Additional Pharmacological Properties Research Articles

In vivo occupancy of the striatal dopamine uptake complex by various inhibitors does not predict their effects on locomotion

We compared the ability of various dopamine (DA) uptake inhibitors to displace the in vivo striatal [ 3H]GBR 12783 (1-[2(diphenylmethoxy) ethyl)-4-(3-phenyl-1[ 3H]-2-propenyl)-piperazine) binding with their stimulant effect on locomotor activity on mice. GBR 12783 (8 mg/kg), GBR 13069 (10 mg/kg), cocaine (20 mg/kg), mazindol (3 mg/kg) or pyrovalerone (2 mg/kg) stimulated locomotion as long as they occupied the DA uptake complex. In contrast, nomifensine (3 mg/kg) did not stimulate locomotion although it completed with [ 3]GBR 12783 for the occupancy of the DA uptake complex at a significant level (> 50%). Administered at their ED 50 doses, GBR 12783, BTCP (N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine, GBR 13069, amineptine and dexamphetamine significantly increased locomotor activity whereas the other inhibitors tested did not. The locomotor response elicited by GBR 12783 (10 mg/kg) was not decreased by desipramine (20 mg/kg) nor by oxaprotiline (10 mg/kg). The increase in locomotion elicited by GBR 12783 was positively correlated with the basal locomotor activity of the mice. The stimulant effect of GBR 12783 was potentiated by SKF 525A and by budipine. Additional pharmacological properties might conceal the relationship between the effects of some DA uptake inhibitors on locomotion, and on in vivo occupancy of DA uptake sites.

Pharmacology of β-Blockers

All clinically used beta-blockers share the common feature of being competitive antagonists at beta-adrenoceptors. They differ, however, in additional pharmacological properties, such as beta1/beta2-selectivity ratios, presence or absence of intrinsic sympathomimetic activity (ISA), and/or local anesthetic activity. Furthermore, beta-blockers differ widely in their pharmacokinetic properties. The mammalian beta1- and beta2-adrenoceptors are the products of different genes but the receptor proteins show a certain degree of homology. Both span the cell membrane seven times. The cytoplasmic part of the receptor protein is the site of phosphorylations and hence involved in the process of receptor internalization. Upon exposure of tissues or organs to beta-blockers, characteristic changes emerge at the cellular level. There is an increase in the density of beta-adrenoceptors in the surface membrane, termed upregulation. This upregulation is subtype-specific, i.e., nonselective beta-blockers increase the density of both beta1- and beta2-adrenoceptors whereas beta1-selective antagonists upregulate only the former subtype. In contrast, beta-blockers with pronounced ISA downregulate beta-adrenoceptors. Beta-adrenoceptor density also changes in pathological situations. There is a downregulation of cardiac beta-adrenoceptors in dilated cardiomyopathy, probably as a consequence of increased sympathetic tone. A rapid upregulation of beta-adrenoceptors is characteristic of myocardial ischemia. This upregulation occurs in spite of a massive release of norepinephrine from cardiac adrenergic nerves during ischemia. Both norepinephrine release and upregulation of cardiac beta-adrenoceptors lead to an adrenergic overstimulation of ischemic myocardium. Blockade of beta-adrenoceptors inhibits the catecholamine component of this vicious circle and may explain part of the beneficial effects of beta-blockers in coronary artery disease and myocardial infarction.

Buspirone, a new approach to the treatment of anxiety.

Anxiety has historically been treated by agents with a sedative component to their action. In the last decade or so it has been determined that gamma-aminobutyric acid (GABA) receptors may mediate the anxiolytic actions of the benzodiazepines, propanediol carbamates, barbiturates, and ethanol. However, inasmuch as these drugs have additional pharmacological properties (sedation, muscle relaxation, seizure control), the search for an anxioselective drug was continued. Buspirone appears to be such a drug. Clinical studies have clearly demonstrated the efficacy of buspirone in the treatment of generalized anxiety disorder without the ancillary pharmacology of earlier anxiolytics. Buspirone does not act on the GABA receptor. Rather, its most salient interaction with neurotransmitter receptors occurs at the 5-HT1A serotonin receptor. This action is supported by studies focused on receptor binding, anatomical localization, biochemistry, neurophysiology, and animal behavior. The recognition that action at 5-HT1A receptors may be a viable approach to the pharmacotherapy of anxiety is evidenced by the number of other agents of this class under development by a number of pharmaceutical companies.

