Biomedical subjects

W E Heydorn

Publications and source records attributed to W E Heydorn.

At least 19 recordsLinked to original sources

PubMed2000

Zaleplon - a review of a novel sedative hypnotic used in the treatment of insomnia.

Zaleplon (N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide) is a non-benzodiazepine recently introduced for clinical use. This agent is indicated for the short-term treatment of insomnia. Preclinical studies have shown that the benzodiazepines triazolam and Ro17-1812 can substitute for zaleplon in animals trained to distinguish zaleplon from saline. The benzodiazepine antagonist flumazenil can antagonise the discriminative stimulus effect of zaleplon. These findings suggest that zaleplon is recognised by animals as a benzodiazepine agent. Zaleplon is active after ip. and oral administration in a variety of motor performance tests, including locomotor activity, rotarod and the loaded grid. Zaleplon has been shown to be active in a number of different anticonvulsant models, including the pentylenetetrazole, isoniazid and electroshock models. The compound is also reported to be active against convulsions induced by bicuculline, picrotoxin and strychnine. Studies in anxiolytic models suggest that zaleplon may have weak anxiolytic activity. From preclinical studies, it appears zaleplon possesses a reduced risk of tolerance compared to triazolam, is less likely to potentiate the effects of ethanol and is unlikely to produce amnestic effects. In man, zaleplon is rapidly absorbed and undergoes extensive presystemic metabolism. The compound has a plasma half-life of approximately one hour and is metabolised primarily via the aldehyde oxidase system to form 5-oxo-zaleplon. This metabolite, along with other minor metabolites formed in vivo, do not appear to contribute to the activity of zaleplon. Metabolites of zaleplon are excreted primarily via the urine. Phase I studies suggest that single daytime doses of zaleplon up to 15 mg are well-tolerated. Short-term impairment of performance occurs when zaleplon is administered during the day at doses epsilon 20 mg. However, given the short half-life of the compound, significant impairment of daytime performance is unlikely if zaleplon is administered at bedtime or shortly after retiring for the evening. Results from Phase II/III studies suggest that zaleplon (5 - 20 mg) produces a dose-dependent reduction in sleep latency in patients suffering from primary insomnia. The clinical efficacy of zaleplon persists for at least four weeks at doses of 10 mg and 20 mg. Studies in patients with a history of drug abuse suggest that the abuse potential of zaleplon (at doses above the therapeutic dose range) is similar to that seen with the benzodiazepine triazolam.

Acetamides↗

PubMed1999

Paroxetine: a review of its pharmacology, pharmacokinetics and utility in the treatment of a variety of psychiatric disorders.

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI). In vitro studies show that it is able to produce a concentration-dependent competitive inhibition of serotonin uptake into brain synaptosomes. This effect can also be demonstrated following in vivo administration of the compound to animals. Paroxetine is almost completely absorbed following oral administration. However, the drug undergoes extensive first pass metabolism. As a result, less than 50% of a single dose of paroxetine reaches the general circulation. Paroxetine is primarily metabolised by the cytochrome P4502D6 isoenzyme. The compound has also been shown to inhibit the activity of this enzyme. As a result, plasma levels of compounds metabolised by the cytochrome P4502D6 isoenzyme can be increased in patients given paroxetine. Paroxetine has been extensively evaluated in clinical studies in depressed patients. The compound shows efficacy superior to placebo, and similar to that obtained with standard tricyclic or tetracyclic agents. Paroxetine also appears to be as efficacious as other SSRIs. The efficacy seen in short-term studies with paroxetine in the treatment of depression is maintained when the drug is given chronically. More recently, paroxetine has been shown to be efficacious in the treatment of panic disorder, obsessive-compulsive disorder, and social anxiety disorder. Nausea, headache and somnolence are the most common adverse events reported by patients given paroxetine. As with other selective serotonin re-uptake inhibitors, a significant percentage of men under therapy with paroxetine report abnormal ejaculation. Paroxetine is well-tolerated by elderly patients, and appears to be associated with few serious adverse events.

Journal Article↗

PubMed1999

Summary from the 152nd meeting of the American Psychiatric Association.

