The effects of chronic oral ingestion of lead in doses ranging from 20-80 ppm were compared with those seen after the subacute exposure of rats to a 10 mg/kg daily dose of the heavy metal for 7 days. Irrespective of the treatment regimen used, lead treatment significantly increased the activities of renal pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase. The observed enhancement of kidney gluconeogenic enzymes in chronically treated animals was associated with a stimulation of the adenylate cyclase-cyclic AMP system, a rise in blood blucose and urea as well as a depression in hepatic glycogen and serum immunoreactive insulin (IRI) levels. In contrast, subacute exposure to lead failed to significantly alter cyclic AMP metabolism and the concentrations of liver glycogen, blood glucose, serum urea or IRI. Whwereas the insulinogenic index (the ratio of serum IRI to blood glucose concentration) was markedly suppressed in chronically treated rats, this ratio remained within normal limits following subacute exposure to the heavy metal. However, a marked decrease in the insulinogenic index was observed in subacutely treated rats 15 min after the administration of a glucose load. The data provide evidence to show that increased glucose synthesis as well as suppressed pancreatic function may be responsible for lead-induced disturbances in glucose homeostasis.

Adenylyl Cyclases↗

PubMedDate not supplied

Modification by phenobarbital of chlorphentermine-induced changes in lung morphology and drug-metabolizing enzymes in newborn rats.

Treatment of newborn rat pups with 60 mg/kg.d chlorphentermine for 7 d produced on accumulation of alveolar foam cells accompanied by an increase in relative pulmonary tissue weight. In contrast, administration of 20 mg/kg.d for 1 wk did not markedly alter lung ultrastructure or weight in newborns. Both doses of chlorphentermine elevated the activity of pulmonary aminopyrine N-demethylase but not that of aniline hydroxylase. The increase in relative liver weight was associated with stimulation of the activities of aniline hydroxylase and aminopyrine N-demethylase in newborns administered either chlorphentermine dose. Phenobarbital treatment produced an increase in relative liver weight accompanied by elevated activities of pulmonary aminopyrine N-demethylase and hepatic aniline hydroxylase and aminopyrine N-demethylase. Simultaneous barbiturate and chlorphentermine administration produced stimulation in liver enzymes to the same extent as phenobarbital alone. In contrast, phenobarbital potentiated the chlorphentermine-induced rise in pulmonary aminopyrine N-demethylase. In the case of 60 mg/kg chlorphentermine and barbiturate, the observed potentiation of lung enzyme activity was associated with a reduction in the number of alveolar foam cells. The results suggest that chlorphentermine and phenobarbital stimulate drug-metabolizing enzyme in lung and liver of newborn rats and that phenobarbital may provide protection against phospholipidosis through stimulation of pulmonary, drug-metabolizing enzymes.

Aminopyrine N-Demethylase↗

PubMedDate not supplied

Strain as a determinant factor in the differential responsiveness of rats to chemicals.

The beneficial effects derived from the use of chemicals in agriculture, energy production, transportation, pharmaceuticals, and other products that improve the quality of life are clearly established. However, continued exposure to these chemicals is only advantageous in conditions where the benefit far outweighs toxic manifestations. By law, determination of risk of toxicity necessitates the use of laboratory animals to establish whether chemical exposure is safe for humans. To simulate the human condition, it is incumbent upon investigators to choose a species in which pharmacokinetic and toxicokinetic principles are established and resemble those of humans. Some of the advantages to the use of rat in chemical toxicity testing include (a) similarities in metabolism, anatomy, and physiological parameters to humans; (b) the short life span, especially for carcinogenesis study; (c) the availability, ease of breeding, and maintenance at a relatively low cost; and (d) the existence of a large database to enable comparison of present to reported literature findings. However, the choice of rat can be complicated by several factors such as sex, age, and nutrition, but especially strain, where currently there are over 200 different strains of rat known to exist. The aim of this review is to demonstrate that there are differences in the responsiveness of rat strains to chemicals and that the susceptibility observed is dependent on the tissue examined. It is evident that the genotype differs among strains, and this may be responsible for differences in sensitivities to chemicals. Awareness of strain as a factor in susceptibility to toxicant action needs to be taken into account in interpretation of relevance of risk of toxicity for humans.