Pharmacological Characteristics of β Blockers and Their Role in Clinical Practice

Since beta-adrenoceptor blocking drugs were originally discovered and shown to be important therapeutic agents in the management of both angina pectoris and hypertension, many other similar drugs have become available. These share the common property of beta-adrenoceptor antagonism, though they may vary in terms of potency. However, they differ from one another in terms of their additional pharmacological properties--cardioselectivity, partial agonist activity, and membrane stabilizing activity. Cardioselectivity refers to the ability of some drugs, notably atenolol and metoprolol, to block beta 1 receptors without blocking beta 2 receptors. This has been considered to be of potential importance in patients with obstructive airways disease, patients with peripheral vascular disease, and patients with insulin-dependent diabetes during hypoglycemic crisis. Partial agonist activity is the intrinsic activity that some drugs have to stimulate the beta adrenoceptor while they are competitively antagonizing catecholamines. In consequence, they may have less effect on resting heart rate, cardiac output, peripheral vascular blood flow, and resting respiratory function. However, there is no good evidence that major adverse effects of beta-adrenoceptor blocking drugs such as congestive heart failure, bronchospasm, or symptoms of peripheral vascular disease are prevented by drugs with partial agonist activity: bradycardia may be improved, but its importance has probably been overemphasized. Membrane-stabilizing activity appears to be unimportant. As far as pharmacokinetic differences between drugs are concerned, lipid solubility is seen to be of increasing importance. The more water-soluble drugs have longer elimination half-lives, produce less interindividual variation in steady-state plasma concentrations, and penetrate the central nervous system less readily.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiinflammatory polysaccharide produced by serratia piscatorum

Crude preparations of protease and culture filtrate of Serratia piscatorum IFO 12527 contained a heat-resistant, large molecular and non-proteinous anti-inflammatory ingredient(s) (PLS). The active ingredient was precipitated with Rivanol or Cetavlon, and purified by extraction with n-butanol or by adsorption with Lloyd’s reagent. From these and other chemical data, PLS is considered to be an acid polysaccharide. PLS injected i.m. inhibited the edema induced by carrageenin and anti-serum in rat feet. The effect on carrageenin edema was 37 times as potent as that of indomethacin and 200 times that of hydrocortisone acetate. These anti-edema effects were not observed by oral administration. PLS, i.m., inhibited cotton pellet granuloma more markedly than hydrocortisone acetate, without decreasing the weight of the adrenals and thymus. It had weak activating effect on kinin-forming systems in the rat plasma in vitro. Additional pharmacological properties of PLS are also described.

Reserpine antagonists and their effects on reserpine-induced catecholamine depletion of the rat adrenal medulla

The effects of various psychotropic compounds on reserpine-induced catecholamine depletion of the rat adrenal medulla were demonstrated with histochemical techniques. Compounds which block reserpine-induced catecholamine release include the monoamine oxidase (MAO) inhibitors iproniazid, isocar☐azid, tranylcypromine and harmaline; the anti-depressants imipramine and desmethylimipramine; the central nervous system stimulant, non-MAO-inhibiting compound Ro 2-0853; and the benzoquinolizine derivative tetrabenazine. D-amphetamine, the basic MAO inhibitors Ro 5-1025 and Ro 5-1753, chlorpromazine, chlorprothixene, scopolamine and trihexyphenidyl hydrochloride were inactive. With the exception of tetrabenazine, which probably acts by a different mechanism, a good correlation exists between anti-reserpine effect as demonstrated in the adrenal test and clinical efficacy as anti-depressant; but the fact that anti-reserpine activity is exerted by compounds with different pharmacologic activities indicates a low order of specificity. Animal tests measuring reserpine antagonism are useful for the screening of antidepressant drugs, but they must be evaluated with consideration of all additional pharmacological properties of the compounds involved.