Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease:A dose-finding study

In advanced stages of Parkinson's disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias

Rapid Responders to Frovatriptan in Acute Migraine Treatment: Results from a Long-Term, Open-Label Study

Background. the Chronic Nature of Migraine and the Reliance on Acute Treatment Constitute the Basis of the Present Long-Term, Open-Label Study. Objectives. First, Assessment of the Tolerability and Safety of Frovatriptan, 2.5-7.5 Mg Taken Orally over 24 Hours, for the Acute Treatment of Migraine, Repeatedly over a 12-Month Period. Second, Assessment of the Efficacy and Tolerability of a Second, Double-Blind Dose of 2.5-Mg Frovatriptan, Compared with Placebo, for Nonresponse at 2 Hours after Treatment of Moderate or Severe Headache with 2.5-Mg Frovatriptan. Results. with Regard to the First Attack Treated, 173 (36%) of the 486 Subjects in the Study Did Not Take a Second Dose at 2 Hours for Nonresponse. at 2 Hours and 4 Hours, These Rapid Responders Experienced a Decrease in Headache Intensity from Moderate or Severe to Mild or No Pain in 84% and 98%, Respectively ( Headache Response ). Six Percent of Them Experienced Recurrence of Moderate or Severe Headache within 24 Hours Following a Response at 4 Hours and 12% Took Rescue Medication. the Response, Measured in Terms of Median Time to Complete Migraine Relief, Was Maintained over 30 Subsequent Migraine Attacks, Treated from Attack 2 Onwards over the Course of 12 Months. Conclusion. Frovatriptan Provides a Remarkably Fast and High Headache Response in a Subgroup of More Than One-Third of Migraineurs, with a Very Low 24-Hour Headache Recurrence and Low Rescue Medication Intake. © 2009 American Academy of Pain Medicine

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model

International audienceBACKGROUND:Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.METHODS:Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).RESULTS:Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.CONCLUSION:Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies

Safinamide inhibits in vivo glutamate release in a rat model of Parkinson's disease

To investigate whether the reversible MAO-B inhibitor and sodium channel blocker safinamide impairs glutamate release under parkinsonian conditions in vivo, and this effect is dependent on MAO-B inhibition, safinamide (and rasagiline as a comparator) were administered to 6-hydroxydopamine hemilesioned rats, a model of Parkinson's disease, and haloperidol-treated rats, a model of neuroleptic-induced parkinsonism. A microdialysis probe was implanted in the dopamine-depleted dorsolateral striatum, globus pallidus, subthalamic nucleus or substantia nigra reticulata of 6-hydroxydopamine hemilesioned rats. Glutamate and GABA release was stimulated by reverse dialysis of veratridine, and safinamide or rasagiline were acutely administered before veratridine at doses inhibiting MAO-B > 50%. A microdialysis probe was implanted in the substantia nigra reticulata of naive rats to monitor glutamate and GABA release following acute haloperidol and safinamide administration. Safinamide inhibited the veratridine-evoked glutamate release in the globus pallidus and subthalamic nucleus but not in the striatum and substantia nigra. Moreover, it reduced pallidal and nigral GABA release. Conversely, rasagiline failed to modify the veratridine-induced glutamate and GABA release in the basal ganglia. Safinamide also inhibited the haloperidol-induced nigral glutamate release. MAO-B inhibitors safinamide and rasagiline differ in their abilities to inhibit depolarization-evoked glutamate release in the basal ganglia of parkinsonian rats. The ineffectiveness of rasagiline suggests that MAO-B inhibition does not contribute to the anti-glutamatergic activity of safinamide. The glutamate-inhibiting action of safinamide within the subthalamo-external pallidal loop, which shows abnormal activity in Parkinson's disease, might contribute to its therapeutic actions of improving motor performance without provoking troublesome dyskinesia

Safinamide's potential in treating nondystrophic myotonias: Inhibition of skeletal muscle voltage-gated sodium channels and skeletal muscle hyperexcitability in vitro and in vivo

The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson's disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNav1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of −120 mV, the half-maximum inhibitory concentrations (IC50) were 160 and 33 μM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420 μM for closed channels and 9 μM for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of −90 mV and 50-Hz stimulation, safinamide inhibited INa with an IC50 of 6 μM, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC50 of 13 μM. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED50 of 1.2 mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility

FDA Public Workshop Summary-Addressing Challenges in Inhaled Antifungal Drug Development

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On September 25, 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.</p