Biomedical subjects

E P Monaghan

Publications and source records attributed to E P Monaghan.

8 recordsLinked to original sources

PubMed2000

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.

Anticonvulsants↗

PubMed2000

Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study Group.

PURPOSE: A double-blind, randomized, placebo-controlled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed. METHODS: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner. RESULTS: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. Kaplan-Meier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc chi2 probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group. CONCLUSIONS: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity.

Adolescent↗

PubMed1997

Initial human experience with ganaxolone, a neuroactive steroid with antiepileptic activity.

PURPOSE: Studies were conducted to establish the safety, tolerability, and pharmacokinetics of the antiepileptic drug (AED) ganaxolone. Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the gamma-aminobutyric acid type A (GABA[A]) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals. METHODS: Ninety-six healthy male and female volunteers received ganaxolone in a variety of formulations, doses, and dosing regimens. The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented. RESULTS: Ganaxolone was well tolerated after single doses (< or =1,500 mg) and after multiple doses (< or =300 mg b.i.d. for 10 days). Steady-state plasma levels (trough) occurred after approximately 7 days of dosing, with mean steady-state plasma concentrations (Cmax) in multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or life-threatening adverse events attributed to the drug were observed. The majority of adverse events reported were mild (82%) to moderate (14%) and were limited to headache, dizziness, somnolence, gastrointestinal disturbances, and malaise. CONCLUSIONS: Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg. Pharmacokinetic analysis revealed a linear and proportional increase in the area under the curve (AUC) and Cmax values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable.

Administration, Oral↗

PubMed1996

Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, double-blind, placebo-controlled trial.

Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3, 0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.

Adult↗

PubMed1993

Brain lesions affect penile reflexes.

Electrolytic lesions of several potential brain afferents to the spinal nucleus of the bulbocavernosus (SNB) affect the display of penile reflexes. Ablation of the median and pontine raphe areas significantly potentiates the expression of cups and flips. Animals with a bilateral lesion of the paraventricular nucleus of the hypothalamus have a shorter latency to the first erection but otherwise display normal reflex behavior. Although bilateral destruction of the lateral vestibular nucleus (LVN) completely eliminated penile reflex activity, it also caused significant motor impairment thus clouding conclusions concerning the normal role of the LVN in penile reflex behavior. These and other results support the hypothesis that these brain regions which project to the SNB region normally modulate spinal reflex behavior of the rat penis.

Afferent Pathways↗

PubMed1992

The role of the bulbocavernosus in penile reflex behavior in rats.

The sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) innervates the bulbocavernosus (BC) and levator ani (LA), striated perineal muscles. By transecting the pudendal nerve just proximal to the BC muscle, we removed spinal input to both muscles while leaving them mechanically intact. Such denervation of the BC/LA muscles virtually eliminated the display of reflexive penile cups, while having no significant effect on penile erections, or flips.

Animals↗

PubMed1991

Brain sites projecting to the spinal nucleus of the bulbocavernosus.

Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) occupy a distinct dorsomedial position in the ventral horn of lumbar segments 5 and 6 and innervate sexually dimorphic striated muscles of the rat perineum, including the bulbocavernosus and levator ani. To begin the study of brain influences upon SNB function, we used retrograde tracers to identify brain regions that project to the area of SNB motoneurons. Our findings provide strong evidence that lateral vestibular and several reticular nuclei innervate the SNB. Additional possible afferents include the superior and medial vestibular nuclei, raphe nucleus, red nucleus, interstitial nucleus of the medial longitudinal fasciculus, and paraventricular nucleus.

Animals↗

PubMed1986

Naltrexone blocks the effects of prenatal stress on sexual behavior differentiation in male rats.

The male offspring of rats stressed three times daily during days 14-21 of pregnancy were more likely to show lordotic behavior when tested in adulthood than were control males. This feminization of sexual behavior was not observed if the mothers were injected with the opioid antagonist naltrexone before being stressed. These data suggest that endogenous opioids released under conditions of stress can alter the normal process of sexual behavior differentiation in the fetal male rat.

Animals↗