Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.

Transfer constants for blood-brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid.

The cause of the toxic mussel poisoning episode in 1987 was traced to a plankton-produced excitotoxin, domoic acid. Experiments were undertaken to quantitate the degree to which blood-borne domoic acid can permeate the microvasculature to enter the brain. Pentobarbital-anesthetized, adult rats received an i.

Interlaboratory testing of the transferability of a candidate reference method for total cholesterol in serum.

In 1975 the Centers for Disease Control, in cooperation with the American Association for Clinical Chemistry Cholesterol Reference Method Study Group, began an investigation to develop a reference method for total cholesterol. Five potential reference methods were compared with the definitive method developed by the National Bureau of Standards before the chemical method of Abell et al. (J Biol Chem 1952;195:357-66) was selected as the recommended reference method.

Serum enzymes in the BB rat before and after onset of the overt diabetic syndrome.

As part of a six-month prospective study of the effects of neonatal thymectomy in the spontaneously diabetic BB Wistar rat, activities of the following enzymes were determined: alkaline phosphatase (AP), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and UDP-galactosyltransferase (UDPG). In prediabetics, AP and LDH levels were higher than in sham-operated, non-diabetic controls; however, this increase was seen in nearly all diabetes-prone BB rats, diminishing the usefulness of these changes in discerning potential diabetics from asymptomatic, diabetes-prone rats. After onset of the syndrome, there was a striking elevation of AP values in all diabetics with no similar alteration in asymptomatic, diabetes-prone rats suggesting this was a diabetes-related phenomenon.

Time course of serum glucoregulatory variables and lipids following neonatal thymectomy of diabetes-prone and control BB Wistar rats fed a defined diet.

The acute diabetic syndrome in the BB Wistar rat resembles human type 1 (insulin-dependent) diabetes, including a possible association with T cell-mediated, (auto)immune processes. In most previous studies 'normoglycemic' littermates of diabetic BB rats have been used as controls and little attention has been paid to the role of diet. It now appears that asymptomatic/diabetes-prone littermates of diabetics have immune system defects as well as metabolic abnormalities.

An immunofluorescence study of anti-pancreatic islet cell antibodies in the spontaneously diabetic BB Wistar rat.

Sera from BB Wistar rats and Wistar control rats were evaluated for the presence of islet cell antibodies in a prospective study using an indirect immunofluorescence assay on pancreatic islet cell suspensions from cultured rat islets. Islet cell surface antibodies were detected in sera from all animals of the spontaneously diabetic BB Wistar rat colony. The antibody could be detected well before the clinical onset of the disease and was present throughout the course of study of all diabetic animals.

Comparison of four commercial methods for the determination of fast hemoglobins.

The performance of three commercial kits, based on microchromatographic techniques for the determination of glycosylated hemoglobins (fast hemoglobins) has been evaluated. All three kits showed good precision, provided the laboratory temperature remained constant. Temperature variations of even one degree C had a profound effect on the kits from Helena Laboratories and Isolab Inc.

Effect of analgesic nephropathy in women on the metabolism and excretion of 14C-acetaminophen.

Nephropathy due to excessive consumption of phenacetin-containing analgesic mixtures has been a problem in Canada. Following the withdrawal of phenacetin it seems probable that acetaminophen consumption will increase and this study investigated the metabolism of 14C-Acetaminophen in patients with nephropathy and in healthy women. The respective alpha T1/2s of excretion of Acetaminophen and its metabolites were 2.

Effect of fasting on free and esterified carnitine levels in human serum and urine: correlation with serum levels of free fatty acids and beta-hydroxybutyrate.

Serum levels of free L-carnitine, acylcarnitines, creatinine, beta-hydroxybutyrate, free fatty acids, cholesterol, triglycerides, and glucose were determined in healthy volunteers during a 24-36-hr fast. The effect of oral administration of free L-carnitine (1 g/person) on these parameters was studied. Urinary excretion of carnitine and creatinine was monitored throughout.

Carnitine content of blood and amniotic fluid.

Free carnitine levels were determined in amniotic fluids between the 10th and 40th week of gestation. They were found to decrease significantly with gestational age. Blood levels of carnitine were lower in pregnant than in nonpregnant women.

Serum UDP-galactose: glycoprotein galactosyltransferase in diabetics with microangiopathy.

1. Levels of serum UDP-galactose:glycoprotein galactosyltransferase in 117 unselected diabetics were compared with those in 60 non-diabetic healthy controls. 2.

Determination of phosphodiesterase I activity in human blood serum.

Phosphodiesterase I (EC 3.1.4.