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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 199 records · Page 11Linked to original sources
PubMed1991

Human calcium absorption from whole-wheat products.

Fractional calcium absorption from wheat products and the influence of co-ingested wheat products on calcium absorption from milk were measured in a series of randomized crossover studies in healthy adult women. The wheat had been intrinsically labeled with 45Ca during growth. In the first study, fractional calcium absorption from leavened whole-wheat bread averaged 0.817 +/- 0.124. By comparison, absorption from milk, ingested at a comparable load in the same women, averaged only 0.589 +/- 0.111. When labeled bread was co-ingested with milk, at the same aggregate load as for bread alone, bread calcium absorption fell to 0.748 +/- 0.103 (P less than 0.05). In a second study, calcium absorption from an extruded cereal prepared from intrinsically labeled wheat bran was compared with milk. Calcium absorption from the cereal (0.223 +/- 0.046) was significantly less than from milk (0.375 +/- 0.072) (P less than 0.001). When the two were co-fed at the same total load, milk calcium absorption fell to 0.258 +/- 0.055 (P less than 0.001). In a third study, the effect of phytate hydrolysis through yeast fermentation and of Maillard browning on calcium absorption was investigated using leavened bread and underbaked and overbaked cookies, each made with intrinsically labeled wheat flour. Calcium absorption from cookies was not affected by the extent of browning and averaged 0.652 +/- 0.087. However, calcium absorption from bread in these same women averaged 0.703 +/- 0.108. This was significantly more than from the cookies (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Leukotriene B4 increases intracellular calcium concentration and phosphoinositide metabolism in mouse osteoblasts via cyclic adenosine 3',5'-monophosphate-independent pathways.

Leukotriene B4 is one of a number of agents which stimulate bone resorption by acting on osteoblasts. Some agonists, such as PTH or prostaglandins, are known to activate adenylate cyclase in osteoblasts, whereas others, such as vitamin D3, have no effect on adenylate cyclase. Recent evidence suggests that both classes of agonist may raise the intracellular calcium concentration, although the relative importance for bone resorption of calcium mobilization and adenylate cyclase activity in the osteoblast is not clear. Here it is shown 1) that leukotriene B4 does not activate but may be inhibitory toward adenylate cyclase in intact osteoblasts or membrane preparations, 2) that leukotriene B4 causes an elevation of intracellular calcium levels in osteoblast monolayers, 3) leukotriene B4 rapidly activates phosphatidylinositol bisphosphate breakdown in osteoblast membranes and intact osteoblasts, and 4) that leukotriene B4 stimulates phosphatidylinositol kinase activity concurrently with phosphoinositidase C in intact osteoblasts over a similar timescale. These results suggest that leukotriene B4 may increase the concentration of intracellular calcium in osteoblasts by stimulating phosphoinositide turnover, and support the proposal that calcium signaling rather than activation of adenylate cyclase in osteoblasts may be of overriding importance in the regulation of bone resorption.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Spinal and supraspinal components of cannabinoid-induced antinociception.

The purpose of this study was to investigate whether cannabinoids produce antinociception spinal and supraspinal sites of action. The antinociceptive effect of delta 9-tetrahydrocannabinol (3 or 10 mg/kg), a naturally occurring cannabinoid, and CP-55,940 (0.1, 0.3, or 0.5 mg/kg), a potent synthetic cannabinoid, were assessed in spinally transected and intact rats. Each drug, administered i.v., produced a potent, long-lasting elevation of tail-flick latencies in the intact animals. This antinociception was significantly attenuated by spinal transection. Administration of each cannabinoid (i.t.) to the lumbar region of the spinal cord produced a weak, but long-enduring antinociceptive effect. In contrast, spinal administration of CP-55,940 to the upper thoracic region failed to elevate tail-flick latencies above base-line values. Additionally, i.t. administration of CP-55,940 (30 or 100 micrograms) continued to have a weak antinociceptive effect in spinal rats. In contrast, i.t. administration of CP-56,667, the (+)-enantiomer of CP-55,940, failed to elevate tail-flick latencies above base line at a dose of 1000 micrograms, thus indicating stereoselectivity. Finally, the biodisposition of 3H-delta 9-tetrahydrocannabinol after either i.v. or i.t. administration to spinal and intact rats was also assessed. The levels of radioactivity did not differ between spinal and intact animals in either whole brain, spinal cord, or plasma when the drug was administered i.v. When the drug was administered i.t., however, surgical transection of the spinal cord led to a decreased concentration of labeled substances in the whole brain and plasma. These converging lines of evidence indicate that cannabinoids produce antinociception through multiple mechanisms at the spinal and supraspinal levels of the central nervous system.

