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Biomedical subjects

W R Martin

Publications and source records attributed to W R Martin.

At least 109 records · Page 6Linked to original sources
PubMed1989

Cyanide-induced parkinsonism: clinical, MRI, and 6-fluorodopa PET studies.

A 46-year-old man ingested 1,500 mg of potassium cyanide in a suicide attempt. He survived, but later developed a severe parkinsonian syndrome. MRI revealed multiple areas of low-signal intensity in the globus pallidus and posterior putamen. A 6-fluorodopa PET study revealed bilateral decreased uptake in the basal ganglia. This evidence of functional impairment of dopaminergic nigrostriatal neurons is related either to direct toxicity of cyanide or to the effects of cerebral hypoxia secondary to cyanide intoxication.

Cyanides↗
PubMed1988

Kinetics of in vitro decarboxylation and the in vivo metabolism of 2-18F- and 6-18F-fluorodopa in the hooded rat.

The metabolisms of L-18F-2-fluoro-DOPA (L-2-18F-DOPA) and L-18F-6-fluoro-DOPA (L-6-18F-DOPA) were compared in vitro and in vivo in the carbidopa-pretreated male hooded rat. In vivo, the sole metabolites in plasma were O-methylated derivatives. The peripheral formation of the O-methylated derivative of L-2-18F-DOPA was approximately twice as great as that for the 6-isomer. Animals were killed at 10 and 60 min after administration of the 18F-DOPAs, and samples of striatum and vermis were analyzed by HPLC. L-2-18F-DOPA passed less readily into brain than did L-6-18F-DOPA. Whereas significant amounts of 6-18F-fluorodopamine and metabolites were formed in the striatum, no decarboxylated derivatives of L-2-18F-DOPA were found. Determination of the Michaelis-Menten kinetic constants for aromatic amino acid decarboxylase AADC, EC 4.1.1.26) indicated that the Km for L-2-18F-DOPA (982 +/- 115 microM) was considerably higher than that for L-6-18F-DOPA (101 +/- 22 microM). The low substrate affinity for AADC and the relatively more rapid rate of O-methylation in the periphery account for the lack of formation of 2-18F-fluorodopamine in vivo. The ratio of total radioactivity between striatum and other brain regions is related to the decarboxylation of radiolabeled tracer and the relative persistence of the decarboxylated derivatives in the striatum. Since L-2-18F-DOPA is not decarboxylated in rat striatum, it is not a promising agent for the study of cerebral DOPA metabolism in humans by means of positron emission tomography.

Animals↗
PubMed1988

Asymptomatic striatal dopamine depletion: PET scans in unilateral MPTP monkeys.

In cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, chemical, and pathological alterations that are similar to those found in Parkinson's disease. Unilateral carotid injections of this toxin produce ipsilateral nigrostriatal dopamine depletion while sparing the contralateral dopaminergic pathways. In order to study the damage to the nigrostriatal dopamine system in asymptomatic animals after unilateral MPTP administration, positron emission tomography (PET) scans were performed with [18F]fluoro-L-dopa (6-FD). This study demonstrates that clinically asymptomatic MPTP lesions may be assessed in vivo using 6-FD and PET.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Flumazenil oral absorption in dogs.

Flumazenil is rapidly absorbed after oral or gastric fistula administration to the dog reaching peak plasma concentrations in about an hour. Plasma level decrease rapidly thereafter reaching barely detectable levels by four hours. The onset of signs of flumazenil precipitated abstinence in diazepam-dependent dogs is well correlated with the rise of flumazenil plasma levels, however, precipitated abstinence seizures occur when plasma levels have markedly decreased. Oral dosing is a more efficient way of administering flumazenil than gastric fistula dosing.

Administration, Oral↗
PubMed1988

Opioid and nicotinic medullary hyperalgesic influences in the decerebrated rat.

The effects of ethylketazocine (EKC) administered intraperitoneally and the nicotinic ligands (-)- and (+)-nicotine, (-)-cytisine, (-)-lobeline, and (+)-2-methylpiperidine administered into the 4th ventricle on the latency of the thermally evoked withdrawal reflex of the decerebrate rat were investigated. EKC administered intraperitoneally produced both hyperalgesia and analgesia. (-)-Nicotine administered into the 4th ventricle produced a biphasic dose related effect on the latency of the withdrawal reflex; low doses produced a dose related analgesia while higher doses produced hyperalgesia. (-)-Cytisine and (-)-lobeline administered into the 4th ventricle produced biphasic effects. (+)-2-Methylpiperidine administered into the 4th ventricle produced a significant degree of hyperalgesia. Both the analgesic and hyperalgesic effects of (-)-nicotine were antagonized by mecamylamine (1 mg/kg) and naltrexone (5 mg/kg). The hyperalgesic action of (+)-2-methylpiperidine was antagonized by naltrexone but not by mecamylamine. These observations suggest that there are both medullary opioidergic and nicotinic cholinergic mechanisms for modulating both analgesic and hyperalgesic processes and that nicotinic ligands have multiple mechanisms of action in the brain.