The 152nd meeting of the American Psychiatric Association was held between 15th and 20th May 1999 in Washington DC; over 15,000 clinicians and researchers were expected to attend. The majority of the data presented at the meeting focused on new clinical research results for recently marketed products. Results from late stage clinical trials on new chemical entities in development were also presented at the conference.

Journal Article↗

PubMed1998

Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia.

We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1998

Summary of the 34th annual meeting of the Drug Information Association.

A variety of issues relating to clinical aspects of drug development were discussed at the 34(th) annual meeting of the Drug Information Association. Among the topics covered at this conference were the following: 1, development of CNS compounds; 2, the Common Technical Document (CTD); and 3, labelling of drugs for use in pregnancy. Issues surrounding the development of CNS compounds were discussed by regulatory authorities from the USA and Europe. In almost all aspects covered, the regulatory requirements for approval in Europe appear to be consistent with those in the USA. Efforts aimed at developing a CTD are ongoing under the auspices of the ICH. The goal of this effort is to develop a common technical information package that can be submitted to regulatory authorities in the USA, the EU and Japan. It is recognised, however, that a number of sections of regulatory submissions will remain outside of the CTD. New initiatives in the labelling of drugs for use in pregnancy in the USA were reviewed. These efforts are being led by the Pregnancy Labeling Task Force of the USA FDA. The overall goal of this effort is to more clearly define by labelling, the relative risks of pharmaceutical agents that must be administered to pregnant women.

Journal Article↗

PubMed1997

Donepezil (E2020): a new acetylcholinesterase inhibitor. Review of its pharmacology, pharmacokinetics, and utility in the treatment of Alzheimer's disease.

Donepezil is an acetylcholinesterase inhibitor under development for the treatment of mild-moderately Alzheimer's disease. In vitro, donepezil is about 10 times more potent than tacrine as an inhibitor of acetylcholinesterase. Donepezil is 500 - 1000 fold selective for acetylcholinesterase over butyrylcholinesterase. In animal models, donepezil produces positive effects on both working memory and long term memory. In man, donepezil is slowly absorbed from the gastrointestinal (GI) tract. The compound has a terminal elimination half-life of 50 - 70 h in young volunteers; in elderly volunteers, the half-life of the compound is extended to over 100 h. Donepezil is extensively metabolised after oral administration. The parent compound is 93% bound to plasma proteins. Results from two clinical trials with donepezil were published. The largest of these trials was a 12 week 161 patient Phase II investigation in the USA. Results from this investigation showed that donepezil produced dose-related improvements, with statistically significant effects occurring at doses of 3 and 5 mg/day. The results published to date suggest that donepezil will be a useful agent in the symptomatic treatment of Alzheimer's disease.

Journal Article↗

PubMed1997

The 98th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics.

The 98th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics was held on March 5-8, 1997. Over 850 researchers and clinicians pre-registered for this meeting. Papers presented at the conference focused on new observations. Firstly, novel therapeutic agents were discussed, then compounds that represent standard therapy for a number of different disease states were addressed. State of the art lectures provided concise updates on the status of a number of different issues. The following is a summary of some of the highlights and presentations at the conference. This summary is divided into four sections. Section 1 focuses on the Public Policy Debate on the ethics and utility of the placebo-controlled trial. Part 2 is a summary of the current status of gene therapy with particular reference to cystic fibrosis treatment. Part 3 is a summary of data on two recently approved compounds (donepezil and zafirlukast). The last part of this article discusses the results of drug therapy in two different disease states (benign prostatic hypertrophy and migraine).

Journal Article↗

PubMed1995

Use of ex vivo magnetic resonance imaging to detect onset of vigabatrin-induced intramyelinic edema in canine brain.