Analgesics↗
PubMed1991

Modeling the cannabinoid receptor: a three-dimensional quantitative structure-activity analysis.

The structure-activity relationship studies that have been reported for cannabinoids suggest that 1) the conformation of the C-ring at the C9 position, 2) the A-ring phenolic hydroxyl, and 3) the hydrophobic side chain are important determinants for the production of analgesia, as well as other cannabinoid effects. However, either these previous structure-activity studies described for cannabinoid compounds have not been quantitative in nature or the prediction of the activity of known and unknown compounds based on molecular structure has not been tested in a comprehensive manner. In this study we describe a three-dimensional molecular modeling program using comparative molecular field analysis to derive quantitative structure-activity relationships fitting pharmacological potencies and binding affinities of cannabinoids. The analysis has proven to accurately fit the pharmacological activity of cannabinoid analogs, with cross-validated r2 values of greater than 0.3 and final analysis r2 values of greater than 0.88. Additionally, this study has further characterized the steric and electrostatic properties that account for the variations in their potency. The results from this study indicate that steric repulsion behind the C-ring is associated with decreased predicted binding affinity and pharmacological potency. On the other hand, the steric bulk of a side chain that is extended up to seven carbons contributes to predictions of increased binding affinity and potency. The electrostatic fields of cannabinoid analogs also contribute to the predicted in vitro and in vivo potencies. If the biological activities we have investigated are assumed to be the result of interaction with a single binding site, this method indicates the structural and physicochemical properties necessary for binding to the receptor and producing an effect. By defining cannabinoid binding affinity and behavioral activity pharmacophores, this method can be used for designing cannabinoid agonists and it is capable of predicting the activity of unknowns, thereby serving to facilitate rational drug design.

Animals↗
PubMed1991

Cocaine inhalation in the rat: pharmacokinetics and cardiovascular response.

Despite the great attention given to the pharmacological actions of cocaine in recent years, the mechanisms leading to acute intoxication and related deaths after cocaine smoking have not been fully elucidated. The present study was therefore undertaken to examine the pharmacokinetics and pharmacological effects of cocaine by the inhalation route. Cannulated, male Sprague-Dawley rats were exposed to a constant concentration of cocaine vapor (13.6 +/- 0.4 micrograms cocaine per ml mainstream air), during which time their biodispositional profile and cardiovascular responses were evaluated. The bioavailable doses of cocaine were 0.26 +/- 0.05 and 1.54 +/- 0.46 mg/kg, after 1.5- and 5.0-min exposures, respectively. Peak cocaine plasma concentrations of 95 +/- 26 and 205 +/- 58 ng/ml, for the 1.5- and 5.0-min exposures, respectively, occurred 1 min after the start of exposure. Increasing the duration of exposure significantly increased the bioavailability from 0.29 to 1.03 (P less than .05). Transient changes in heart rate and arterial blood pressure were generally dose-dependent and correlated temporally with peak cocaine plasma concentrations. During exposure, 70% of the animals demonstrated electrophysiological aberrations consistent with atrial arrhythmia and incomplete heart block. These findings suggest that a direct cardiotoxic effect resulted from inhalation of cocaine.

Absorption↗
PubMed1990

Withdrawal from chronic treatment with (+/-)-DOI causes super-sensitivity to 5-HT2 receptor-induced head-twitch behaviour in mice.

Mice were injected once daily for 13 days with (+/-)-DOI ((+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and the induced head-twitch response (HTR) was scored. On days 2-5 HTR was reduced to less than 50% of day 1, and then returned to control levels by day 13. Challenge doses of (+/-)-DOI administered on days 15, 17 or 19 elicited significantly exaggerated responses. Thus, chronic treatment with (+/-)-DOI may cause an initial down-regulation followed by an up-regulation of 5-HT2 receptor function after cessation of such treatment.

Amphetamines↗
PubMed1990

Insulin alters the target size of the peripheral cyclic AMP phosphodiesterase but not the integral cyclic GMP-stimulated cyclic AMP phosphodiesterase in liver plasma membranes.