Analgesics, Opioid↗
PubMed1988

The comparative binding characteristics of nicotinic ligands and their pharmacology.

Five drugs [(-)- and (+)-nicotine, (-)-lobeline, (-)-anabasine and (-)-cytisine] were infused IV into the urethane-pentobarbital anesthetized rat. Changes in heart rate, blood pressure, respiratory rate, minute and tidal volume, which appeared to be largely centrally mediated, were studied. Each of these compounds produced different pharmacologic profiles. The nature of these dissimilarities is not readily explained on the basis of pharmacokinetic considerations suggesting that the drugs have different mechanisms of action. Binding data obtained with these compounds using the rat brain P2 preparation also show differences. (-)-Lobeline and (-)-anabasine, like the nicotinic antagonists mecamylamine and hexamethonium, bind predominantly to low affinity sites with KDs in the micromolar range whereas (-)-cytisine binds only to a single high affinity site with a KD in the nanomolar range. Further, the binding patterns of these drugs are different from (-)- and (+)-nicotine which bind to both high and low affinity sites but differ from each other in binding characteristics. Thus the binding data are consistent with the pharmacologic data in suggesting that the drugs have different modes of action and support the concept that the low affinity site has an important role in the central nervous system action of these compounds.

Alkaloids↗
PubMed1988

Cotton fleahopper and associated microorganisms as components in the production of stress ethylene by cotton.

Excised cotton terminal buds incubated with adults or nymphs of the cotton fleahopper (CFH), Pseudatomoscelis seriatus (Reuter), produced ethylene at theoretical abscission-inducing rates by 24 h after introduction of the insect. Inoculation of cotton shoot tips with three microorganisms commonly associated with CFH and cotton in all cases promoted ethylene production to theoretical abscission-inducing rates by 24 h after inoculation. CFH alone or injection of microorganisms consistently caused cotton shoot tips to darken and become soft. These changes paralleled the rise in ethylene production and did not occur in control shoot tips. Of the three microorganisms, Xanthomonas campestris pv malvacearum (Smith) Dye (XCM) produced little ethylene when grown in culture, while the two fungi, Penicillium purpurogenum Stoll and P. glabrum (Wehmer) Westling, produced higher levels. The parallel between plant response to CFH, XCM, and CFH + XCM suggests a similar mechanism of ethylene induction by these two stress agents. Since a portion of the CFH were devoid of microorganisms, yet their impact on ethylene production by cotton tissue was uniform, we propose that the primary mechanism of ethylene induction involves the insect's salivary fluids which contain cell wall hydrolyzing enzymes.

Journal Article↗
PubMed1988

Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs.

Dogs were made dependent on p.o. administered diazepam (24 or 36 mg/kg/day) or nordiazepam (18 mg/kg/day). Flumazenil (2, 6 or 18 mg/kg) administered p.o. once a week according to a Latin Square design precipitated abstinence in both groups of dogs. Abstinence was evaluated using a Nordiazepam Precipitated Abstinence Scale (NPAS) of various signs of abstinence and by counting seizure episodes. Flumazenil caused dose-related increases in the NPAS scores of both diazepam- and nordiazepam-dependent dogs; the slopes of the two dose-response lines were not different. Both groups of dogs also had both clonic and tonic-clonic seizures after flumazenil administration. CGS-8216 (2, 6 or 18 mg/kg) administered p.o. did not cause a dose-related elevation in NPAS scores for either group of dogs but clonic and tonic-clonic seizures were seen. Thus, flumazenil precipitates the benzodiazepine abstinence syndrome, as evidenced by tremors, tachypnea and other signs, including seizures, whereas CGS-8216 may have some selectivity in precipitating seizures without other signs of abstinence.

Analysis of Variance↗
PubMed1987

Altered metabolism of [18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521.

[18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

[Beta interferon therapy in hairy cell leukemia].

Eleven patients with histologically proven hairy-cell leukemia were treated for 2 to 6 months with a natural beta-interferon (beta-IFN) preparation (3 X 4 million units week i.v.). Three of the eight evaluable patients experienced a partial response, two a minor response, and three no improvement. A reduction of the hairy-cell infiltration of the bone marrow was observed in one patient. Typical IFN side-effects with flu-like symptoms were noted. These results demonstrate that IFN-beta has some clinical efficacy in hairy-cell leukemia.

Adult↗
PubMed1987

Cerebral glucose and dopa metabolism in movement disorders.

