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Biomedical subjects

W R Martin

Publications and source records attributed to W R Martin.

At least 145 records · Page 8Linked to original sources
PubMed1985

Positron emission tomography in movement disorders.

Positron emission tomography provides a method for the quantitation of regional function within the living human brain. Studies of cerebral metabolism and blood flow in patients with Huntington's disease, Parkinson's disease and focal dystonia have revealed functional abnormalities within substructures of the basal ganglia. Recent developments permit assessment of both pre-synaptic and post-synaptic function in dopaminergic pathways. These techniques are now being applied to studies of movement disorders in human subjects.

Brain↗
PubMed1985

Structure-activity relationships of some pyridine, piperidine, and pyrrolidine analogues for enhancing and inhibiting the binding of (+/-)-[3H]nicotine to the rat brain P2 preparation.

Previous studies have shown that (+/-)-[3H]nicotine binds to multiple sites in the rat brain P2 preparation. Using a series of pyridine, piperidine and pyrrolidine analogues, the present studies identified drugs with specificity for a separate up-regulatory site that increases the density of nicotine binding at another site. Of these compounds, (+/-)-2-methylpiperidine was the most specific. Some compounds inhibited without enhancing (+/-)-[3H]nicotine binding, but none bound with the very high affinity exhibited by nicotine and none could be classified as specific in inhibiting binding at a specific site. Structural changes in the 1- and 2-positions of pyridine and piperidine appear to be important for conferring specificity for the up-regulatory site whereas 3-position changes may be important for binding specificity.

Acetylcholine↗
PubMed1985

Parkinson's disease: a comparison of mesulergine and bromocriptine.

Previous studies with mesulergine (CU 32-085) demonstrated safety and efficacy in short-term observations of patients with Parkinson's disease. We compared mesulergine with bromocriptine in 20 patients with Parkinson's disease. Eighteen patients completed the randomized, double-blind, crossover study. Clinical assessments employed the UBC scale and "Mini-Mental State" examination; neurophysiologic measurements were undertaken on wrist rigidity and speed and accuracy of hand movement, and toxicity screening tests were compared. There were no significant differences between the effects of mesulergine (mean dosage, 27.4 mg/d) and bromocriptine (mean dosage, 40.8 mg/d).

Adult↗
PubMed1985

N-desmethyldiazepam physical dependence in dogs.

Dogs, surgically implanted with a chronic gastric fistula, were chronically dosed with N-desmethyldiazepam (32 mg/kg/day) in four divided doses to attain N-desmethyldiazepam plasma levels comparable to those observed in dogs dependent on diazepam (60 mg/kg/day). The time course of N-desmethyldiazepam abstinence was studied, beginning not less than 2 weeks after stabilization levels had been achieved. The abstinence syndrome observed after abrupt discontinuation of N-desmethyldiazepam was similar to the diazepam abstinence syndrome but differed in several important aspects. In diazepam-dependent dogs, there was a short burst of tremor very early in withdrawal (approximately 1-2 hr after the last dose of diazepam) that was not seen in N-desmethyldiazepam-dependent dogs. Signs of abstinence such as tremor, hot foot walking and twitches and jerks were more frequently observed in N-desmethyldiazepam-dependent dogs than in diazepam-dependent dogs as were decreases in food and water intake and in body weight. The overall intensity of abstinence, as measured by the Diazepam Withdrawal Abstinence Scale, was greater in N-desmethyldiazepam-dependent dogs than in dogs dependent on either lorazepam or diazepam. Plasma levels of N-desmethyldiazepam and oxazepam were nearly equal in dogs dependent on diazepam or on N-desmethyldiazepam and were 4 to 10 times greater than the plasma levels of diazepam or lorazepam in diazepam- or lorazepam-dependent dogs, respectively. Furthermore, the plasma levels of N-desmethyldiazepam and oxazepam declined much more slowly than the levels of diazepam and lorazepam. These results suggest that physical dependence on diazepam is caused by the accumulation and actions of N-desmethyldiazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1984

Cerebral blood volume, blood flow, and oxygen metabolism in cerebral ischaemia and subarachnoid haemorrhage: an in-vivo study using positron emission tomography.

A characteristic sequence of metabolic and haemodynamic changes has been shown to occur in the brain as cerebral perfusion pressure is reduced in experimental animals. Increased cerebral blood volume (CBV) occurs initially, followed by a fall in blood flow (CBF) and, finally, a fall in oxygen metabolism (CMRO2). By measuring CBV, CBF, and CMRO2 with positron emission tomography in patients with vasospasm associated with subarachnoid haemorrhage and in patients with arteriosclerotic occlusion or stenosis of extraparenchymal cerebral arteries, we have demonstrated the presence of similar changes distal to such lesions in man. These findings suggest the presence of a local decrease in perfusion pressure. This study demonstrates the utility of positron emission tomography in the assessment of cerebral circulation and metabolism in man. Measurements of regional CBV must be included for a complete assessment of the dynamics of the cerebral circulation.

