Biomedical subjects

B G McCarthy

Publications and source records attributed to B G McCarthy.

9 recordsLinked to original sources

PubMed1998

Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. The Sertindole Study Group.

Sertindole is an atypical antipsychotic that is efficacious in schizophrenia and is associated infrequently with extrapyramidal symptoms (EPS). This study assessed time to treatment failure with 24 mg/day sertindole or 10 mg/day haloperidol in 282 clinically stable neuroleptic-responsive outpatients with schizophrenia. During a 5-week transition period, patients were randomized to treatment with sertindole or haloperidol; other treatments were gradually discontinued. Patients then received treatment through Day 365. Time to treatment failure was numerically superior in sertindole-treated patients compared with haloperidol-treated patients, although this difference was not statistically significant. Sertindole-treated patients, however, remained free of hospitalization for exacerbation of schizophrenia and remained medically compliant significantly longer than did haloperidol-treated patients. In addition, there were significantly fewer reports of EPS in sertindole-treated patients and sertindole therapy was generally well tolerated. Patients transitioned well from other antipsychotic agents to sertindole. Sertindole appears to be an effective long-term treatment for schizophrenia.

Adolescent↗

PubMed1995

Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy.

OBJECTIVE: To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. BACKGROUND: Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. METHODS: Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-microns free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. RESULTS: Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean +/- SEM) was 17.84 +/- 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p = 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 +/- 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 +/- 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. CONCLUSION: Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.

Adult↗

PubMed1991

Exclusion of linkage between familial Mediterranean fever and the human serum amyloid A (SAA) gene cluster.

We studied the relationship between the autosomal recessive trait familial Mediterranean fever (FMF) and the serum amyloid A (SAA) genes by comparing alleles of a highly polymorphic dinucleotide repeat and a conventional restriction fragment length polymorphism (RFLP) in the SAA gene cluster in Israeli FMF kindreds. By haplotype analysis, our data indicate a minimum crossover frequency of 22% between the SAA gene marker and FMF. By conventional linkage analysis this eliminates a minimum of 10.4 cM including and surrounding the SAA gene cluster as the site of the FMF mutation although SAA proteins are prominent physiologic markers of the acute attacks.

Crossing Over, Genetic↗

PubMed1991

5-benzyloxytryptamine: a relatively selective 5-hydroxytryptamine 1D/1B agent.

The ability of nineteen tryptamine derivatives to interact with putative 5-hydroxytryptamine1D (5-HT1D) receptor binding sites in bovine caudate was analyzed. Sixteen of the nineteen agents competed, with variable potency, for these binding sites with Hill slopes of approximately unity. By contrast, 5-carboxyamidotryptamine (5-CT), sumatriptan and 5-benzyloxytryptamine (5-BT) competed with Hill slope values significantly less than unity. These three drugs share, in comparison to the sixteen other tryptamines, relatively large substitutions at the 5-position of the indole moiety. Additional radioligand binding studies with 5-BT indicate that the drug shows relative selectivity for 5-HT1D/1B binding sites. Functionally, 5-BT and sumatriptan inhibit 3H-5-HT release from guinea pig cortical synaptosomes with equal potency but 5-BT is significantly less efficacious than sumatriptan. These data indicate that 5-BT is a relatively selective partial agonist at 5-HT1D receptors.

Animals↗

PubMed1989

Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study.

The binding affinities of a series of arylpiperazine derivatives at [3H]quipazine-labeled central 5-HT3 sites were investigated. Features determined to be important for binding include the N4 piperazine nitrogen atom (but not the N1 piperazine nitrogen), and a quinolinyl group. The quinoline nitrogen atom of quipazine also contributes to affinity and its replacement by carbon reduces affinity by 20-fold. The entire quinoline nucleus is not necessary for binding, and certain monocyclic arylpiperazines, particularly those with a chloro group meta to the position of the piperazine ring (e.g. mCPP, MK-212), also bind at 5-HT3, sites; however, the affinities of these agents are at least an order of magnitude less than that of quipazine itself. Taking advantage of the fact that tertiary amines are not well tolerated at 5-HT1B sites, but that N-methyl substituents have little effect on 5-HT3 binding, we designed and synthesized a tertiary amine analog of quipazine, i.e., N-methylquipazine (NMQ). NMQ binds at 5-HT3 sites with an affinity similar to that of quipazine; however, unlike quipazine, NMQ shows very little affinity (IC50 greater than 10,000 nM) for central 5-HT1B sites.

