Rheumatology (Oxford). 2023 Oct 23;62(SI3):SI237-SI241. doi: 10.1093/rheumatology/kead307.

ABSTRACT

Polypharmacy is increasingly common in rheumatology due to the complex nature of managing chronic autoimmune diseases. To date there has been limited research into the impact of polypharmacy on rheumatology patients. In this article we reviewed the literature to characterize the prevalence of polypharmacy and its effect on patients. In addition, we have highlighted some key drug-drug interactions to consider involving DMARDs as well as complementary and alternative medicines. There is emerging evidence demonstrating that polypharmacy contributes to adverse outcomes and alters treatment response. This association is best described in RA and is less clear in other patient cohorts. It is also unclear whether polypharmacy is directly harmful or just a surrogate marker for other factors affecting outcomes. Rheumatologists should be aware of the risk of polypharmacy as well as specific drug-drug interactions that can occur in managing chronic autoimmune disease.

PMID:37871915 | DOI:10.1093/rheumatology/kead307

JAMA Netw Open. 2023 Oct 2;6(10):e2339446. doi: 10.1001/jamanetworkopen.2023.39446.

NO ABSTRACT

PMID:37870837 | DOI:10.1001/jamanetworkopen.2023.39446

J Clin Oncol. 2023 Oct 23:101200JCO2302005. doi: 10.1200/JCO.23.02005. Online ahead of print.

ABSTRACT

PURPOSE: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.

PATIENTS AND METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS).

RESULTS: primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3-43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6-17.8); median PFS, 6.9 months (95% CI, 5.6-8.0); median OS, 13.4 months (95% CI, 11.9-15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4-72.4); median DOR, 22.1 months (95% CI, 9.6-not reached); median PFS, 11.9 months (95% CI, 8.2-13.0); median OS, 21.1 months (95% CI, 15.3-29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.

CONCLUSION: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

PMID:37870536 | DOI:10.1200/JCO.23.02005

Cureus. 2023 Sep 21;15(9):e45675. doi: 10.7759/cureus.45675. eCollection 2023 Sep.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have been discovered to be associated with autoimmune toxicities that may present as dermatologic, gastrointestinal, hepatic, pulmonary, endocrine, and rarely hematologic reactions. Recent studies have also discovered hematological adverse effects as a result of ICI use of which isolated neutropenia is the gravest and the rarest manifestation. Asymptomatic neutropenia cannot be ignored, and close monitoring is, at least, warranted. Severe neutropenia with neutropenic fever needs hospital admission and prompt treatment to avoid further morbidity and/or mortality. In this report, we present a rare case of Grade 4 neutropenia resulting from nivolumab, anti-PD-1 antibody, in a patient diagnosed with invasive bladder cancer. The patient was successfully treated with steroids and supportive measures.

PMID:37868579 | PMC:PMC10590144 | DOI:10.7759/cureus.45675

Drug Alcohol Depend. 2023 Oct 5;253:110987. doi: 10.1016/j.drugalcdep.2023.110987. Online ahead of print.

ABSTRACT

Despite the thousands of lives lost during the ongoing opioid crisis, a scarcity of new and effective clinical treatments for opioid use disorder (OUD) remains. To address this unmet need, some researchers have turned to dissociative and psychedelic drugs to treat multiple psychiatric conditions. In particular, low doses of ketamine have been shown to attenuate opioid withdrawal and drug use in clinical and preclinical studies. However, ketamine has misuse liability and dissociative side effects that may limit its widespread application as a treatment for OUD. More recently, (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite that lacks misuse potential, has gained attention for its effectiveness in depression and stress models. To uncover its role in OUD, we tested the time-dependent effects of (2R,6R)-HNK on oxycodone withdrawal and reinstatement of oxycodone conditioned place preference (CPP). In male and female oxycodone-dependent mice, we found that 24h pretreatment with (2R,6R)-HNK (10 or 30mg/kg, s.c.) reduced the frequency of withdrawal-like behaviors and global withdrawal scores during naloxone-precipitated withdrawal, whereas 1h pretreatment with (2R,6R)-HNK only reduced paw tremors and the sum of global withdrawal scores but not GWS Z-scores. In other experiments, both 1h and 24h pretreatment with (2R,6R)-HNK (30mg/kg, s.c.) blocked drug-induced reinstatement of oxycodone CPP. Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.

PMID:37864957 | DOI:10.1016/j.drugalcdep.2023.110987

J Neurooncol. 2023 Oct 21. doi: 10.1007/s11060-023-04456-7. Online ahead of print.

ABSTRACT

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM.

METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR.

RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence.

CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

PMID:37864646 | DOI:10.1007/s11060-023-04456-7

Medicine (Baltimore). 2023 Oct 20;102(42):e35370. doi: 10.1097/MD.0000000000035370.

ABSTRACT

To explore the impact of continuous care on chemotherapy patients with advanced colorectal cancer. Six hundred forty patients who received chemotherapy from June 2015 to December 2022 were included in this retrospective study and divided into the observation group (n = 332) and control group (n = 308) based on different care methods that they received. The observation group patients were followed up using the continuous care team model, the control group patients using the traditional telephone follow-up model. A comparative analysis was conducted on the effects of 2 modes on patients self-care ability, treatment compliance, anxiety, depression, communication ability with nurses, level of hope, as well as the effects of toxic side effects and cancer-related fatigue. The self-care ability and treatment compliance of patients in the observation group were significantly better than those in the control group (P < .05), with lower anxiety and depression scores, toxic side effects, and cancer-related fatigue compared to the control group (P < .05). The communication ability and patient hope level of nurses in the observation group were also significantly stronger than those in the control group (P < .05). The application of continuous care can improve patients self-care ability and treatment compliance, effectively reduce anxiety and depression in in patients with advanced colorectal cancer undergoing chemotherapy, and improve nurses communication skills and patients hope level. Therefore, this practice is worth promoting clinically.

PMID:37861562 | PMC:PMC10589560 | DOI:10.1097/MD.0000000000035370

Medicine (Baltimore). 2023 Oct 20;102(42):e34773. doi: 10.1097/MD.0000000000034773.

ABSTRACT

Osteoporosis is a prevalent age-related disease that poses a significant public health concern as the population continues to age. While current treatments have shown some therapeutic benefits, their long-term clinical efficacy is limited by a lack of stable curative effects and significant adverse effects. Traditional Chinese Medicine has gained attention due to its positive curative effects and fewer side effects. Liuwei Dihuang Pill has been found to enhance bone mineral density in patients with osteoporosis and rats, but the underlying mechanism is not yet clear. To shed more light on this problem, this study aims to explore the pharmacological mechanism of Liuwei Dihuang Pill in treating osteoporosis using network pharmacology and molecular docking. The findings indicate that Liuwei Dihuang Pills treat osteoporosis through various targets and channels. Specifically, it mainly involves TNF, IL17, and HIF-1 signaling pathways and helps regulate biological processes such as angiogenesis, apoptosis, hypoxia, and gene expression. Furthermore, molecular docking demonstrates excellent binding properties between the drug components and key targets. Therefore, this study offers a theoretical foundation for understanding the pharmacological mechanism and clinical application of Liuwei Dihuang Pills in treating osteoporosis more comprehensively.

PMID:37861542 | PMC:PMC10589576 | DOI:10.1097/MD.0000000000034773

J Immunother Cancer. 2023 Oct;11(10):e007305. doi: 10.1136/jitc-2023-007305.

ABSTRACT

BACKGROUND: Lung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients.

METHODS: We performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels.

RESULTS: We found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell-cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort.

CONCLUSIONS: Our data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting.

PMID:37857527 | DOI:10.1136/jitc-2023-007305

PLoS One. 2023 Oct 19;18(10):e0293302. doi: 10.1371/journal.pone.0293302. eCollection 2023.

ABSTRACT

BACKGROUND: Large observational studies have demonstrated the real-world effectiveness of nirmatrelvir-ritonavir in preventing severe COVID-19 in higher risk individuals, but have provided limited information on other aspects of nirmatrelvir-ritonavir use. Our objective was to evaluate prescribing outcomes such as the prevalence of drug-drug interactions (DDI), adverse drug events (ADE) and treatment adherence in an outpatient community clinic setting.

METHODS: We conducted a single-centre retrospective cohort study of adult outpatients prescribed nirmatrelvir-ritonavir in our community COVID-19 assessment clinic in Toronto, Ontario between March 3 and September 20, 2022. We performed a descriptive analysis of the patient population, DDIs, DDI interventions, treatment adherence, ADEs and clinical outcomes of patients prescribed nirmatrelvir-ritonavir.

