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Biomedical subjects

W R Martin

Publications and source records attributed to W R Martin.

At least 127 records · Page 7Linked to original sources
PubMed1987

An analysis of naltrexone precipitated abstinence in morphine-dependent chronic spinal dogs.

Graded doses of naltrexone (0.31, 1.125, 5.0, 20.0 and 80.0 micrograms/kg) were administered to five beagle-type dogs dependent on increasingly large stabilization doses of morphine (0.5, 1.0, 2.0, 4.0, 8.0, 16.0 and 24.0 mg/kg/day) and the intensity of precipitated abstinence (PAS) was determined by a previously developed scoring system. A complete crossover design was executed with all dogs receiving all doses of both naltrexone and morphine. The data were analyzed using a two-way analysis of variance (dogs and treatments). Treatment variance was partitioned into a regression and residual component. A mathematical model for relating the intensity of abstinence (PAS) to the concentrations of morphine and naltrexone was developed using the law of mass action and assuming that the degree of morphine physical dependence is related directly to the number of mu receptors occupied by morphine and the intensity of PAS is proportional to the number of receptors from which morphine is displaced by the antagonist. Using the mathematical model the deviations of the observed values from the calculated values were minimized using an iterative curve-fitting procedure which varied the values of the dissociation constants of morphine (KA) and naltrexone (KB) and the activity coefficient for morphine (alpha). The analysis of variance showed that the treatment effect was significant and that the regression accounted for most of this variance. The values which provided the best fit were: KA, 1.58 mg/kg; KB, 0.95 microgram/kg; and alpha, 245.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Determination of plasma [18F]-6-fluorodopa during positron emission tomography: elimination and metabolism in carbidopa treated subjects.

An investigation of the metabolism of [18F]-6-fluorodopa (FDOPA) given to carbidopa treated subjects for scanning by positron emission tomography (PET) has been carried out by analysis of plasma. Reverse phase ion pair HPLC and alumina extraction were employed to fractionate and identify the [18F]-labelled compounds of plasma over a two hour period. During this time, the plasma levels of both total 18F and FDOPA decreased as a bi-exponential function of time. The rates of 18F, but not FDOPA, elimination were observed to decrease with age. In addition to FDOPA, only one other major peak of radioactivity was resolved by HPLC. Identification of this compound as the O-methylated derivative of FDOPA (MeFDOPA) is based on its shared HPLC elution time with in vitro synthesized O-[methyl-14C]-FDOPA. The ratio of the concentration of MeFDOPA to FDOPA (MeFDOPA/FDOPA) in plasma increased linearly with time, and the slope of this linear relationship decreased with the age of the individual.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Cerebral metabolism of glucose in benign hereditary chorea.

Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by chorea of early onset with little or no progression. There is marked clinical variability in this disease with some subjects having onset in infancy and others with onset in early adulthood. In contrast to Huntington's disease (HD), there is no dementia. Computed tomography is normal in all subjects with no evidence of caudate nucleus atrophy. We present the results of positron emission tomography using 18F-2-fluorodeoxyglucose on three patients with this disorder from two families. Cerebral glucose metabolism in one patient was decreased in the caudate nucleus, as previously reported in HD. The other two persons from a second family showed a relative decrease in metabolic rates of glucose in the caudate when compared with the thalamus. It appears that caudate hypometabolism is not specific for HD. These findings suggest that the caudate nucleus may play a significant role in the pathophysiology of some persons with BHC.

Adult↗
PubMed1986

Relationship of CNS tryptaminergic processes and the action of LSD-like hallucinogens.

Tryptamine produces pharmacologic effects in man and the chronic spinal dog which are similar to those produced by LSD, mescaline, psilocin, DMT, DOM and DOB. These effects include tachycardia, tachypnea, mydriasis, hyperreflexia, behavioral changes and in man, hallucinations. Chronic spinal dogs treated chronically with LSD became tolerant to its ability to produce mydriasis, tachycardia, tachypnea and hyperreflexia, and were cross tolerant to the ability of tryptamine, psilocin, mescaline, DMT, DOM and DOB to produce these same effects. Further, it was found that the brain and spinal cord contained tryptamine and could release it. Further tryptamine levels were higher in the brainstem and spinal cord above the level of transection in the chronic spinal dog that in intact dogs, and the same in the spinal cord below the level of transection. These observations suggested that there were both ascending and descending tryptaminergic pathways. Supporting this hypothesis were the observations that L-tryptophan also produced hyperreflexia in the acute, but not the chronic, spinal dog and cat, and that L-tryptophan hyperreflexia was antagonized by alpha-methyldopa but not pCPA. These observations and others argue that the spinal cord and brain have tryptaminergic mechanisms which are distinct from serotoninergic mechanisms, and that LSD-like hallucinogens act in part through a tryptaminergic mechanism.

5-Hydroxytryptophan↗
PubMed1986

Fourth ventricle effects of nicotine, 2-methylpiperidine and cytisine in dogs.

