencing?

METHODS: Natural Language Processing (NLP) was used to identify mentions of "xylazine" from posts by Reddit subscribers who also posted on drug-related subreddits. Posts were qualitatively evaluated for xylazine-related themes. A survey was developed to gather additional information about the Reddit subscribers. This survey was posted on subreddits that were identified by NLP to contain xylazine-related discussions from March 2022 to October 2022.

RESULTS: 76 posts mentioning xylazine were extracted via NLP from 765,616 posts by 16,131 Reddit subscribers (January 2018 to August 2021). People on Reddit described xylazine as an unwanted adulterant in their opioid supply. 61 participants completed the survey. Of those that disclosed their location, 25/50 (50%) participants reported locations in the Northeastern United States. The most common eoute of xylazine use was intranasal use (57%). 31/59 (53%) reported experiencing xylazine withdrawal. Frequent adverse events reported were prolonged sedation (81%) and increased skin wounds (43%).

CONCLUSIONS: Among respondents on these Reddit forums, xylazine appears to be an unwanted adulterant. PWUDs may be experiencing adverse effects such as prolonged sedation and xylazine withdrawal. This appeared to be more common in the Northeast.

PMID:36993695 | PMC:PMC10055471 | DOI:10.1101/2023.03.13.23287215

Sci Rep. 2023 Mar 29;13(1):5101. doi: 10.1038/s41598-023-31215-5.

ABSTRACT

Progressive massive pulmonary fibrosis among coal miners has unexpectedly increased. It would likely due to the greater generation of smaller rock and coal particles produced by powerful equipment used in modern mines. There is limited understanding of the relationship between micro- or nanoparticles with pulmonary toxicity. This study aims to determine whether the size and chemical characteristics of typical coal-mining dust contribute to cellular toxicity. Size range, surface features, morphology, and elemental composition of coal and rock dust from modern mines were characterized. Human macrophages and bronchial tracheal epithelial cells were exposed to mining dust of three sub- micrometer and micrometer size ranges at varying concentrations, then assessed for cell viability and inflammatory cytokine expression. Coal had smaller hydrodynamic size (180-3000 nm) compared to rock (495-2160 nm) in their separated size fractions, more hydrophobicity, less surface charge, and consisted of more known toxic trace elements (Si, Pt, Fe, Al, Co). Larger particle size had a negative association with in-vitro toxicity in macrophages (p < 0.05). Fine particle fraction, approximately 200 nm for coal and 500 nm for rock particles, explicitly induced stronger inflammatory reactions than their coarser counterparts. Future work will study additional toxicity endpoints to further elucidate the molecular mechanism causing pulmonary toxicity and determine a dose-response curve.

PMID:36991007 | PMC:PMC10060429 | DOI:10.1038/s41598-023-31215-5