Drugs in Research & Development最新文献

{"title":"Development of a Biosimilar of Agalsidase Beta for the Treatment of Fabry Disease: Preclinical Evaluation.","authors":"André B P van Kuilenburg,&nbsp;Carla E M Hollak,&nbsp;Ana Travella,&nbsp;Melisa Jacobs,&nbsp;Lucas D Gentilini,&nbsp;René Leen,&nbsp;Karen M M Ghauharali-van der Vlugt,&nbsp;Femke S Beers Stet,&nbsp;Susan M I Goorden,&nbsp;Sanne van der Veen,&nbsp;Marcelo Criscuolo,&nbsp;Mariana Papouchado","doi":"10.1007/s40268-023-00421-x","DOIUrl":"https://doi.org/10.1007/s40268-023-00421-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.</p><p><strong>Methods: </strong>Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.</p><p><strong>Results: </strong>AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.</p><p><strong>Conclusion: </strong>These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"141-153"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/84/bf/40268_2023_Article_421.PMC10293523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9709367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability of Cariban^® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.","authors":"Paula Saz-Leal, Laura Zamorano-Domínguez, Jesús Frías, Pedro Guerra, Marc Saura-Valls, Ramón Roca-Juanes, Joaquín Nebot-Troyano, Eva García-Aguilar, Tatiana Vilchez, Katia Urso","doi":"10.1007/s40268-023-00425-7","DOIUrl":"10.1007/s40268-023-00425-7","url":null,"abstract":"<p><strong>Background: </strong>Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban^® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.</p><p><strong>Objectives: </strong>In the present study, we aimed to characterize the bioavailability performance of Cariban^® in vitro and in vivo.</p><p><strong>Methods: </strong>An in vitro dissolution test was performed to evaluate the release profile of Cariban^®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban^® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.</p><p><strong>Results: </strong>Cariban^® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.</p><p><strong>Conclusion: </strong>Cariban^® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"185-195"},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/42/40268_2023_Article_425.PMC10293548.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma.","authors":"Takuji Okusaka, Manabu Morimoto, Yuichiro Eguchi, Shinichiro Nakamura, Shuichi Iino, Rie Kageyama","doi":"10.1007/s40268-023-00416-8","DOIUrl":"10.1007/s40268-023-00416-8","url":null,"abstract":"<p><strong>Background and objective: </strong>For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC.</p><p><strong>Methods: </strong>Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy.</p><p><strong>Results: </strong>In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%.</p><p><strong>Conclusions: </strong>These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"99-107"},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9b/41/40268_2023_Article_416.PMC10293504.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9704732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Simultaneously Induced Neutropenia and Hemolysis After a Single Metamizole Dose.","authors":"Raphael Allgaier,&nbsp;Arne Kandulski,&nbsp;Karsten Gülow,&nbsp;Lars Maier,&nbsp;Martina Müller,&nbsp;Hauke Christian Tews","doi":"10.1007/s40268-023-00415-9","DOIUrl":"https://doi.org/10.1007/s40268-023-00415-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Metamizole is a non-opioid ampyrone sulfonate compound with potent analgesic, antipyretic, and spasmolytic effects. Agranulocytosis is a rare life-threatening complication of metamizole.</p><p><strong>Case: </strong>Here, we present the case of a 62-year-old patient who developed agranulocytosis as well as hemolysis after a single administration of metamizole.</p><p><strong>Conclusion: </strong>This case illustrates the inherent allergic potential of metamizole and its effects on different hematopoietic cell types.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"93-98"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/47/97/40268_2023_Article_415.PMC10293139.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Centre Real-World Study on Drug Survival and Effectiveness of Brodalumab for Treatment of Psoriasis and Psoriatic Arthritis.","authors":"Cathrine Dawn Büttner Elgaard,&nbsp;Lars Iversen,&nbsp;Kasper Fjellhaugen Hjuler","doi":"10.1007/s40268-023-00422-w","DOIUrl":"https://doi.org/10.1007/s40268-023-00422-w","url":null,"abstract":"<p><strong>Background: </strong>Clinical trials have established the efficacy of brodalumab in treatment of psoriasis and psoriatic arthritis. Real-world evidence is needed to fully evaluate the drug.</p><p><strong>Objective: </strong>Here we investigate drug survival and clinical effectiveness of brodalumab in patients with psoriasis and psoriatic arthritis in a real-world setting.</p><p><strong>Methods: </strong>This was a retrospective single-centre study enrolling patients receiving brodalumab for psoriasis at the Department of Dermatology, Aarhus University Hospital, Denmark. The primary endpoints were drug survival, reasons for discontinuation, percentage of patients achieving a Psoriasis Area and Severity Index (PASI) ≤ 2 and clinical effectiveness against psoriatic arthritis.