Four distinguishable nicotinic binding sites have been identified as well as four nicotinic ligands with different specificities: (+/-)-2-methylpiperidine which binds to a very high affinity site (Site 1) and produces up-regulation of the high affinity site (Site 2); (-)-nicotine which binds to Site 1 and Site 2 as well as to a low affinity site (Site 4); (+)-nicotine which binds to Site 1, Site 4 and Site 3 which is also a high affinity site; and (-)-cytisine which binds to Sites 1 and 2. These drugs were injected into the 4th ventricle of 5 dogs in graded concentrations (12.5 to 400 micrograms) and their effects on the EEG, skin twitch reflex latency, heart rate, rectal temperature, pupillary diameter, blood pressure and the amplitude of the flexor reflex were measured. Drugs which act predominantly on Site 1 [(+/-)-2-methylpiperidine and (+)-nicotine] produced EEG synchronization and hyperalgesia while drugs which interact with Sites 2 and 4 produce EEG desynchronization, analgesia and tachycardia. These data indicate that nicotinic ligands which have different binding specificities have different actions in medullary function and support the hypothesis that the different binding sites have different pharmacologic significance.

Alkaloids↗
PubMed1986

The use of positron emission tomography in pion radiotherapy.

The radioactive debris produced by pion radiotherapy can be imaged by the technique of Positron Emission Tomography (PET) as a method of non-invasive in situ verification of the pion treatment. This paper presents the first visualization of the pion stopping distribution within a tumor in a human brain using PET. Together with the tissue functional information provided by the standard PET scans using radiopharmaceuticals, the combination of pion with PET technique can provide a much better form of radiotherapy than the use of conventional radiation in both treatment planning and verification.

Brain Neoplasms↗
PubMed1986

Benzodiazepine antagonist, CGS-8216, in diazepam- or pentobarbital-dependent and non-dependent rats.

CGS-8216, a benzodiazepine antagonist, was administered to rats acutely dosed with diazepam, and to rats chronically dosed with diazepam or pentobarbital. The effects of an acute dose of diazepam were antagonized by CGS-8216 but signs of precipitated abstinence were not observed. An apparent arousing effect was seen in non-dependent rats when CGS-8216 was administered after placebo, but no arousal was observed when Ro15-1788 was administered after placebo in non-dependent rats. A precipitated abstinence syndrome was elicited with CGS-8216 in rats chronically dosed with diazepam and was very similar to the abstinence syndrome precipitated by Ro15-1788 in diazepam-dependent rats. Like Ro15-1788, CGS-8216 elevated Precipitated Abstinence Scale (PAS) scores in a dose-related manner until a plateau was reached with 5 mg/kg. No signs of precipitated abstinence were observed when CGS-8216 was administered to rats dependent on phenobarbital.

Animals↗
PubMed1986

Clinical evidence for different narcotic receptors and relevance for the clinician.

Analgesics such as morphine are toxic drugs that kill by producing respiratory depression. Further morphine-like drugs produce a high level of physical dependence and are highly reinforcing in some subjects. A systematic search, conducted over the last 50 years, for safer and less addicting analgesic has revealed that opioid analgesics act on different types of opioid receptors (mu, kappa, and sigma), and that they may function as mixed agonist-antagonists or as partial agonists. Thus some mixed agonists function as competitive antagonists at the mu receptor and as partial or strong agonists at the kappa or sigma receptor. When mixed agonists produce the same pharmacologic effects (eg, analgesia) by acting on different receptors, they invoke the principle of receptor dualisms. Drugs that produce agonist (analgesic) effects by acting on the kappa receptors are an order of magnitude safer than the mu agonists and produce a lesser degree of physical dependence than strong mu agonists. Thus safer, less addicting analgesics have been produced that act either as agonist-antagonists or by being partial agonists.

Analgesics↗
PubMed1986

Regression model for predicting dissociations of regional cerebral glucose metabolism in individuals at risk for Huntington's disease.

This article describes and partially validates a method for predicting whether an observed regional metabolic value is consistent with the observed value of another region. A regression equation was generated from a set of normal metabolic values, and then this equation was applied to patients with symptomatic Huntington's disease and patients at risk for this disorder. The results of the regression method were consistent with observations of the absolute rate for the normal subjects and Huntington's patients. For the at-risk patients, 6 of 18 were found to have reduced caudate metabolism relative to observed thalamic values. Since the initial scan, one of these identified at-risk individuals has developed symptomatic Huntington's disease. The method may be appropriate for other disorders where there are potential subgroups (e.g., schizophrenia) within a diagnostic category.

Brain↗
PubMed1986

Comparison of PET, MRI, and CT with pathology in a proven case of Alzheimer's disease.