Vigabatrin (VGB) causes intramyelinic edema (microvacuolation) in brain of dogs and rodent, which has encouraged development of noninvasive methods to monitor for this effect during clinical trials. We report the qualitative ex vivo magnetic resonance imaging (MRI) changes observed in a neuropathology study in dogs to detect time of onset and regression of VGB-induced intramyelinic edema. Beagles were randomly assigned to 18 groups of 6 dogs per group and administered vigabatrin orally (p.o.) at a dose of 300 mg/kg/day (2 males, 2 females) or placebo (1 male, 1 female). Animals were killed and examined at weekly intervals during the 12 weeks of treatment and at 1, 2, 4, 8, 12, and 16 weeks after discontinuation of drug treatment. Myelin microvacuolation in thalamus, hypothalamus, and fornix were noted histologically after 4-5 weeks of treatment. Increases in MRI T2 intensity were observed in hypothalamus after 4 weeks and in thalamus and columns of the fornix after 7 weeks. Both MRI T2 intensity and microvacuolation continued to increase during 12-week VGB treatment. When VGB treatment was discontinued after 12 weeks, both MRI T2 intensity and microvacuolation began to decrease. Sixteen weeks after VGB discontinuation, histopathology had returned to normal and MRI examination demonstrated a marked trend toward reversal of the increased T2 signal intensity. MRI thus has potential as a noninvasive surveillance technique in certain experimental and clinical conditions associated with intramyelinic edema.

Animals↗

PubMed1994

MRI monitoring of vigabatrin-induced intramyelinic edema in dogs.

Chronic administration of vigabatrin (gamma-vinyl GABA) in dogs produces reversible microvacuolation (intramyelinic edema) in discrete brain regions. Histologic changes are most notable in the columns of the fornix and regions of the hypothalamus, thalamus, optic tract, and hippocampus. In an attempt to image these changes in vivo, we performed high-field MRI on seven treated and four control dogs at baseline and after 15 weeks of dosing with vigabatrin (300 mg/kg/d). All dogs underwent parallel electrophysiologic assessment to determine the effects of vigabatrin on afferent conduction. At 15 weeks, all treated dogs showed increased T2- and decreased T1-weighted signals, with changes from baseline most prominent in the columns of the fornix and to a lesser degree in the surrounding hypothalamus and thalamus. MRIs performed on control dogs were unremarkable. We then perfused a random selection of four treated and two control dogs and imaged their brains ex vivo prior to sectioning. Ex vivo imaging confirmed the in vivo findings and strongly correlated with both electrophysiologic and subsequent histopathologic findings. Imaging was repeated in the surviving dogs 5 and 12 weeks after discontinuation of dosing. Signal abnormalities in the treated dogs progressively diminished during recovery, paralleling the electrophysiologic and histopathologic results. These findings demonstrate that MRI can detect signal changes anatomically congruent with vigabatrin-induced intramyelinic edema and suggest that MRI may provide a useful noninvasive tool for monitoring patients during clinical trials.

4-Aminobutyrate Transaminase↗

PubMed1992

Effects of high-dose gamma-vinyl GABA (vigabatrin) administration on visual and somatosensory evoked potentials in dogs.

gamma-Vinyl GABA (GVG, vigabatrin) is a GABA transaminase-inhibiting antiepileptic agent. In dogs, chronic GVG administration produces reversible microvacuolation (intramyelinic edema) in discrete brain regions and slowing in central afferent transmission as measured by somatosensory evoked potentials (SEPs). Because this microvacuolation is especially prominent in the optic tract, this study tested the sensitivity of visual evoked potentials (VEPs) to GVG-induced changes in conduction. We also replicated the earlier SEP findings. Eight beagles received daily oral vigabatrin at the maximum tolerated dose (300 mg/kg/day); four were placebo controls. Cortical VEPs and SEPs were recorded using scalp needle electrodes at baseline and every 2 weeks throughout treatment. One treatment dog died at 2 weeks. The remainder showed an increase in central latencies beginning at 6 weeks, attaining significance (p < 0.05) at 8 and 10 weeks for SEPs and VEPs, respectively. No changes occurred in peripheral or spinal conduction in treated dogs, or in any measure in control dogs. Three GVG and two control dogs were followed after drug was withdrawn; both VEP and SEP measures returned to baseline values within 5 weeks. These findings support the use of VEPs and SEPs to monitor patients receiving vigabatrin therapy.

Aminocaproates↗

PubMed1989

Quantification of proteins in discrete brain regions of androgen-insensitive testicular feminized Tfm mice.

