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Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings

Tsai JJ, Wu T, Leung H, Desudchit T, Tiamkao S, Lim KS, et al.

Acta Neurol. Scand., 2018 Apr;137(4):378-391.
PMID: 29214650 DOI: 10.1111/ane.12879

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Matched MeSH terms: Pyridones/therapeutic use*
Fulltext Combined oral and parenteral iron chelation in beta thalassaemia major

Balveer K, Pyar K, Wonke B

Med J Malaysia, 2000 Dec;55(4):493-7.
PMID: 11221163

Thalassaemics in Malaysia are poorly chelated because desferrioxamine is too expensive and cumbersome for long term compliance. The efficacy and tolerability of the oral chelator deferiprone, and the effects of using a combination therapy in our patients were studied. Ten patients completed the study and the mean serum ferritin reduced from 7066.11 ug/L (2577-12,896 ug/L) to 3242.24 ug/L (955-6120 ug/L). The liver iron concentration did not show a significant drop (19.6 vs 18.2 mg/g dry weight) although 3 patients showed reductions ranging from 30-40%. Concomitant use of desferrioxamine increased the urinary excretion from a mean of 13.66 mg/day to 27.38 mg/day. Main side effects seen were nausea and rashes.

Matched MeSH terms: Pyridones/therapeutic use
Fulltext A post hoc analysis of the long-term safety and efficacy of perampanel in Asian patients with epilepsy

Inoue Y, Kaneko S, Hsieh PF, Meshram C, Lee SA, Aziz ZA, et al.

Epilepsia, 2019 03;60 Suppl 1:60-67.
PMID: 30869167 DOI: 10.1111/epi.14645

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.

Matched MeSH terms: Pyridones/therapeutic use*
Enhanced Solubility and Bioavailability of Dolutegravir by Solid Dispersion Method: In Vitro and In Vivo Evaluation-a Potential Approach for HIV Therapy

Chaudhary S, Nair AB, Shah J, Gorain B, Jacob S, Shah H, et al.

AAPS PharmSciTech, 2021 Apr 09;22(3):127.
PMID: 33835317 DOI: 10.1208/s12249-021-01995-y

Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 μg/mL) when compared to the physical mixture (4.12 μg/mL) and pure drug (3.45 μg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 μg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 μg/h/mL) and pure drug (49.27±6.16 μg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.

Matched MeSH terms: Pyridones/therapeutic use
Profile of Patients Diagnosed With Acute Venous Thromboembolism in Routine Clinical Practice: The RE-COVERY DVT/PE™ Study

Goldhaber SZ, Ageno W, Casella IB, Chee KH, Schellong S, Singer DE, et al.

Am J Med, 2020 08;133(8):936-945.
PMID: 32325043 DOI: 10.1016/j.amjmed.2020.03.036

BACKGROUND: The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions.
METHODS: In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later.
RESULTS: A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke.
CONCLUSIONS: These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.

Matched MeSH terms: Pyridones/therapeutic use