Receptors and receptor binding methods in drug discovery.

Receptor binding methods provide the most direct measure of drug-receptor interaction currently available. They provide information, inexpensively, rapidly, and reliably on the interaction of chemical agents with receptors. Furthermore, receptor binding may be used to gain insight into receptor dysfunctions that may underlie a variety of diseases. Binding studies have been and will continue to be important in identifying the locus of action of psychotherapeutic drugs. This is not to suggest that in vivo testing should be supplanted by receptor binding assays, but that these assays represent a powerful weapon in the drug discovery team's armementarium and should not be overlooked.

Chronic arachidonic acid eicosanoid imbalance: a common feature in coronary artery disease, hypercholesterolemia, cancer and other important diseases. Significance of desaturase enzyme inhibition and of the arachidonic acid desaturase-independent pathway.

A chronic imbalance between the essential fatty acid metabolites arachidonic acid, gamma-linolenic acid and eicosapentaenoic acid and of their respective eicosanoid derivatives appears to be implicated in the etiology of many intractable disease. Most notable among these are coronary artery disease, cancer and chronic inflammation. The factors leading to such an imbalance and their relatively simple prophylactic and therapeutic circumvention are discussed briefly.

Drug-pyridoxal phosphate interactions.

In this review it has been pointed out that vitamin B6 and its vitamers can be involved in many interactions with a number of drugs, as well as with the actions of various endocrines and neurotransmitters. Nutritional deficiencies, especially of vitamins and proteins, can affect the manner in which drugs undergo biotransformation, and thereby may also modify the therapeutic efficacy of certain drugs. The differences between nutritional vitamin B6 deficiency and the hereditary disorder producing pyridoxine dependency are discussed. In addition to a pyridoxine deficiency being able to adversely affect drug actions, the improper supplementation with vitamin B6 can in some instances also adversely affect drug efficacy. A decrease by pyridoxine in the efficacy of levodopa used in the treatment of Parkinsonism is an example. The interrelationships and enzymatic interconversions among pyridoxine vitamers, both phosphorylated and non-phosphorylated, are briefly discussed, particularly regarding their pharmacokinetic properties. The ways in which the normal biochemical functions of vitamin B6 may be interfered with by various drugs are reviewed. (1) The chronic administration of isoniazid for the prevention or treatment of tuberculosis can produce peripheral neuropathy which can be prevented by the concurrent administration of pyridoxine. An acute toxic overdose of isoniazid causes generalized convulsions, and the intravenous administration of pyridoxine hydrochloride will prevent or stop these seizures. (2) The acute ingestion of excessive monosodium glutamate will, in some individuals, cause a group of symptoms including among others headache, weakness, stiffness, and heartburn, collectively known as the 'Chinese Restaurant Syndrome.' These symptoms can be prevented by prior supplementation with vitamin B6. The beneficial effect is ascribed to the correction of a deficiency in the activity of glutamic oxaloacetic transaminase, an enzyme that is dependent on pyridoxal phosphate. Some interesting relationships are pointed out between vitamin B6, picolinic acid, and zinc. It is postulated that the intestinal absorption of zinc is facilitated by picolinic acid, a metabolite of tryptophan. The derivation of picolinic acid from tryptophan depends on the action of the enzyme kynureninase, which is dependent on pyridoxal phosphate; therefore, the adequate absorption of zinc is indirectly dependent on an adequate supply of vitamin B6. The formation of pyridoxal phosphate, on the other hand, appears to be indirectly dependent on Zn2++ which activates pyridoxal kinase.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: This review examines the interaction of pyridoxal phosphate with select neuroendocrine and neuropharmacological systems and their health related therapeutic implications. Vitamin B6 and its vitamers can be involved in many interactions with a number of drugs as well as the actions of various endocrines and neurotransmitters. Nutritional deficiencies, particularly of vitamins and proteins, can affect the manner in which drugs undergo biotransformation and thus may modify the therapeutic efficacy of certain drugs. In addition to pyridoxine deficiency adversely affecting drug actions, improper supplementation with viatmin B6 can in some instances also adversely affect drug efficacy. A decrease by pyridocxine in the efficacy of levodopa used in the treatment of Parkinsonism is an example. The interrelationships and enzymatic interconversions amony pyridoxine vitamers, both phosphorylated and nonphosphorylated, are briefly discussed, particularly concerning their pharmacokinetic properties. The chronic administration of isoniazid for the prevention or treatment of tuberculosis can produce peripheral neuropathy which can be prevented by the concurrent administration of pyridoxine. An acute toxic overdose of isoniazid causes generalized convulsions, and the intravenous administration of pryidoxine hydrochloride prevents or stops these seizures. The acute ingestion of excessive monosodium glutamate will, in some persons, cause a group of symptoms, including headache, weakness, stiffness, and heartburn, collectively known as the "Chinese Restaurant Syndrome." These symptoms can be prevented by prior supplementation with vitamin B6. It is postulated that the intestinal absorption of zinc is facilitated by picolinic acid, a metabolite of tryptophan. The derivation of picolinic acid from tryptophan depends on the action of the enzyme kynureninase, which is dependent on pyridoxal phosphate. Therefore, the adequate absorption of zinc is indirectly dependent on an adequate supply of vitamin B6. The formation of pyridoxal phospate appears to be indirectly dependent on Zn2++ which activates pyridoxal kinase. Treatment with daily pyridoxine can reverse a state of depression induced in women who take oral contraceptives (OCs). 1 hypothesis to explain this effect is that the OC is somehow causing a deficiency of seroton serotonin in the brain and that the vitamin B6 helps to overcome this deficiency through the stimulation of 5-hydroxytryptophan decarboxylase by pyridoxal phosphate. In sum, the stimulation of 5-hydroxytryptophan decarboxylase by pyridoxal phosphate. In sum, pyridoxal phosphate in physiological concentrations seems to function as an endogenous "down regulator" of several receptor sites, including estrogen, progesterone, and androgen.

[Problems in dose finding from the view of the clinical pharmacologist (author's transl)]. / Probleme der Dosisfindung aus der Sicht des klinischen Pharmakologen

The dose of a drug applied to a patient is determined by his physiological and pathological data, by specific properties of the drug and by the mode of application. The most important physiological data which influence the dose are body weight, sex, age, a pregnancy, genetic variations and circadian rhythm. Pathological findings such as organ insufficiencies (kidneys, heart, liver, endocrinium, transport protein in the blood, etc.) are also to be considered. Particularities of the drug kinetics (insignificant absorption, excessive biological half-life, specific affinities to tissues, etc.), of metabolism (first-pass effect, toxic metabolites, saturable detoxification, stress, etc.) or a high toxicity are other parameters of consequence. Finally attention has to be paid to the mode of application (p.o., i.v., etc.), to the kind of galenic preparation (liquid or solid, slow-releasing preparation, etc.), to interactions if using combinations of drugs and to a long-lasting pharmacotherapy. Aditional problems are encountered in clinical trials especially in early phases while determining the tolerable therapeutic dose.