The effect of the testicular feminization mutation (Tfm) on the concentration of specific proteins in the medial preoptic area (MPO), ventromedial hypothalamus (VMH) and parietal cortex (CX) was examined. Adult Tfm and Swiss-Webster male mice were decapitated, the brains were removed and sectioned. Proteins from the three microdissected areas were separated by two-dimensional gel electrophoresis. Gels were stained with silver and then analyzed by quantitative computerized scanning densitometry. Of the 195 proteins quantified, the Tfm mutation significantly influenced the concentration of 16 proteins measured from gels of MPO tissue, 21 from VMH gels and 11 from CX. Of these, three proteins were affected in all brain regions; and three additional proteins were shown to vary in both MPO and VMH. One protein higher in the MPO and VMH of Tfm mice was identified as the glial fibrillary acidic protein. It is suggested that the proteins influenced by the Tfm mutation are regulated by steroids, most likely androgens. Thus, these proteins may prove to be important in hormone-regulated physiological functions.

Androgen-Insensitivity Syndrome↗

PubMed1987

Incorporation of amino acids into proteins of the hypothalamus of prepuberal female rats after estradiol treatment.

The arcuate nucleus-median eminence complex (AM) undergoes major structural and functional changes during normal puberty or if exposed to a pulse of estradiol in the prepuberal period. Those changes are expressed by increased synaptogenesis and by a drastic alteration in the feedback control of anterior pituitary gland hormone release. In this study we investigated the effects of estradiol benzoate (EB) on specific proteins in this hypothalamic area. Prepuberal, 25-day-old female rats were administered 10 micrograms of EB s.c. in oil or sesame oil vehicle. The animals were decapitated either 17 or 42 h after treatment. The brains were removed, blocked and serially sections at 300 micron using a Vibratome. The AM was dissected out and incubated for 6 h in a medium containing 35S-methionine and 35S-cysteine. Proteins from the AM were separated by two-dimensional gel electrophoresis, and the gels were exposed to X-ray film. The resulting autofluorographs were analyzed by scanning densitometry. The results show that the incorporation of labeled amino acids was increased in 10 proteins and decreased in 2 proteins in rats killed 17 h after EB. At 42 h after EB, 6 proteins showed an increased incorporation of amino acids and two proteins showed a decrease. Our results suggest that one or several of these proteins might be involved in the neuroendocrine and structural changes observed in the AM during puberty.

Animals↗

PubMed1986

Isolation of specific proteins affected by estradiol in the arcuate-median eminence of prepuberal female rats.

Prepuberal female rats (25 days of age) were injected with estradiol benzoate (EB 10 micrograms/rat, s.c. in oil) or oil vehicle. Forty-eight hours after treatment, all animals were decapitated, their brains removed and sectioned. The arcuate nucleus of the hypothalamus and median eminence were microdissected and processed for isoelectric focusing followed by slab gel electrophoresis. The resulting two-dimensional electrophoretic gels were analyzed to quantitate the specific proteins resolved using a scanning microdensitometric method. Out of 235 proteins measured, 8 proteins were found to be significantly increased and 4 were decreased by EB treatment. The proteins which increased in concentration ranged in molecular weight from 15 to 43 kDa and isoelectric points (pI) of 4.9 to 7.0. The 4 proteins decreased by the EB treatment were 44, 67, 74 and 80 kDa in molecular weight and their pI's ranged from 6.5 to 7.1. It is suggested that these proteins might be involved in some of the neuroendocrine effects that are induced by estradiol in this region of the brain.

Animals↗

PubMed1986

Subfornical organ: effects of salt loading and water deprivation on in vitro radioamino acid incorporation into individual proteins.

The subfornical organ of the brain has a role in the regulation of fluid balance in higher animals. In this study the effects of salt loading and water deprivation on specific proteins in this organ were investigated. For 4 days, 3 groups of rats were given an appropriate fluid diet (control, 2% NaCl and water deprived), with all groups having free access to food. Animals were killed by decapitation, and the subfornical organ was quickly dissected out and incubated for 6 h in a medium containing [35S]methionine and [35S]cysteine. Proteins from these organs were then separated by two-dimensional electrophoresis, and the resulting autofluorographs were analyzed by scanning densitometry. The results show that the incorporation of labeled amino acids into 8 proteins was changed due to the experimental manipulations.

Animals↗

PubMed1986

Effect of 5,7-dihydroxytryptamine on the concentration of individual proteins in different areas of the rat brain.

