The main pharmacokinetic and pharmacodynamic features of althesin are described. Though relatively new, this steroid is now widely employed in anaesthesiological practice. From the pharmacological standpoint, the high therapeutic index of althesin, the fact that its metabolic fate is known, its rapid elimination, and the prompt, complete awakening of patients when it is used mean that it can be reliably employed in all forms of surgery and on all types of patient. The absolute contraindications coincide with those preventing the employment of general anaesthesia in any form, while the relative contraindications, i.e. those involving particular care in its administration, are linked to the presence of diseases interfering with its mechanism and elimination, the existence of allergy, or cardiovascular disorders of a fairly substantial nature. Althesin, in fact, while not responsible for frank cardiovascular changes, cannot be regarded as entirely innocuous. In other words, it is subject to the same limitations as the barbituric and non-barbituric drugs commonly employed in the i.v. induction of anaesthesia.

Many of the biotransformation reactions which have been described for xenobiotic substances in mammals have been demonstrated in fish in both in vitro and in vivo experiments. Several of these biotransformation reactions have been shown to occur in fish at rates which are sufficient to have significant effects on the toxicity and residue dynamics of selected chemicals. Inhibition of these reactions can lead to increased toxicity and bioaccumulation factors for certain chemicals. Several classes of compounds, including some polychlorinated biphenyls, are metabolized slowly, and their disposition in fish may not be influenced to any great extent by biotransformation. Metabolites of compounds which are biotransformed rapidly may appear in certain fish tissues, and in many instances these are not accounted for by conventional residue analysis methods. Microsomal mixed-function oxidases in several species of fish have been demonstrated to be induced by specific polycyclic aromatic hydrocarbons and by exposure of fish to crude oil. Induction of these enzymes in fish can result in both qualitative and quantitative differences in the metabolic disposition of xenobiotics to which fish are exposed.

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

Anesthetic agents, including most inhalation anesthetics, the barbiturates, narcotics, local anesthetic amides and curare-like compounds are metabolized inside the liver cell. Consequently, drug metabolism in the liver has become an increasingly important consideration in the practice of anesthesiology. Hepatic metabolism is, first and foremost, a mechanism that converts drugs and other compounds into products that are more easily excreted and that usually have a lower pharmacologic activity than the partent compound. Thus, duration and intensity of drug action are limited. However, there are exceptions. In certain instances a metabolite may have higher activity and/or greater toxicity than the original drug. Intrahepatic metabolism hinges upon the oxidative reactions that are catalyzed by a group of mixed oxidases, the P-450 cytochromes. Their concentration and activity can be enhanced by certain drugs or environmental chemicals that are ingested by the individual. This usually is beneficial, in that this mechanism of enzyme induction promotes the detoxification of pharmaca, which is the normal aspect of drug metabolism. If, however, the normal metabolite is more toxic than the parent compound, or there exists an alternate, abnormal metabolic pathway that produces a toxic metabolite, then enzyme induction may have serious consequences. Inorganic fluoride is a normal metabolite of methoxyflurane. It is responsible for the high-output renal failure that can be observed after anesthesia with this inhalation agent. A patient with induced enzyme activity is especially at risk to develop methoxyflurane-related renal failure. The picture of halothane toxicity is not as clear. There are indications that an abnormal metabolite, produced in sufficient quantities via an alternate pathway with induced enzyme activity, may be capable of causing liver damage.

Chronic or preoperative drug therapy may contribute to the overall risk of anesthesia by modifying organ function directly, or by altering the response of the patient to anesthetic agents or adjuvants. Many drug-patient and drug-drug interactions can be predicted from analysis of their expected effects upon the neurohumoral control systems that normally maintain physiological homeostasis, especially those involving the release or termination of action of catecholamines or acetylcholine. Current concepts of biotransformation, especially as regards hepatic microsomal function, are so broad that estimates of the toxic potential of the metabolites of anesthetic drugs still require an empirical approach for each agent considered.

The wide-spread use of pesticides in modern agriculture has created a need to investigate the chemical transformation of pesticides in plants and animals. This paper reviews the chemical and biochemical fate of various pesticides and other xenobiotics. Photochemical mechanisms appear to be the most common pathways for the abiotic transformation of these chemicals. Biotic transformation includes a large group of biochemical reactions which may result in either deactivation (detoxication) or activation (toxication) of bioactive compounds. The need for quality control in the production of pesticides is also discussed.

The induction of drug metabolizing enzymes in mammals is summarized including both enzymes of the cytochrome P-450-dependent microsomal mixed function oxidase system and glutathione S-transferases. Particular emphasis is placed on the role of pesticides as inducers, the early work being summarized while investigations carried out at North Carolina States University are considered in greater detail. Finally, the possible significance of induction is considered.

Ornithine decarboxylase, the initial enzyme in the polyamine biosynthetic pathway, is induced in target tissues in response to a variety of trophic agents including polypeptide and amine trophic hormones, cyclic AMP analogs, drugs, and trophic steroid hormones. The induction of ornithine decarboxylase in these systems is regulated at a transcriptional level and is proportional to the extent of stimulation. Because of its rapid half-life (10-20 min), a general maximum of induction is detectable within 4-5 h of stimulation, and its induction pattern can serve as a rapid, specific index of increased RNA and protein synthesis. Implications for its usefulness to pharmacologists, endocrinologists, physiologists, and biochemists are summarized.

Although a great deal of descriptive information has been obtained about the actions of nerve growth factor on its target tissues, its structure, its receptors, and even its biosynthesis, there is no clear understanding, as yet, of the intracellular events mediating its transcriptional involvements. Work in this laboratory over the past five years has uncovered a number of nerve growth factor-initiated intracellular changes in sympathetic neurons and other nerve growth factor-sensitive systems, and has provided a framework into which they might fit. This article is written in an attempt to collect the data in a single communication and to suggest at least one mechanism by which the nerve growth factor may work.

Hormones play a role in the regulation of gene expression by inducing changes in enzyme patterns in target cells mediated by the synthesis of specific RNA molecules. Erythropoiesis has been used as a system for studying the molecular mechanism of regulation of gene action by means of two hormones: erythropoietin and testosterone. Experiments designed to correlate the biochemical action of both hormones on rat marrow cells are herein reported. Both factors seems to act at different biochemical and citological levels. Erythropoietin triggers the erythropoietic process acting on the erythropoietin sensitive cells (ESC), in which the hormone induces the synthesis of a high molecular weight RNA, which is the precursor of a functional 9 S messenger RNA. Testosterone seems to act on polychromatophilic erythroblasts, in which the synthesis of ribosomal RNA or its precursor is stimulated. The steroid enhances the nuclear ribonuclease activity, which could represent a control mechanism for the processing (maturation) of high molecular weight RNAs. The incorporation of 3H-GTP and 3H-UTP into RNA by isolated rat bone marrow nuclei is stimulated by erythropoietin and testosterone. Using alpha-amanitine and different ionic strength conditions it was found that erythropoietin enhances preferentially RNA polymerase II activity while testosterone increases RNA polymerase I activity. It is postulated that erythropoietin and testosterone act synergically to create the biochemical machinery for hemoglobin synthesis, the macromolecule that characterizes the erythropoietic process.