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Background: There is a dearth of research on the factors linked with adverse events (AEs) associated with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL), particularly in the elderly. Therefore, this study aimed to investigate self-reported AEs and identify factors associated with the occurrence of AEs following NMVr or MOL treatment among survey participants aged 60 years or older in South Korea., Methods: This nationwide survey was conducted through in-person interviews using structured questionnaires, from July 24 to August 31, 2023. Eligible participants included individuals aged 60 years or older who had been diagnosed with coronavirus disease 2019 (COVID-19) and received NMVr or MOL. The study outcomes included self-reported demographic, lifestyle, and health characteristics associated with the occurrence of AEs. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of each characteristic in participants with and without AEs., Results: Of the 520 participants, 123 (23.7%) experienced at least one AE with oral COVID-19 treatment: 21.0% (96/458) for NMVr and 43.5% (27/62) for MOL. None of the participants reported any serious AEs. Increased odds of AE occurrence were observed in participants treated with MOL compared to those treated with NMVr (aOR, 3.05; 95% CI, 1.67-5.57), a history of two or more compared to one COVID-19 diagnosis (1.93; 1.03-3.62), and self-reported health status as "Unhealthy" compared to "Healthy" (2.65; 1.31-5.36)., Conclusion: No AEs required further evaluation to change treatment strategies in elderly patients on NMVr or MOL. Several factors, including the use of MOL, history of COVID-19, and reported health status, were associated with an increased incidence of AEs. Both treatments may still be useful choices for patients with non-severe COVID-19 aged 60 years or older. However, close monitoring of unidentified potential harm and further investigation of the factors associated with the occurrence of AEs are needed., Competing Interests: Ju-Young Shin received grants from the Korea Institute of Drug Safety and Risk Management. Other authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objectives: Previous research reported inconsistent results on the efficacy of molnupiravir in treating COVID-19. Moreover, efficacy was not assessed in the intended-use population (IUP), as defined by the FDA. Therefore, we aimed to evaluate the effectiveness and safety of molnupiravir for the treatment of COVID-19 in the IUP., Methods: We performed a retrospective cohort study on all IUP in Israel's Clalit Health Services from January 16, 2022, to February 16, 2023. The effectiveness outcome was the incidence of hospitalization or death due to COVID-19, and the safety outcome was the incidence of all-cause mortality within 35 days of SARS-CoV-2 infection. Cox-proportional hazard models were used to analyse the data after 1:5 propensity-score matching., Results: A total of 49 515 patients met the eligibility criteria. Of them, 3957 molnupiravir-treated patients were matched to 19 785 untreated patients. In molnupiravir-treated patients, 70 out of 3957 (5.1 per 10 000 person per day) experienced COVID-19-related hospitalization or death, compared with 699 out of 19 785 untreated patients (10.4 per 10 000 person per day); RR: 0.50 (95% CI, 0.39-0.64). All-cause mortality was also lower in the treated group, with 41 out of 3957 (3.0 per 10 000 person per day) experiencing mortality compared with 414 out of 19 785 untreated patients (6.1 per 10 000 person per day); RR: 0.50 (0.36-0.68)., Discussion: In a real-world cohort of IUP, molnupiravir therapy was associated with a significant reduction in hospitalizations or deaths due to COVID-19 and all-cause mortality., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis., Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed., Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%])., Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated., Funding: Orphazyme., Competing Interests: Declaration of interests MB reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association; as well as consulting fees from Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. The University of Miami licensed some of MB's research data to Biogen to aid in the design of the ATLAS trial; MB receives a royalty payment received by the University of Miami as part of this licensing agreement. DR received consulting fees from Orphazyme for biostatistical consulting services for the ORARIALS-01 protocol. LHvdB reports consulting fees from Amylyx, Biogen, Ferrer, Corcept, Orion, and Orphazyme, as well as payment for scientific advisory board activities from Takeda. AC reports grants from the Italian Ministry of Health, the Italian Ministry of University and Research, the European Commission, Biogen, and the ALS Association; as well as consulting fees from Mitsubishi Tanabe, Biogen, Roche, Sanofi, Denali Pharma, Cytokinetics, Eli Lilly, and Amylyx Pharmaceuticals; he has received a research