The development of positron emission tomography (PET) has enabled us to perform in vivo measurements of certain aspects of regional cerebral function. Regional cerebral glucose metabolism may be readily quantified with [18F] fluoro-2-deoxyglucose (FDG) and presynaptic dopaminergic function may be studied with the labelled dopa analog 6-[18F] fluoro-L-dopa. We have applied a model to the analysis of 6-FD/PET data with which in vivo age-related changes in dopaminergic function may be demonstrated in normal subjects. With this technique, we have studied a series of asymptomatic MPTP-exposed subjects and have shown evidence of subclinical nigrostriatal pathway damage. Studies of regional cerebral glucose metabolism with FDG in early Huntington's disease have shown a characteristic impairment in caudate function which precedes the development of caudate atrophy. In addition, some asymptomatic individuals who are at risk for HD have caudate hypometabolism. We feel that, at the present time, PET provides information which is complementary to the clinical examination in establishing a diagnosis of HD. In the future these studies may also help in the investigation of at risk individuals.

Animals↗
PubMed1987

Cerebral blood volume measured with inhaled C15O and positron emission tomography.

Local cerebral blood volume (CBV) has been measured previously with inhaled 11CO and positron emission tomography (PET). The model used assumes that equilibrium in tracer concentration has occurred between arterial and systemic venous blood before the PET measurement is made. To verify that this model may be used with the much shorter half-lived C15O, we have simultaneously measured arterial and venous blood radioactivity following C15O inhalation. Equilibrium occurred 95 +/- 39 s after inhalation (n = 7). If the PET measurement is commenced prior to arteriovenous equilibrium, significant errors occur in calculated CBV. These data indicate that C15O may be used as a tracer for CBV measurement provided that emission data collection commences at approximately 120 s after inhalation. Strict quality control measures must be maintained to minimize the contamination of administered C15O with 15O-labeled CO2.

Administration, Inhalation↗
PubMed1987

The metabolism of [18F]6-fluoro-L-3,4-dihydroxyphenylalanine in the hooded rat.

The metabolism of the positron-emitting compound [18F]6-fluoro-L-3,4-dihydroxyphenylalanine (*F-DOPA) was studied in carbidopa-pretreated male hooded rats. Thirty minutes following carbidopa administration (5 mg/kg i.p.), animals received *F-DOPA (500 micrograms/kg; specific activity, 175-230 Ci/mol) as an intrajugular bolus. Blood samples were taken at various times between 5 and 90 min, and the plasma was analyzed by HPLC with gamma counting of fractions. *F-DOPA disappeared rapidly from plasma in concert with the formation of the 3-O-methylated metabolite, Me-*F-DOPA. Animals were killed from 5 to 120 min after injection, and the brains were rapidly dissected. The disappearance of *F-DOPA from both vermis and striatal samples was rapid. Me-*F-DOPA, the sole metabolite observed in the vermis, was the major labeled material in the striatum at greater than or equal to 20 min after injection. Fluorodopamine was an important metabolite in the striatum, making up 25% of total radioactivity at early intervals. Striatal samples also contained fluoro-3,4-dihydroxyphenylacetic acid, which constituted approximately 10% of the total radioactivity, and traces of two radiolabeled compounds, tentatively identified as fluorohomovanillic acid and fluoro-3-methoxytyramine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Positron emission tomography and histopathology in Pick's disease.

PET using 18F-2-fluoro-2-deoxyglucose was carried out on a case of Pick's disease established by necropsy. A sharply decreased cortical metabolic rate for glucose was obtained in specific gyri, especially in the frontal lobes, where there was extensive gliosis and neuronal loss. More moderate decreases were found in areas with numerous Pick bodies and inflated neurons but less gliosis. The PET pattern was sufficiently distinctive to suggest that it might be possible to distinguish Pick's from Alzheimer's disease premortem.

Aged↗
PubMed1987

Lesions of the putamen: their relevance to dystonia.

Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.

Adult↗
PubMed1987

The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington's disease.

Twenty-three persons at risk for Huntington's disease (HD) have been studied using a polymorphic human linked DNA marker (D4S10) and positron emission tomography (PET). We determined the likelihood of inheritance of the gene for HD in 13 persons, using DNA polymorphism studies. Of these, eight persons had a greater than 90% probability of being presymptomatic heterozygotes for HD. Three of these eight subjects had caudate glucose utilization detected by PET that was more than 2 standard deviations (SD) below the age-matched control mean. Measurement of caudate glucose utilization in the other five presumed presymptomatic heterozygotes revealed results between 1 and 2 SD below the mean. Five persons had a less than 10% likelihood of having inherited the abnormal gene for HD. Of these, four had normal rates of glucose utilization in the caudate nuclei. However, one individual with DNA results indicating a low risk of developing HD had abnormally low measures of caudate glucose utilization. This suggests that a recombination had occurred between the linked marker and the gene in this person. These studies suggest that PET studies of caudate glucose utilization may help to confirm results of DNA studies in some persons, and may provide an opportunity to detect when DNA results may be incorrect due to recombination.

Brain↗