Animals↗

PubMed1989

Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites.

The ability of sumatriptan (GR 43175; 3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5 methane sulphonamide) to interact with 13 neurotransmitter receptor sites was determined using radioligand binding techniques. Sumatriptan displayed the highest affinity for 5-HT1D (Ki = 17 nM) and 5-HT1B (Ki = 27 nM) binding sites and was slightly less potent at 5-HT1A binding sites (Ki = 100 nM). By contrast, sumatriptan was essentially inactive (Ki greater than 10,000 nM) at each of the 10 other binding sites analyzed. These data indicate that sumatriptan interacts selectively with 5-HT1B and 5-HT1D sites and suggest that these interactions may be the basis of its apparent efficacy in the acute treatment of migraine.

Animals↗

PubMed1989

Comparative neuropharmacology of dihydroergotamine and sumatriptan (GR 43175).

The potency of dihydroergotamine (DHE) was determined at 13 neurotransmitter receptors using radioligand binding techniques. DHE is a potent agent (i.e. affinity value less than 100 nM) at 5-hydroxytryptamine1A (5-HT1A), 5-HT1C, 5-HT1D, 5-HT2, dopamine2, alpha1- and alpha2-adrenergic binding sites. DHE displays moderate affinity (i.e. affinity values = 100 - 1000 nM) for beta-adrenergic and dopamine1 sites and is completely inactive at 5-HT3, muscarinic and benzodiazepine receptors. These results were then compared to similar data on sumatriptan (formerly called GR 43175), a novel acute anti-migraine agent. The only pharmacological property shared by both agents is high affinity for 5-HT1D and 5-HT1A receptors. Therefore, these data suggest that 5-HT1D and/or 5-HT1A receptors may play an important role in the pathophysiology of migraine.

Animals↗

PubMed1989

The clinical utility of pharmacological agents that act at serotonin receptors.

The past decade has seen important advances in the clinical utility of serotonergic agents. The putative novel anxiolytic effects of 5-HT1A partial agonists such as buspirone, the antidepressant effects of selective serotonin (5-HT) uptake blockers such as fluoxetine, and the unique and potent antiemetic effects of 5-HT3 antagonists in cancer chemotherapy are excellent examples of the clinical relevance of selective 5-HT receptor agents. The increasing ability to modulate serotonergic neurotransmission through distinct 5-HT receptor subtypes should greatly facilitate the analysis of 5-HT in both normal and abnormal human brain function.

Animals↗

PubMed1988

Differentiation of muscarinic cholinergic receptor subtypes in human cortex and pons: implications for anti-motion sickness therapy.

Radioligand binding studies were used to analyze muscarinic cholinergic receptor subtypes in human cortex and pons. Muscarinic cholinergic receptors were labeled by 3H-quinuclidinyl benzilate (3H-QNB). Scopolamine was equipotent in both brain regions and did not discriminate subtypes of 3H-QNB binding. By contrast, the M1 selective antagonist pirenzepine was approximately 33-fold more potent in human cortex than pons. Carbachol, a putative M2 selective agonist, was more than 100-fold more potent in human pons than cortex. These results demonstrate that the human pons contains a relatively large proportion of carbachol sensitive muscarinic cholinergic receptors. Drugs targeted to this subpopulation of muscarinic cholinergic receptors may prove to be effective anti-motion sickness agents with less side effects than scopolamine.

Carbachol↗