grant from Biogen. PMA report grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Ulla-Carin Lindquist Foundation, NEURO, the Brain Foundation, and the European Commission; as well as consulting fees from Biogen, Avrion, Arrowhead, Regeneron, uniQure, Orphazyme, and Roche. P-FP reports meeting and travel support from Orphazyme. PVD reports grant from CSL Behring; speakers fees from Biogen and Amylyx; and participation in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, and VectorY. SP reports grants from Cytokinetics, Biogen, and Roche; consulting fees from Cytokinetics, Amylyx, Biogen, Roche, and Zambon; payment or honoraria from Biogen, Zambon, Roche, Amylyx, Italfarmaco, and Desitin; meeting and travel support from Biogen, Desitin, Zambon, Amylyx, Italfarmaco, PTC Therapeutics, and Ferrer; and participation in data safety monitoring boards or advisory boards for ORION Pharma, Amylyx, Biogen, Roche, and Zambon. SL reports consulting fees from Biogen and Amylyx; and participation in a data safety monitoring board (chair) for Neurosense Therapeutics. NAG reports grants from Abcuro, Amylyx, Alexion, Annelixis, Annexon, Brainstorm Cell Therapeutics, Calico, Cytokinetics, Fulcrum, Healey, Janssen, Kezar, Medicinova, MT Pharma, Octapharma, PTC, Sanofi, and Transposon; consulting fees from Abcuro, Alexion, Amylyx, Annexon, Argenx, Astrazeneca, CSL Behring, Fulcrum, Kezar, MT Pharma, Sanofi Genzyme, Sarepta, and UCB; and speakers fees from Argenx and CSL. CQ reports grants from Sanofi, Biogen, and Amylyx; consultant fees from Amylyx and Biogen; and honoraria from Seattle Science Foundation. AG reports consulting fees from Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics; support for attending meetings and travel from Amylyx, Mitsubishi Tanabe Pharma, QurAlis, Alexion, and ALS Pharmaceuticals; has a leadership role in ALS Canada; has stock or stock options in QurAlis; and has received equipment, materials, drugs, medical writing, gifts or other services from Amylyx. LZ reports grants from ALS Canada, Amylyx, Biogen, and Mitsubishi Tanabe Pharma; consulting fees from Amylyx, Cytokinetics, Mitsubishi Tanabe Pharma, Neurosense, and Biogen; and participation in a data safety monitoring board (chair) for Amylyx. CS reports speakers fees from Mitsubishi Tanabe Pharma Canada; participation in an advisory board for Biogen; and unpaid roles in Canadian ALS Research Consortium and Scientific Medical Advisory Board for ALS Canada. CN received compensation for consultant fees and training activities by Biogen, Roche, Genzyme, and Mitsubishi Tanabe. JMS reports grants from NINDS, ALS Association, AB Sciences, Acorda Therapeutics, Alector, Amylyx, Biogen, Cytokinetics Incorporated, Ionis, Mitsubishi Tanabe Pharma America, Quralis, PTC, Sanofi, Wave, and Myolex; consulting fees from Amylyx, Cytokinetics, Denali, GSK, Mitsubishi Tanabe Pharma America, Neurosense, Orthogonal, Pinteon, RRD, Acurastem, Revalasio, Apellis, Novartis, Sanofi, and Immunity Pharma; participation in data safety monitoring boards or advisory boards for Swanbio and Braingate; and stock or stock options in Aural Analytics. MRT reports salary support from the Motor Neurone Disease Association; royalties or licences from Oxford University Press, Oneworld, and Karger; speakers' honoraria from University of Miami; and participation in advisory board for Biogen and Novartis. JW reports grants from the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association. TH, MAG, TB, RB, HD, and CS are previous employees of Orphazyme. MK-K reports research support from the JPND by the National Center for Research and Development, and from E-Rare by the National Science Center of Poland. MK-K also reports paid consulting fees from Amylyx, Ferrer, and Cytokinetics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19., Methods: In an open-label, parallel-group, multicenter trial in Thailand, participants with moderate COVID-19 and at least one factor associated with severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir or oral favipiravir (standard of care). Phone calls for remote symptom assessment were made on Days 6, 15, and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging., Results: Nine hundred seventy-seven participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; P = 0.021); all-cause death in 0% (0/483) and <1% (1/482); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); treatment-related adverse event in 1% (5/483) and 1% (4/486); and serious adverse event in 1% (4/483) and 1% (4/486)., Conclusions: Favipiravir and molnupiravir had a similar efficacy and safety profile. Whether either of the two reduced the risk of complications during the omicron era in this population with a low risk of pulmonary involvement and a high vaccine coverage remains unclear. There were no differences in any of the safety endpoints., Thai Clinical Trials Registry Id: TCTR20230111009., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Source Citation: Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386:509-20. 34914868.