Animals↗

PubMedDate not supplied

Effect of over-the-counter drugs on the unborn child: what is known and how should this influence prescribing?

The developing organism is unique in its responsiveness to drugs. The predictability of therapeutic effectiveness and safety of drugs in pregnancy using the adult as a model for pharmacokinetics and pharmacodynamics can result in grave consequences in the fetus. There exists a general misconception that since over-the-counter (OTC) drugs are readily available, these pharmaceutical agents can be viewed as safe to use by adults. Ingestion of OTC preparations during pregnancy results in placental transfer and accumulation of these drugs in the fetus. As the fetus lacks the ability to handle pharmaceutical agents, since renal function, metabolic pathways, etc. are not fully developed, drug exposure in utero may produce deleterious effects in the fetus but not the mother. Clinicians are aware of drug-induced effects on the fetus and have dramatically reduced the use of prescription drugs during pregnancy. However, the use of self-medication (OTC) has significantly increased during pregnancy through extensive, effective advertising by the pharmaceutical industry and lack of sufficient data indicating an OTC effect on the fetus. However, the consequences of OTC drug use need to be established, since these compounds continue to be used extensively, especially during pregnancy.

Adult↗

PubMedDate not supplied

Cationic lipophilic drugs: mechanisms of action, potential consequences, and reversibility.

Explore the source record for details and available documents.

Animals↗

PubMedDate not supplied

The use of morphologic tissue examinations as novel technique for estimation of drug adverse reactions in hospitalized patients.

Morphologic evaluation of tissue specimens from a hospital population was used to identify and classify adverse reactions to drugs. With the use of this novel technique, the incidence of adverse tissue reactions was found to be 3.6% out of which 1.5% were found to be definitely caused by a specific pharmacological agent. Adverse tissue reactions were both sex- and age-related occurring more often in women and more frequently between the ages of 51-60 years. Although adverse tissue reactions were noted less frequently in males, a definite causative agent was identified in over 50% of males in which a tissue reaction was observed. Endometrium and liver were the predominant tissues altered morphologically in our hospital population. Estrogenic preparations and alcohol were found to be most frequently implicated in the observed adverse tissue reactions. In comparison to the observation of symptoms associated with drug use, our study provides an alternate means of relating an adverse reaction to pharmacological agent employed in that subjective bias can successfully be removed. Although the present system described appears to be more rigorous in identification of adverse reactions, evidence indicates that tissue adverse reaction technique may be advantageous in determination of an unwanted response in patients under 60 years of age. It is hoped that the tissue adverse reaction evaluation may provide a more accurate prediction of possible adverse effects and perhaps may be a more reliable, sensitive system for estimation of adverse effects in hospitalized patients.

Adolescent↗

PubMedDate not supplied

Autopsy tissue examination: a novel method to estimate adverse reactions to pharmacological agents.

Autopsy tissue examination was employed as a measure to remove subjective bias observation in the identification and numerical computation of adverse reactions to drugs. With the the use of this novel technique, the incidence of adverse reactions was 26%, of which 82% were produced by a specific causative agent. Adverse reactions occurred most frequently in autopsied tissues taken from patients who were male and in the 61 and over age group. Further the predominant tissue altered morphologically in autopsied specimens examined was liver. The most common causative agent associated with an adverse tissue reaction was identified as alcohol. In light of the difference between evaluation by physicians of drug adverse reactions and the technique of autopsy tissue examination, our findings provide a more accurate measure of adverse reactions to non-prescription pharmacological agents.

Adolescent↗