</p><p><strong>Results: </strong>Eighty-three patients were included (mean age 49.2 ± 17.4 years, 59.0% male, 9.6% bio-naïve, mean baseline PASI 10.9 ± 6.9). Twenty-seven patients discontinued treatment primarily due to ineffectiveness and adverse events (AEs). Kaplan-Meier-estimated 1-year drug survival was 65.7%. An absolute Psoriasis Area and Severity Index (PASI) ≤ 2 was achieved by 68.2% of patients at end of follow-up, by 70.0% at weeks 12-17 and by 76.2% after 40-60 weeks of treatment. Neither drug survival nor PASI ≤ 2 was associated with baseline PASI ≥ 10, body mass index ≥ 30, previous treatment with > 2 biologics or other IL-17 inhibitors in particular (P > 0.05). Psoriatic arthritis remission or partial remission was achieved by 10 out of 18 patients with psoriatic arthritis; treatment failure was reported in 5 patients.</p><p><strong>Conclusions: </strong>Brodalumab was effective against psoriasis and psoriatic arthritis in a real-world setting. The drug survival was lower than reported in other real-world settings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"155-163"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/be/ed/40268_2023_Article_422.PMC10293129.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9697898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Acetyl-L-Cysteine Reduces Cervical Carcinogenesis by Promoting Apoptosis.","authors":"Wenping Guo,&nbsp;Wang Jing","doi":"10.1007/s40268-023-00423-9","DOIUrl":"https://doi.org/10.1007/s40268-023-00423-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Cervical cancer is the fourth leading cause of cancer death in women, and is one of the most common malignant tumors of the reproductive system. However, more effective treatment for cervical cancer is needed. In this study, we aim to investigate whether N-acetyl-L-cysteine (NAC) could inhibit the proliferation of human papillomavirus (HPV)-positive cells, and reduce cervical carcinogenesis.</p><p><strong>Methods: </strong>The cervical cancer cell lines SiHa, HeLa, HPV-negative cell line C33A, and the immortalized human cervical keratinocyte cells S12 were used. The protein expression was determined using Western blot assay. mRNA expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation was determined by Cell Counting Kit-8 assay. Cell apoptosis was evaluated using Annexin V-FITC apoptosis kits. The numbers of colonies were measured using colony-forming assay. Xenograft tumor necrosis and HPV16 E7 expression were determined using hematoxylin and eosin (H&E) staining and immunohistochemistry.</p><p><strong>Results: </strong>Our results showed that NAC treatment at the concentration of 1.5 mM significantly promoted cell apoptosis and reduced cell growth by inhibiting HPV16 E7 expression. NAC inhibited HPV16-oncoprotein-induced hypoxia-inducible factor (HIF)-1α protein expression and Akt activation in vitro. Additionally, NAC suppressed tumor growth, as evidenced by the smaller tumor size in the xenograft mouse model and decreased HPV16 E7 expression in tumor tissues.</p><p><strong>Conclusion: </strong>Our findings demonstrate that NAC exhibits the potential to promote HPV-positive cell apoptosis, and suppress the proliferation of HPV-positive cells by inhibiting cell inhibitor of apoptosis protein 2 and HIF-1α.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"165-174"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/7e/40268_2023_Article_423.PMC10293158.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9698917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Bioequivalence of Abiraterone Acetate Tablets in Healthy Chinese Volunteers: An Open, Randomized, Single-Dose, Three-Period, Three-Sequence Crossover Study.","authors":"Zhao-Xin Wu,&nbsp;Chen-Jing Wang,&nbsp;Ping Shi,&nbsp;Yan-Ping Liu,&nbsp;Ting Li,&nbsp;Fei-Fei Sun,&nbsp;Yao Fu,&nbsp;Xiao-Meng Gao,&nbsp;Ya-Ping Ma,&nbsp;Yu Cao","doi":"10.1007/s40268-023-00418-6","DOIUrl":"https://doi.org/10.1007/s40268-023-00418-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers.</p><p><strong>Methods: </strong>A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded.</p><p><strong>Results: </strong>Under fasting conditions, the maximum plasma concentration (C_max) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUC_t) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC_∞) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUC_t and AUC_∞ were in the range of 0.8000-1.2500, and the coefficient of variation (CV_WR) of C_max was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500.</p><p><strong>Conclusion: </strong>Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier NCT04863105, registered 26 April 2021-retrospectively registered ( https://register.</p><p><strong>Clinicaltrials: </strong>gov/prs/app/action/SelectProtocol?sid=S000ARAA&selectaction=Edit&uid=U00050YQ&ts=2&cx=-vbtjri.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 2","pages":"121-127"},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/10/21/40268_2023_Article_418.PMC10293147.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9708866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomised Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Palovarotene Ophthalmic Solution.","authors":"William J Foster,&nbsp;Andrew L Strahs,&nbsp;Kent W Small,&nbsp;James M Roach","doi":"10.1007/s40268-022-00410-6","DOIUrl":"https://doi.org/10.1007/s40268-022-00410-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Palovarotene, a selective retinoic acid receptor γ agonist, is under investigation for the treatment of dry eye disease. This study aimed to determine the ocular and systemic safety, tolerability and pharmacokinetics of palovarotene ophthalmic solution (PVO-OS) in healthy adults.