Background: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29., Results: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group., Conclusions: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)., (Copyright © 2021 Massachusetts Medical Society.)

[Figure: see text].

Background and Aims: Molnupiravir is a newer oral antiviral drug that has recently received emergency use authorization (EUA) in USA, UK and India. We aim to conduct an update on our previous systematic review to provide practical clinical guideline for using molnupiravir in patients with COVID-19., Methods: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar until January 5, 2022, using key MeSH keywords., Results: Final result of phase 3 study in 1433 non-hospitalized COVID-19 patients showed a significant reduction in composite risk of hospital admission or death (absolute risk difference, -3.0% [95% confidence interval {CI}, -5.9 to -0.1%]; 1-sided P = 0.02) although with a non-significant 31% relative risk reduction (RRR). RRR for death alone was 89% (95% CI, 14 to 99; P-value not reported). Number needed to treat to prevent 1 death or 1 hospitalization or death composite appears to be closely competitive to other agents having EUA in people with COVID-19. However, cost-wise molnupiravir is comparatively cheaper compared to all other agents., Conclusion: Molnupiravir could be a useful agent in non-pregnant unvaccinated adults with COVID-19 who are at increased risk of severity including hospitalization. However, it is effective only when used within 5-days of onset of symptoms. A 5-days course seems to be safe without any obvious short-term side effects., Competing Interests: Declaration of competing interest We hereby declare that we have no conflict of interest, related to this article titled “An Updated Practical Guideline on Use of Molnupiravir and Comparison with Agents having Emergency Use Authorization for Treatment of COVID-19”., (Copyright © 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis., (© 2022 Environmental Mutagen Society.)

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N 3 -methyladenine and N 7 -methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m 2 daily × 5 may be safely administered with MX 150 mg/m 2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.

Objective: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS)., Methods: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1 -mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS)., Results: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol., Conclusions: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol., Clinicaltrialsgov Identifier: NCT00706147., Classification of Evidence: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol., (© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aim: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity., Materials and Methods: Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function., Results: Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function., Conclusion: These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity., (© 2017 John Wiley & Sons Ltd.)

Introduction: TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed., Purpose: Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression., Methods: Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months., Conclusions: When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER.

Recent years have seen an explosion of research into increasingly prevalent neurodegenerative diseases. Arimoclomol (BRX-220), being developed by CytRx Corp, is an oral therapeutic candidate for the treatment of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. ALS is a fatal, incurable disorder, which can present as sporadic (90 to 95% of cases) or familial (5 to 10% of cases) forms. The etiology of sporadic ALS remains unknown and much of the understanding of ALS pathogenesis has been derived through study of its familial forms; in particular, through study of autosomal dominant mutations in the SOD1 (copper/zinc superoxide dismutase) gene, which cause approximately 20% of familial ALS cases. Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after symptom onset. Clinical trials have reported good tolerability and safety. This paper discusses the rationale for arimoclomol use in ALS, the preclinical and clinical evidence collected to date, the likelihood of its promising preclinical results translating to humans, and the relevance of this research for neurodegeneration as a whole.

Arimoclomol, an amplifier of heat shock protein expression involved in cellular stress response, has emerged as a potential therapeutic candidate in amyotrophic lateral sclerosis (ALS) in recent years. Treatment with arimoclomol was reported to improve survival and muscle function in a mouse model of motor neuron disease. Several single- and multiple-dose safety studies have been completed in healthy control subjects. A 3-month Phase IIa study in people with ALS demonstrated safety at dosages up to 300 mg/day and another study is currently recruiting participants with familial ALS caused by mutations in the superoxide dismutase gene. We review the rationale for testing arimoclomol in sporadic and familial ALS in the context of available safety and pharmacokinetic data. Published and unpublished literature relative to the drug in the past two decades is discussed. The current review attempts to bring together our existing understanding of the actions of arimoclomol with the disease profile of ALS. The pharmacological profile of arimoclomol and the available preclinical data make it a promising therapeutic possibility in ALS.

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned., ((c) 2008 Wiley Periodicals, Inc.)