Radiation inactivation of the two high affinity cyclic AMP phosphodiesterases (PDE) found in liver plasma membranes afforded an estimation of their molecular target sizes in situ. The activity of the peripheral plasma membrane PDE decayed as a single exponential with a target size corresponding to a monomer of circa 54 kDa. The integral, cyclic GMP-stimulated PDE decayed as a dimer of circa 125 kDa. Preincubation of plasma membranes with insulin (10nM), prior to irradiation, caused the target size of only the peripheral plasma membrane PDE to increase. We suggest that insulin addition causes the peripheral plasma membrane PDE to alter its coupling to an integral plasma membrane protein with a target size of circa 90 kDa.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Acute and chronic effects of cocaine on isolation-induced aggression in mice.

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5-5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.

Aggression↗
PubMed1990

Affinity of the enantiomers of alpha- and beta-cyclazocine for binding to the phencyclidine and mu opioid receptors.

The enantiomers in the alpha and beta series of cyclazocine were evaluated for their ability to bind to phencyclidine (PCP) and mu-opioid receptors in order to determine their receptor selectivity. The affinity of (-)-beta-cyclazocine for the PCP receptor was 1.5 greater than PCP itself. In contrast, (-)-alpha-cyclazocine, (+)-alpha-cyclazocine, and (+)-beta-cyclazocine were 3-, 5- and 138-fold less potent than PCP, respectively. Scatchard analysis of saturable binding of [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) also exhibited a homogeneous population of binding sites with an apparent KD of 1.9 nM and an estimated Bmax of 117 pM. [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) binding studies revealed that (-)-alpha-cyclazocine (KD = 0.48 nM) was 31-, 1020- and 12,600-fold more potent than (-)-beta-cyclazocine, (+)-alpha-cyclazocine and (+)-beta-cyclazocine, respectively, for binding to the mu-opioid receptor. These data show that, although (-)-beta-cyclazocine is a potent PCP receptor ligand consistent with its potent PCP-like discriminative stimulus effects, it shows little selectivity for PCP receptors since it also potently displaces mu-opioid binding. However, these cyclazocine isomers, due to their extraordinary degree of stereoselectivity, may be useful in characterizing the structural requirements for benzomorphans having activity at the PCP receptor.

Animals↗
PubMed1990

A computergraphic investigation into the pharmacological role of the THC-cannabinoid phenolic moiety.

There has been much debate as to the nature of the cannabinoid-receptor interaction, whether by traditional interpretation or by means of membrane perturbation. Whichever hypothesis is correct, the structural requirements for pharmacological action need determination. Here, we report a computergraphic investigation into the role of the phenolic hydroxyl moiety in such a receptor interaction. It has been determined by molecular mechanics energy calculations and volume map determinations that the proton of the hydroxyl group may be involved in hydrogen bonding at the putative receptor site.

Computer Graphics↗
PubMed1990

Pharmacological evaluation of water soluble cannabinoids and related analogs.

The two water-soluble cannabinoids 1-[(4-morpholino) butyryloxy]-delta 8-tetrahydro-cannabinol (MB-delta 8-THC) and 5'-trimethylammonium (TMA)-delta 8-THC, as well as structurally similar compounds, were evaluated for cannabimimetic activity in the mouse (locomotor activity, tail-flick antinociception, rectal temperature, and ring-immobility) and dog (static-ataxia) procedures. MB-delta 8-THC possesses full cannabimimetic activity and is approximately equipotent to delta 8-THC. 5'-TMA-delta 8-THC only possesses partial cannabimimetic activity in that it is inactive in the ring-immobility and static-ataxia procedures. However, this analog is potent in other respects. All alterations at the 5' position do not necessarily produce this spectrum of effects, as evidenced by the pharmacological activity of 5'-bromo-delta 8-THC, 5'-OH-delta 8-THC acetate, and 5'-N-dimethyl-delta 8-THC.

Analysis of Variance↗
PubMed1990

Pharmacological characterization of ear-scratch response in mice as a behavioral model for selective 5-HT2-receptor agonists and evidence for 5-HT1B- and 5-HT2-receptor interactions.