Blood Volume↗
PubMed1984

Nature of nicotine binding to rat brain P2 fraction.

(-)-Nicotine may bind to as many as 5 sites in the rat brain P2 preparation: A very high affinity site (KD approximately 2.2 X 10(-11) M); a positive cooperativity site; a high affinity site (KD approximately 5.2 X 10(-9) M); a low affinity site (KD approximately 4.5 X 10(-5) M) and a very low affinity site. The curvilinear nature of both Scatchard plots and kinetic curves indicates the presence of multiple binding sites. Evidence for a positive cooperativity site includes: (1) The configuration of Scatchard plots (at low concentrations) of saturation as well as inhibition curves for (-)- and (+)-nicotine. (2) The Hill number of 1.37 for the binding of low concentrations of (+/-)-[3H]nicotine. (3) Selectivity among cholinergic drugs for producing positive cooperativity. (4) Markedly different specificities of drugs for the positive cooperativity site. Thus while only (+)- and (-)-nicotine interacted with the very high affinity site, acetylcholine, atropine, mecamylamine, lobeline, carbachol, (+)-nicotine and (-)-nicotine enhanced the binding of (+/-)-[3H]nicotine and cytisine, anabasine, cotinine and choline selectively inhibited binding at the high affinity site. Several lines of evidence indicate that there is stereospecificity. (+)-Nicotine was more potent than (-)-nicotine in inducing positive cooperativity whereas (-)-nicotine was 80 times more potent than (+)-nicotine in inhibiting binding at the high affinity site. Further, the specificity of the binding sites can be altered by changing the concentration of the buffer which gives additional evidence for the lability of the nicotine binding site. Although the pharmacologic significance of the different binding sites has not been determined, these data taken together indicate that (+/-)-[3H]nicotine binds with specificity to multiple sites in the rat brain P2 preparation with a complexity not addressed heretofore.

Animals↗
PubMed1984

Cerebral glucose metabolism in Parkinson's disease.

Local cerebral glucose utilization was measured in patients with predominantly unilateral Parkinson's disease using 18F-2-fluoro-deoxyglucose and positron emission tomography. Preliminary results indicate the presence of asymmetric metabolic rates in the inferior basal ganglia. The structure comprising the largest portion of basal ganglia at this level is globus pallidus. These findings are consistent with metabolic studies on animals with unilateral nigrostriatal lesions in which pallidal hypermetabolism on the lesioned side has been demonstrated. Increased pallidal activity is likely secondary to a loss of inhibitory dopaminergic input to the striatum from substantia nigra.

Aged↗
PubMed1984

Dopamine agonists in Parkinson's disease.

Dopamine agonists have yielded two important advances to our understanding of the basal ganglia--they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons--a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect. The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson's disease, but as yet there is no firm evidence. In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.

Bromocriptine↗
PubMed1984

Extracranial-intracranial bypass surgery: hemodynamic and metabolic effects.

After superficial temporal artery-middle cerebral artery bypass, cerebral blood flow (CBF) in the operated hemisphere increased in 6 of 17 patients. Preoperatively, the symptomatic hemisphere showed lower CBF in all six, lower oxygen metabolism in five, higher blood volume in four, and higher oxygen extraction in two. With the postoperative increase in hemispheric CBF, there was a decrease in oxygen extraction, but no change in blood volume or oxygen metabolism. In these patients, chronic regional hypoperfusion followed major vascular occlusion. Compensatory responses included dilation of intraparenchymal vessels and increased transport of oxygen from blood to tissue. These changes were partially reversed by cerebral revascularization.

Adult↗
PubMed1984

New and experimental therapeutic roles for naloxone and related opioid antagonists.

Naloxone and related opioid antagonists have been shown to have therapeutic utility in a variety of conditions. The effects of opioid antagonists in either physiological or pathological processes are most clearly seen when there is excessive occupancy of opioid receptors, as in opiate overdose. Opioid antagonists are also able to reverse several types of cardiovascular shock, conditions in which endogenous opioids appear to be mobilised, resulting in increased opioid receptor occupation. There are also more controversial circumstances in which excessive occupation of opioid receptors may assume pathological significance, such as hypercapnia. Opioid antagonists could be useful in such a situation by re-sensitising the respiratory centres to carbon dioxide. There is some evidence that opioid antagonists may benefit some schizophrenic and manic-depressive patients, suggesting that an endogenous opioid ligand might cause disturbances in mental functioning. The diversity and complexity of opioid mechanisms in the central nervous system suggest that more specific opioid antagonists could be more selective in altering physiological or pathological functioning.