5-(Aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) is an anti-tumour prodrug which recently entered clinical trials in combination with Escherichia coli nitroreductase in a gene-directed enzyme prodrug therapy (GDEPT) context. A Phase I trial of the prodrug, however, revealed dose-limiting hepatotoxicity (transaminitis). The aim of this study was to find out whether the prodrug undergoes reductive metabolism in human liver to cytotoxic metabolites which may contribute to this clinical toxicity. CB 1954 (2.5-250 microM) was incubated with human liver preparations (2-8 mg/mL of S9, cytosolic or microsomal proteins) in the presence of NAD(P)H (1 mM). The NADH- and NADPH-dependent formation of both 2- and 4-nitroreduction products was demonstrated, with NADPH being the preferred cofactor, by HPLC and mass spectrometry. The major metabolite formed in all three human liver preparations was the 4-hydroxylamine, a potent DNA cross-linking cytotoxin. The 2-hydroxylamine and 2-amine metabolites were also detected, both of which have also been demonstrated to be highly cytotoxic. 2-Nitroreduction was far greater in S9 compared with cytosol and was not detected in microsomal preparations. Although 2- and 4-nitroreduction of CB 1954 was inhibited under hyperoxic conditions, substantial metabolism was observed under atmospheric oxygen levels. These studies demonstrate that human liver is capable of aerobic reductive bioactivation of CB 1954 to cytotoxic metabolites in vitro, possibly involving multiple enzymes, which may account for the clinical hepatotoxicity observed.

Drug reactions in patients with HIV infection, e.g. fever or rash, are a frequently occurring clinical problem. These side effects particularly are observed with sulfonamides; however, many other drugs have also shown to induce allergic reactions when given to patients with HIV infection. The production of hydroxylamines has been put forward as one of the explanations for these high incidence of reactions on drugs. Since sulfonamides are the first choice of therapy for the treatment and prophylaxis of Pneumocystis carinii pneumonia, several strategies have been developed to circumvent drug reactions. In general rechallenge or desensitization are recommended in literature. This article discusses the results and risks of rechallenge and desensitization with sulfonamides or other drugs, as mentioned in the literature. Furthermore preliminary results of rechallenge with a sulfonamide, which is not metabolized into hydroxylamines, are presented. From the data in the literature it is concluded that desensitization should be preferred to rechallenge.

Idrapril is the prototype of a new class of ACE inhibitors, characterised by the presence of a hydroxdmic group. Six untreated in-patients with essential hypertension were given single oral doses of the calcium salt of idrapril, idrapril calcium (200 mg) and placebo according to a double blind, randomised experimental design. Supine and upright blood pressure, heart rate, plasma idrapril serum UCE, active renin and angiotensin II were measured at timed intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours (3.01 microgm x ml(-1)), and by 12 hours the compound had almost disappeared (67 ng x ml(-1)). Derived t1/2 was 1.4-2.2 h. ACE activity was suppressed [from 77.9 to 3.3 after 2 hours and 11.8 after 12 hours nmol(-1) x min(-1) x ml] and angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5 (after 24 hours) pg x ml(-1)]. Compared to placebo, idrapril calcium significantly lowered both supine blood pressure starting at 4 hours (idrapril calcium 140/93 mmHg; placebo 157/101 mmHg; placebo 147/100 mmHg), and upright blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100 mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg). Idrapril calcium appears to be an effective ACE inhibitor in essential hypertension, with a hypotensive action for up to 24 h.

Two patients developed symptomatic methemoglobinemia and hemolytic anemia after treatment with phenazopyridine. Methemoglobinemia appears to be a rare occurrence after commonly used doses of phenazopyridine; phenazopyridine-associated hemolytic anemia has been reported both after overdose and after usual doses. The presentation of methemoglobinemia in the first patient and the response to treatment with methylene blue in the second patient were unusual, suggesting that the patients had a red cell defect or were exposed to other oxidizing substances. One of the major metabolites of phenazopyridine is aniline, a known cause of methemoglobinemia. Aniline-induced methemoglobinemia is less responsive to treatment with methylene blue than nitrate- or nitrite-induced methemoglobinemia. This may explain, in part, the poor response to methylene blue by one of our patients.

Study Objective: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents., Design: In-vitro toxicity assay on lymphocytes., Setting: Clinics for adverse drug reactions in an adult and pediatric tertiary care center., Patients: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction., Interventions: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole., Measurements and Main Results: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions., Conclusions: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.