(+/-) 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)-DOI], a phenylisopropylamine hallucinogen, is a 5-HT2-receptor agonist. The drug induced a dose-dependent increase in ear-scratch response (ESR) in mice, and the R(-)-isomer was more than 6 times as potent as its S(+)-enantiomer. The induced behavior was potently inhibited by selective 5-HT2-receptor antagonists such as ketanserin and spiperone. The (+/-)-DOI-induced ESR is also inhibited by stimulation of 5-HT1-receptors and the inhibition seems to be through a 5-HT1B-receptor mechanism. Thus, taken together, the present investigation indicates that ESR is due to selective stimulation of 5-HT2-receptors and that simultaneous costimulation of 5-HT1B-receptors inhibits the induced behavior. The study further suggests that the inability of the indolealkylamine hallucinogens to induce ESR is due to simultaneous excitation of 5-HT1B-receptors which are inhibitory to induction of ESR. Moreover, the data suggest possible inhibitory control mechanisms through 5-HT1-receptor subtypes to provide a damping mechanism to reduce excessive 5-HT2-receptor excitation due to exogenous drug stimulation or pathological conditions.

Amines↗
PubMed1990

Do functional relationships exist between 5-HT1A and 5-HT2 receptors?

To investigate the possible functional relationship between 5-HT1 and 5-HT2 receptors, we studied the effects of a nonselective 5-HT agonist (5-MeO DMT), a 5-HT1A-selective (8-OH-DPAT) and a 5-HT1B/5-HT1C-selective (TFMPP) agonist on the head-twitch behavior induced by the putative 5-HT2-selective receptor agonist (+/-)-DOI. In the mouse (+/-)-DOI produced the head-twitch response in a dose-dependent manner and (-)-DOI was twice as potent as the (+) isomer. Selective 5-HT2 antagonists, ketanserin and spiperone, dose-dependently inhibited the (+/-)-DOI-induced head-twitch response. The nonselective and the 5-HT1A-selective agonists also dose-dependently reduced the behavior, whereas 5-HT1B/5-HT1C-selective agonist (TFMPP) failed to affect the (+/-)-DOI-induced response. Taken together with previously published literature data, we propose a 5-HT1A inhibitory action on the 5-HT2 receptor-mediated response when induced by its selective agonist (+/-)-DOI.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10-substituted cannabidiol and 11- or 12-substituted delta 8-tetrahydrocannabinol.

The synthesis of a variety of novel 10-substituted cannabidiol (CBD) and 11- or 12-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino functional group is described, as well as their pharmacological evaluation in mice. These analogues, which possess only a portion of the full pharmacological spectrum of activity of delta 9-THC, indicate that cannabinoid-mediated reduction of spontaneous locomotor activity, hypothermia, antinociception, and/or catalepsy need not be produced simultaneously, possibly suggesting the existence of more than one mechanism of action. The 10-substituted CBD analogues 3, 4, and 5 with an ethylamino, propylamino, or azido functional group, respectively, proved to be largely inactive, except for the production of central nervous system (CNS) depression concomitant with toxicity. Toxicity and CNS depression may be related phenomena in these nitrogenous compounds since 12-amino and 12-ethylamino analogues (8 and 11) of delta 8-THC also proved to be very toxic. Antinociceptive and hypothermic responses (without reduction of motor activity) were observed at a dose of 10 mg/kg of the 11-ethylamino analogue (9) of delta 8-THC, while a dose of 50 mg/kg of the nitrogen mustard 11-[N,N-bis(2-chloroethyl)amino]-delta 8-THC (12) was necessary to produce any observable pharmacological effect. When selected analogues were evaluated for antagonistic properties, they failed to attenuate the effects of delta 9-THC. Some nitrogen mustard analogues were capable of producing minimal pharmacological effects after either peripheral or direct CNS administration; however, these analogues also failed to attenuate the effects of delta 9-THC either immediately after administration or 24-48 h later.

Analgesics↗
PubMed1990

Cannabis dependence and tolerance production.

The chronic abuse of many drugs produces both marked tolerance and physical dependence. Marked tolerance to cannabis has been observed in experimental animals and humans. However, reports of physical dependence, as characterized by significant withdrawal symptomatology upon cessation of chronic cannabis exposure, has not been well established or clearly defined in any species. The abuse potential of cannabis is more readily observed in humans than in experimental animal investigations. This may be due to the physiochemical characteristics of cannabis or delta 9-THC, which complicates this type of animal experimentation. It is more likely that the greatest dangers of cannabis abuse involve the pharmacological effects of the drug upon the central nervous system and other organs, rather than the development of dependence.

Animals↗