Positron emission tomography (PET) with fluorodeoxyglucose (FDG), magnetic resonance imaging (MRI), and CT were carried out in a patient with Alzheimer's disease 16 months before he died. At autopsy, the gross appearance of the brain correlated with MRI and CT, which showed some regional atrophy. These were much less revealing than PET, which correlated with microscopic findings of neuronal loss and proliferation of glia. In areas of moderately impaired local cerebral metabolic rate of glucose, as revealed by reduced FDG uptake, there was some gliosis, primarily around the numerous senile plaques. In areas of severe metabolic impairment, there was a profound loss of neurons, extensive gliosis, and a diminished appearance of plaques. PET-FDG is a better measure of the severity of Alzheimer's disease than MRI or CT, because it reflects the degree of neuronal pathology.

Aged↗
PubMed1986

PET studies of cerebral glucose metabolism in idiopathic torticollis.

Regional cerebral glucose metabolism was studied in 16 patients with idiopathic torticollis, using positron emission tomography. Analysis of subcortical regions revealed no consistent focal abnormality of cerebral metabolic rate for glucose, but there was a bilateral breakdown of the normal relationships between the thalamus and basal ganglia. The findings suggest disruption of the pallidothalamic projections in this focal dystonia and may imply a disturbance of GABA.

Adult↗
PubMed1986

Positron emission tomography in the early diagnosis of Huntington's disease.

We studied 10 patients with early Huntington's disease and 7 normal age-matched controls with positron emission tomography (PET) using fluorodeoxyglucose. Subjects had little or no caudate nucleus atrophy and had not received any medications. The results demonstrated that hypometabolism of glucose preceded tissue loss. Furthermore, patients with minimal neurologic or psychiatric symptoms and no obvious CT changes may be differentiated from normal persons with high accuracy by PET. PET is helpful in the early diagnosis of Huntington's disease irrespective of the mode of presentation. PET may also be useful for preclinical detection and may supplement information from DNA studies.

Adolescent↗
PubMed1985

Stereospecificity of 2-methylpiperidine binding to a nicotinic up-regulatory site in the rat brain P2 preparation.

(+/-)-2-Methylpiperidine has a high degree of specificity in enhancing the binding of (-)-[3H]nicotine in the rat brain P2 preparation. (-)- and (+)-2-Methylpiperidine have been resolved. The (+) but not the (-) isomer increased the binding of (-)-[3H]nicotine. The two isomers were equally effective in inhibiting the binding of (-)-[3H]nicotine in high concentrations. These data provide additional support for a stereospecific nicotinic up-regulatory site.

Animals↗
PubMed1985

Binding characteristics of (-)- and (+)-nicotine to the rat brain P2 fraction.

Saturation studies employing (-)- and (+)-[3H]nicotine indicate that the isomers bind to different very high and high affinity sites since the binding density for (-)-[3H]nicotine is 10 times that for (+)-[3H]nicotine. Both isomers also bind to a low affinity site (KDS = approximately 10(-5) to 10(-4) M). Competition studies employing unlabelled (-)- and (+)-nicotine reveal greater complexities. The isomers also appear to bind to a separate site which enhances binding at the (-)- and (+)-nicotine high affinity sites. (+)-Nicotine is more effective in increasing the binding of (-)-[3H]nicotine at its high affinity site than (-)-nicotine. Further, (+)-nicotine has a greater specificity for enhancing binding than (-)-nicotine in that it enhances (-)-[3H]nicotine binding at lower concentrations and inhibits binding at higher concentrations than (-)-nicotine.

Animals↗
PubMed1985

An analysis of naltrexone and naloxone's possible agonistic actions in the dog.

Naltrexone (0.01-2.0 mg/kg, i.v.) produced dose-dependent EEG slowing in the conscious dog as did morphine (0.5-8 mg/kg, i.v.) and fentanyl (5-20 micrograms/kg, i.v.). However, the dose-response curve for naltrexone was not parallel to the morphine or fentanyl dose-response curves. Morphine and fentanyl but not naltrexone also produced dose-dependent miosis and increased the skin twitch reflex latency. When administered into the fourth cerebral ventricle naltrexone (60 micrograms), morphine (80 micrograms) and ethylketazocine (30 micrograms) produced EEG slowing. Again, naltrexone did not alter the skin twitch latency whereas morphine lengthened it and ethylketazocine reduced it. The pharmacological profiles obtained from different routes of administration indicate that naltrexone is clearly different from morphine, fentanyl and ethylketazocine. However, naltrexone may act as a partial agonist in the production of EEG slowing at a previously unidentified opioid receptor.

Analgesics, Opioid↗
PubMed1985

Role of agonist-antagonist analgesics in medicine.

The history of efforts to develop new, safer and less addicting analgesic, antidiarrheal and antitussive drugs and the impact of these efforts on the understanding of the physiology of pain perception and affect, the identification of multiple opioid receptors and the finding of new analgesics has been briefly reviewed. These important findings have major implications concerning the pathology of drug abuse, and the strategies for dealing with it. The importance of these discoveries also have major implications concerning the effectiveness of scheduling of drugs under national laws and international treaties. It is argued that the types of information necessary for scheduling of some of the newer analgesics must differ from data used in previous scheduling efforts and must consider cost-benefits consideration as they relate to public health.

Analgesics↗