Alcohol Deterrents↗
PubMed1984

Brain oxygen utilization measured with O-15 radiotracers and positron emission tomography.

We have developed, implemented, and validated a method for the measurement of the local cerebral metabolic rate for oxygen (CMRO2) with positron emission tomography (PET). We use data from a single inhalation of O-15-labeled CO for cerebral blood volume (CBV), an intravenous injection of [O-15]H2O for cerebral blood flow (CBF), and a single inhalation of [O-15]O2 for the final calculation of CMRO2 and the extraction of oxygen (E). The mathematical model used to analyze the data consists of two compartments and accounts for production and egress of water metabolism in the tissue, recirculating water of metabolism, and the arterial, venous, and capillary contents of [O-15]O2 in the brain. We validated our technique in baboons by comparing the PET-measured E with E measured using an intracarotid injection of [O-15]O2. The correlation between these two techniques was excellent. Mathematical simulations were done to examine the effect of errors in CBV, CBF, and recirculating water of metabolism on the measurement of E and CMRO2. The technique was implemented on five normal human subjects in whom the global CMRO2 was 2.93 +/- 0.37 (s.d.) ml/min X 100 g.

Adult↗
PubMed1983

Possible medullary kappa hyperalgesic mechanism. I. A new potential role for endogenous opioid peptides in pain perception.

The kappa-agonist, ethylketazocine, produces hyperalgesia in the acutely decerebrated dog as indicated by a shortening of the skin twitch reflex latency whereas fentanyl is inactive. Naloxone produces analgesia and antagonizes the hyperalgesic effect of ethylketazocine. Spinal cord transection decreases the latency of the skin twitch reflex and allowed the analgesic effect of fentanyl and ethylketazocine on this nociceptive reflex to become manifest. These observations indicate that there is a non-opioid analgesic and kappa hyperalgesic mechanism present in the pontine-medullary region of the dog brainstem. It suggests that the hyperalgesic mechanism is mediated by an endogenous kappa-opioid peptide and that the analgesic effect of naloxone is in part related to antagonism of the activity of this hyperalgesia producing opioid peptide.

Animals↗
PubMed1983

Medullary kappa hyperalgesic mechanisms II. The effects of ethylketazocine administered into the fourth cerebral ventricle of the conscious dog.

Ethylketazocine (EKC) (2 micrograms/100 microliter/min for 15 min) was infused into the fourth cerebral ventricles of conscious dogs. The drug produced hyperalgesia, respiratory depression, miosis, increased EEG electrogenesis and behavioral sedation. Hyperthermia and tremulousness were observed in some animals. These pharmacologic effects reflect the action of EKC on pontomedullary periventricular sites which control nociception, autonomic function and arousal.

Analgesics, Opioid↗
PubMed1983

Cerebellar blood flow and metabolism in cerebral hemisphere infarction.

Positron emission tomography was used to study the effect of supratentorial infarction on cerebellar metabolic rate for oxygen and cerebellar blood flow. In a control group of patients, the mean cerebellar metabolic rate for oxygen was 2.97 +/- 0.11 (standard error of the mean [SEM] ) ml-1 . min-1 . hg-1 and mean cerebellar blood flow was 41.1 +/- 1.5 ml . min-1 . hg-1. No significant right-left asymmetry in either cerebellar metabolic rate for oxygen or cerebellar blood flow was noted. Patients with frontal lobe infarction showed 16.8 +/- 1.8% (cerebellar metabolic rate for oxygen) and 19.6 +/- 2.1% (cerebellar blood flow) differences between cerebellar hemispheres, with the hemisphere contralateral to the cerebral infarction having the lower values. These differences were highly significant (p less than 0.001). In addition, cerebellar blood flow and cerebellar metabolic rate for oxygen were significantly decreased in the ipsilateral cerebellar hemisphere (metabolism: 2.13 +/- 0.19 ml . min-1 . hg-1; p less than 0.002; blood flow: 35.2 +/- 2.4 ml . min-1 . hg-1; p less than 0.05). Patients with parietooccipital infarction also showed a significant bilateral decrease in cerebellar metabolic rate for oxygen (2.43 +/- 0.11 ml . min-1 . hg-1) and cerebellar blood flow (34.6 +/- 2.5 ml . min-1 . hg-1) relative to control subjects, but no significant cerebellar asymmetry. Our findings demonstrate a general depression of cerebellar blood flow and metabolism from cerebral hemisphere infarction unrelated to the site of infarction as well as a specific depression occurring contralateral to infarction involving the frontal lobe. These are among the first quantitative data concerning regional cerebellar metabolic rates for oxygen and cerebellar blood flow in humans.

Adult↗