</p><p><strong>Methods: </strong>This was a randomised, vehicle-controlled phase I study (NCT04762355; retrospectively registered). Participants received either PVO-OS (at 0.025, 0.05 or 0.10 mg/mL) or a vehicle (placebo-to-match PVO-OS) once-daily or twice-daily for seven consecutive days. Safety was assessed by ocular and systemic assessments. Blood samples for pharmacokinetic assessments were collected before and after dose administration.</p><p><strong>Results: </strong>Thirty-six participants were randomised to PVO-OS and 12 to the vehicle. Overall, 89 treatment-emergent ocular adverse events (TEOAEs) were reported by 22 participants (61.1%) receiving PVO-OS and ten TEOAEs were reported by five participants (41.7%) receiving the vehicle. Erythema, irritation and skin dryness of the eyelid were the most common TEOAEs in participants receiving PVO-OS. The incidence of TEOAEs and eyelid-related findings in the PVO-OS groups increased with ascending dose and frequency compared with participants treated with the vehicle. All TEOAEs were mild (96.6%) or moderate (3.4%) and resolved without sequelae. Plasma palovarotene concentrations were generally measurable for up to 3-4 h for 0.025 mg/mL and 0.05 mg/mL and up to 12 h for 0.10 mg/mL dose regimens, independent of the frequency of administration.</p><p><strong>Conclusions: </strong>PVO-OS was generally well tolerated at doses up to and including 0.10 mg/mL twice daily. Similar pharmacokinetic profiles were observed for the once-daily and twice-daily regimens following multiple ascending doses of PVO-OS.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 1","pages":"43-53"},"PeriodicalIF":3.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/22/a5/40268_2022_Article_410.PMC9985528.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9390712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.","authors":"Daniela R Junqueira,&nbsp;Dimitri Bennett,&nbsp;Susanna Y Huh,&nbsp;Kyle Fahrbach,&nbsp;Binod Neupane,&nbsp;Marissa Betts","doi":"10.1007/s40268-023-00413-x","DOIUrl":"https://doi.org/10.1007/s40268-023-00413-x","url":null,"abstract":"<p><strong>Background: </strong>Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis.</p><p><strong>Methods: </strong>We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI).</p><p><strong>Results: </strong>We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs.</p><p><strong>Conclusions: </strong>The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions.</p><p><strong>Registration: </strong>PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 1","pages":"1-20"},"PeriodicalIF":3.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dd/6a/40268_2023_Article_413.PMC9985532.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9408628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyses of Basal and Squamous Cell Carcinoma Reported as an Adverse Drug Reaction and Comparison with Cases from the Cancer Registry from Germany.","authors":"Diana Dubrall,&nbsp;Bernhardt Sachs,&nbsp;Klaus Kraywinkel,&nbsp;Maike Schulz,&nbsp;Matthias Schmid,&nbsp;Wilma Fischer-Barth,&nbsp;Jens Bate","doi":"10.1007/s40268-022-00407-1","DOIUrl":"https://doi.org/10.1007/s40268-022-00407-1","url":null,"abstract":"<p><strong>Introduction: </strong>In Germany, incidence rates of basal cell (BCC) and squamous cell carcinoma (SCC) rose significantly from 1998 to 2010. Ultraviolet (UV) light exposure, immunosuppressants and drugs with photosensitising potential are known to increase the risk to develop BCC and SCC. The aim of our study was to analyse the adverse drug reaction (ADR) reports from Germany referring to BCC and SCC and to compare them to BCC and SCC occurring in the general population.</p><p><strong>Methods: </strong>We analysed all validated spontaneous ADR reports referring to BCC (n = 191) and SCC (n = 75) from Germany contained in the European ADR database EudraVigilance prior to 6 March 2019. These reports were compared to 1,267,210 BCC and 476,903 SCC cases from the German Centre for Cancer Registry Data recorded from 2006 to 2018.</p><p><strong>Results: </strong>The number of BCC and SCC reports as well as the BCC and SCC incidences in the registry increased in the analysed time period. Patients with drug-associated BCC (60 years) and SCC (64 years) were younger than patients with BCC (72 years) and SCC (76 years) in the registry. In 57.1 and 60.0% of BCC and SCC reports immunosuppressants were reported as suspected. The reported suspected drug was assumed to possess a photosensitising potential in 41.9 and 44.0% of BCC and SCC reports.</p><p><strong>Conclusions: </strong>In Germany, drug-associated BCC and SCC occurred at a younger age than in the general population. The results underline the necessity for skin cancer screening of patients treated with immunosuppressants or with drugs with photosensitising potential.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 1","pages":"21-33"},"PeriodicalIF":3.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/82/74/40268_2022_Article_407.PMC9985531.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10840943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}