RESULTS: There were 637 individuals prescribed nirmatrelvir-ritonavir during the study period. The median age was 70, the median number of risk factors for severe disease were 2, 45% were immunocompromised and 82% had received 3 or more COVID-19 vaccine doses. 95% (542/572) completed the 5-day course of therapy with 68% (388/572) having complete symptom resolution by 28-day. Eleven percent (60/572) experienced recurrent symptoms following the completion of nirmatrelvir-ritonavir. Over 70% had one or more clinically significant DDIs requiring mitigation and 62% of patients experienced at least one ADE, which was most commonly dysgeusia or gastrointestinal-related. Ninety-five percent (542/572) of patients completed therapy as prescribed. Overall, hospitalization within 28 days was 3.3% with 1.2% attributed to COVID-19 and there were no deaths.

INTERPRETATION: Nirmatrelvir-ritonavir was associated with a high prevalence of clinically significant DDIs, which required mitigation strategies and a high frequency of mild ADEs. Collaborative assessment to address medication alterations resulted in high treatment adherence.

PMID:37856531 | PMC:PMC10586632 | DOI:10.1371/journal.pone.0293302

Turk J Pediatr. 2023;65(5):719-738. doi: 10.24953/turkjped.2022.765.

ABSTRACT

BACKGROUND: To describe the existing pharmacological managements for Multisystem Inflammatory Syndrome in Children (MIS-C) in a systematic way, to identify the available pharmacological managements in MIS-C, evaluate its safety and efficacy and identify the best treatment procedures for practice recommendation.

METHODS: A systematic search using six databases was conducted on August 18, 2021, updated in January 26th 2023. Terminologies that were used in this search are children, MIS-C/PIMS and SARS-CoV-2. A PRISMA flow diagram was used to report the study selection process. Quality analysis was done based on NOS and GRADE tools. Data synthesis was conducted by extracting the information on drugs used, efficacy and side effects.

RESULTS: From the 32 articles included, a total of 2331 children with MIS-C were studied. The main pharmacological approaches were immunomodulatory therapy, i.e., intravenous immunoglobulin (IVIG) (77.3%), steroids (60.5%), and a combination of IVIG and steroids (41.3%). IVIG and steroids were found to be potentially effective and safe treatments for MIS-C. Combination of IVIG and steroids was found favorable in severe cases with higher recovery rate. Refractory treatments include second dose of initial treatment and biological response modifier drugs like anakinra, tocilizumab, infliximab. A small number of studies investigating supportive treatment consisted of vasoactive, inotropic and anticoagulation. The mortality rate was 1.28% and only three studies reported side effects from the treatment. Evidence of outcome from GRADE were mostly at moderate, low and very low levels.

CONCLUSIONS: This review provides preliminary evidence to support the current standard treatment practices in managing MIS-C pharmacologically. However, comprehensive investigation is required using clinical trials to provide stronger outcome evidence.

PMID:37853964 | DOI:10.24953/turkjped.2022.765

Adv Ther. 2023 Oct 19. doi: 10.1007/s12325-023-02695-8. Online ahead of print.

ABSTRACT

INTRODUCTION: Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug's safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEs by MedDRA Preferred Term that occur at ≥ 2% in drug and with greater incidence than in placebo. We suggest that the drug label can be more informative for both patients and physicians if it includes, in addition to AE incidence (percent of subjects who reported the AE out of the total subjects in treatment), the absolute prevalence (percent of subject-days spent with an AE out of the total subject-days spent in treatment) and expected duration (days required for AE incidence to be reduced by half). We also propose a new method to analyze AEs in RCTs using drug-placebo difference in AE prevalence to improve safety signal detection.

METHODS: AE data from six RCTs in schizophrenia were analyzed (five RCTs of the dopamine D2 receptor-based antipsychotic lurasidone and one RCT of the novel trace amine-associated receptor 1 [TAAR1] agonist ulotaront). We determined incidence, absolute prevalence, and expected duration of AEs for lurasidone and ulotaront vs respective placebo. We also calculated areas under the curve of drug-placebo difference in AE prevalence and mean percent contribution of each AE to this difference.

RESULTS: A number of AEs with the same incidence had different absolute prevalence and expected duration. When accounting for these two parameters, AEs that did not appear in the 2% incidence tables of the drug label turned out to contribute substantially to drug tolerability. The percent contribution of a drug-related AE to the overall side effect burden increased the drug-placebo difference in AE prevalence, whereas the percent contribution of a placebo-related AE decreased such difference, revealing a continuum of risk between drug and placebo. AE prevalence curves for drug were generally greater than those for placebo. Ulotaront exhibited a small drug-placebo difference in AE prevalence curves due to a relatively low incidence and short duration of AEs in the ulotaront treatment arm as well as the emergence of disease-related AEs in the placebo arm.