Proteins which are apparently regulated in concentration in two different areas of the rat brain by the indole neurotransmitter serotonin were identified using two-dimensional gel electrophoresis combined with computerized scanning densitometry. Reduction in central serotonin levels produced a decrease in the concentration of 3 different proteins (2 in the parietal cortex, 1 in the hippocampus). Two proteins, both in the hippocampus, were elevated in concentration following serotonin depletion. These results demonstrate that there exist in the brain a limited number of proteins whose concentration is influenced by serotonin.

5,7-Dihydroxytryptamine↗

PubMed1986

Effects of bilateral lesion of the locus coeruleus and of neonatal administration of 6-hydroxydopamine on the concentration of individual proteins in rat brain.

The role that norepinephrine plays in regulating the concentration of different proteins in the parietal cortex, hippocampus and cerebellum was assessed by investigating the effects of either a bilateral lesion of the locus coeruleus or neonatal administration of 6-hydroxydopamine. Two weeks after lesioning the locus coeruleus, the concentration of two different proteins was elevated in the hippocampus; a third protein was reduced in concentration in this brain area as a result of the lesion. Three proteins were affected in concentration in the cerebellum after the locus coeruleus lesion--two were elevated in concentration and one was reduced in concentration. No proteins were altered in concentration in the parietal cortex as a result of the lesion. Seventy days after neonatal treatment with 6-hydroxydopamine, a total of 6 proteins were found to be changed. Four of these (one in the hippocampus and 3 in the parietal cortex) were reduced in concentration while two proteins (both in the cerebellum) were elevated in concentration after neonatal treatment with the catecholamine neurotoxin. There was little overlap between those proteins affected in concentration by the bilateral lesion of the locus coeruleus and those changed by neonatal treatment with 6-hydroxydopamine. These results suggest that the concentration of a number of different proteins may, under normal physiological conditions, be regulated in vivo by norepinephrine in the brain.

Animals↗

PubMed1986

The beta subunit of the guanine nucleotide regulatory proteins: identification of its location on two-dimensional gels of brain tissue and its regional and subcellular distribution in brain.

The beta subunit of the guanine nucleotide regulatory proteins (also termed G proteins) has been examined in both rat and human brain. Proteins contained within samples of fresh rat and human brain tissue were separated by two-dimensional gel electrophoresis and either stained with silver or reacted with various antisera raised against the G proteins. In both rat and human brain, a single protein of molecular weight 36,000 daltons and pI 5.8 reacted the antisera. This protein also comigrated with one of the proteins present in a purified preparation of bovine brain G proteins. Based upon molecular weight, pI, and reaction with specific antisera, it was concluded that this protein is the beta subunit of the G proteins in brain. Using this information, the regional and subcellular distribution of the G protein beta subunit was studied in rat brain. Of 25 distinct neuroanatomical areas examined, cortical regions were generally found to contain the largest amount of this protein. The subcellular distribution of the G protein beta subunit revealed that large amounts are present in the synaptic membrane, crude synaptic vesicles, and microsomes. These studies serve to identify another protein visible on silver-stained two-dimensional electrophoretograms of rat and human brain. The regional and subcellular distribution of the G protein beta subunit correlate well with the proposed physiological function of this protein.

Animals↗

PubMed1986

Effect of chronic treatment with clorgyline on the relative concentration of specific proteins in the hippocampus and parietal cortex of the rat.

The effect of the chronic administration of clorgyline, a type A inhibitor of monoamine oxidase, on the relative concentration of proteins from the brain of the rat was examined by analysis of two-dimensional electrophoretic gels. The results from this study showed that the administration of clorgyline for 3 weeks produced a significant elevation in the relative concentration of two proteins in the parietal cortex (mol. wt 23,000 and 30,000) and one protein in the hippocampus (mol. wt 25,000). In contrast, the relative concentration of three proteins (mol. wt 31,000, 42,000 and 45,000) was significantly reduced in the parietal cortex by chronic treatment with clorgyline. No protein in the hippocampus was found to be significantly reduced by treatment with clorgyline. Since a previous study has indicated that the relative concentration of three different proteins were significantly altered by the repeated administration of desipramine, the results from the present experiment indicate that different changes in proteins are produced by repeated treatment with the type A monoamine oxidase inhibitor, clorgyline, as compared to those produced by the tricyclic antidepressant, desipramine. These results support previous suggestions that different classes of antidepressant compounds may exert their effects through different mechanisms of action.

Animals↗