CONCLUSION: Reporting AE absolute prevalence and expected duration for each RCT and incorporating them in the drug label is possible, is clinically relevant, and allows standardized comparison of medications. Our new metric, the drug-placebo difference in AE prevalence, facilitates signal detection in RCTs. We piloted this metric in RCTs of several neuropsychiatric indications and drugs, offering a new way to compare AE burden and tolerability among treatments using existing clinical trial information.

PMID:37855974 | DOI:10.1007/s12325-023-02695-8

Rev Med Suisse. 2023 Oct 18;19(846):1940-1947. doi: 10.53738/REVMED.2023.19.846.1940.

ABSTRACT

Medication intake during the postpartum period is common with discontinuation of breastfeeding sometimes unnecessarily recommended for fear of adverse effects in the breastfed infant, while exposure through human milk is generally low. The assessment of risks associated with medication intake during breastfeeding is based, among other things, on the little clinical evidence available in specialized sources of information, and on pharmacokinetic principles. A decision-making support is presented to facilitate communication with mothers, foster medication adherence and prevent unnecessary interruption of breastfeeding.

PMID:37850807 | DOI:10.53738/REVMED.2023.19.846.1940

PLoS One. 2023 Oct 17;18(10):e0292037. doi: 10.1371/journal.pone.0292037. eCollection 2023.

ABSTRACT

BACKGROUND: In Switzerland, 20,000 people are hospitalized each year as result of drug related problems (DRPs). The sources of DRPs can be related to patients' behavior (i.e., wrong administration) or to health processes (i.e., drug-drug interaction). No community pharmacy (CP) service focus on DRPs related to patients' behavior is currently recognized or remunerated in Switzerland. A medication review with follow up (MRF) has been developed to evaluate prescription and non-prescription medication.

OBJECTIVE: To evaluate the impact of MRF service for the identification and management DRPs associated to patients' behavior and to describe pharmaceutical interventions carried out through MRF.

METHODS: A pre-post intervention study with a cluster design and one intervention group will be carried out in CPs in the canton of Vaud (Switzerland) for 15 months. Volunteer pharmacists will be trained on the identification and management of DRPs related to patients' behavior. After training, they will include randomly selected adults taking four or more chronic drugs prescribed for at least three months prior to recruitment. Then, they will conduct three pharmacist-patient face-to-face consultations at 6-month intervals. Tasks will be differentiated by pharmacy technician or pharmacist to triage expired medication or to manage DRPs in a structured manner, respectively. The primary outcome is the identification of DRPs associated to patients' behavior. Secondary outcomes are to assess patients' medication knowledge, number of expired medications, interventions carried out by pharmacists and pharmacists' satisfaction. The study will begin in April 2023 in 19 to 35 pharmacies that will recruit at least 162 patients. A sub analysis will be carried out for patients with 65 years old or over.

CONCLUSIONS: The MRF intervention features a training designed for an enhanced evaluation of patient's behavior towards their medication. The study will allow the assessment and management of DRPs in Swiss CPs with the support of the local health authorities and pharmacist association.

TRIAL REGISTRATION: Clinicaltrials.gov NCT05348538.

PMID:37847695 | PMC:PMC10581489 | DOI:10.1371/journal.pone.0292037

Am J Perinatol. 2023 Oct 17. doi: 10.1055/s-0043-1776061. Online ahead of print.

ABSTRACT

The prompt identification of at-risk newborns for drug-induced hypoglycemia can minimize the risk for adverse side effects, inappropriate investigations, and considerable unnecessary costs. Existing literature discusses drug-induced hypoglycemia, but a systematic description of neonatal hypoglycemia induced or exacerbated by maternal medications is missing. We reviewed the association between neonatal hypoglycemia and maternal medications. We systematically searched the literature according to the PICOS model on drug-induced hypoglycemia in neonates born to nondiabetic women treated with medications during the pregnancy or the labor. The main outcomes of the review were: (1) prevalence of hypoglycemia, (2) risk factors and potential confounders, (3) time at onset and severity of hypoglycemia, (4) dose-response gradient, (5) metabolic features of hypoglycemia, (6) modalities to treat hypoglycemia, and (7) quality of the studies. We included 69 studies in this review and we identified 11 groups of maternal drugs related to neonatal hypoglycemia. Results were classified for each outcome. Our review aims at supporting clinicians in the identification of the newborn at risk for hypoglycemia and in the differential diagnosis of neonatal hypoglycemia. Further studies are necessary to assess the risk of neonatal hypoglycemia associated with common maternal medications. KEY POINTS: · A systematic description of neonatal hypoglycemia induced or exacerbated by maternal medications is missing.. · In our review we identified 11 groups of maternal drugs related to neonatal hypoglycemia.. · Our review aims at supporting clinicians in the identification of the newborn at risk for hypoglycemia..

PMID:37848046 | DOI:10.1055/s-0043-1776061

Pediatr Rheumatol Online J. 2023 Oct 17;21(1):124. doi: 10.1186/s12969-023-00881-0.

ABSTRACT

BACKGROUND: Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs.

METHODS: This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses.

RESULTS: A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions.

CONCLUSION: The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.

PMID:37848905 | DOI:10.1186/s12969-023-00881-0

Pharmacogenomics. 2023 Oct 17. doi: 10.2217/pgs-2023-0093. Online ahead of print.

ABSTRACT

Intravenous pentamidine is used for prophylaxis against Pneumocystis jirovecii pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by CYP2C19, which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as P. jirovecii pneumonia prophylaxis. The primary objective was the association between CYP2C19 phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and P. jirovecii pneumonia infection rates were low.

PMID:37846549 | DOI:10.2217/pgs-2023-0093

N Engl J Med. 2023 Oct 19;389(16):1447-1449. doi: 10.1056/NEJMp2307908. Epub 2023 Oct 14.

NO ABSTRACT

PMID:37843109 | DOI:10.1056/NEJMp2307908

Cochrane Database Syst Rev. 2023 Oct 16;10(10):CD009945. doi: 10.1002/14651858.CD009945.pub3.

ABSTRACT

BACKGROUND: This is an updated version of an original Cochrane Review published in 2013 (Walker 2013). Epilepsy is a common neurological disorder affecting 0.5% to 1% of the population. Pharmacological treatment remains the first choice to control epilepsy. However, up to 30% of people do not respond to drug treatment, and therefore do not achieve seizure remission. Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy.

OBJECTIVES: To assess the efficacy and tolerability of immunomodulatory interventions on seizures, adverse effect profile, cognition, and quality of life, compared to placebo controls, when used as additional therapy for focal epilepsy in children and adults.

SEARCH METHODS: For the latest update, we searched the following databases on 11 November 2021: Cochrane Register of Studies (CRS Web) and Medline (Ovid) 1946 to 10 November 2021. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. We placed no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies.

SELECTION CRITERIA: Randomised placebo-controlled trials of add-on immunomodulatory drug interventions, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. Eligible participants were children (aged over 2 years) and adults with focal epilepsy.

DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. We assessed the following outcomes. 1. 50% or greater reduction in seizure frequency. 2. Seizure freedom. 3. Treatment withdrawal for any reason. 4. Quality of life. 5.

ADVERSE EFFECTS: We used an intention-to-treat (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (95% Cl).

MAIN RESULTS: We included three randomised, double-blind, placebo-controlled trials on a total of 172 participants. All trials included children and adults over two years of age with focal epilepsy. Treatment phases lasted six weeks and follow-up from six weeks to six months. One of the three included trials described an adequate method of concealment of randomisation, whilst the other two trials were rated as having an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in all three trials. All analyses were by ITT. One trial was sponsored by the manufacturer of an immunomodulatory agent and therefore was at high risk of funding bias. Immunomodulatory interventions were significantly more effective than placebo in reducing seizure frequency (risk ratio (RR) 2.30, 95% confidence interval (CI) 1.15 to 4.60; 3 studies, 172 participants; moderate-certainty evidence). For treatment withdrawal, there was insufficient evidence to conclude that people were more likely to discontinue immunomodulatory intervention than placebo (RR 1.04, 95% CI 0.28 to 3.80; 3 studies, 172 participants; low-certainty evidence). The RR for adverse effects was 1.16 (95% CI 0.84 to 1.59; 1 study, 66 participants; low-certainty evidence). Certain adverse effects such as dizziness, headache, fatigue, and gastrointestinal disorders were more often associated with immunomodulatory interventions. There were little to no data on cognitive effects and quality of life. No important heterogeneity between studies was found for any of the outcomes. We judged the overall certainty of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals.

AUTHORS' CONCLUSIONS: Immunomodulatory interventions as add-on treatment for children and adults with focal epilepsy appear to be effective in reducing seizure frequency. It is not possible to draw any conclusions about the tolerability of these agents in children and adults with epilepsy. Further randomised controlled trials are needed.

PMID:37842826 | PMC:PMC10577807 | DOI:10.1002/14651858.CD009945.pub3

Drug Ther Bull. 2023 Oct 16:dtb-2023-000056. doi: 10.1136/dtb.2023.000056. Online ahead of print.

NO ABSTRACT

PMID:37845001 | DOI:10.1136/dtb.2023.000056