Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.     

The fate of isoprene inhaled by rats: comparison to butadiene

Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isoprene vapor at four concentrations from 8 to 8200 ppm. The percentage of the inhaled isoprene that was metabolized decreased with increasing exposure concentration. The percentage of the total metabolites (that is, non-isoprene-retained 14C) excreted in urine and feces or expired was determined as a function of vapor concentration. About 75% of the total metabolites was excreted in urine. This was independent of inhaled isoprene concentration. After exposure to 8200 ppm, a larger percentage of the metabolites was excreted in feces than after exposure to lower concentrations. Using vacuum line techniques, blood metabolite concentrations were determined as functions of both vapor concentration and exposure duration. At one exposure concentration (1480 ppm) metabolites were measured in the nose, lungs, liver, kidney, and fat, as well as in blood. A mutagenic metabolite, isoprene diepoxide, was tentatively identified in all tissues examined. Between 0.0018 and 0.031% of the inhaled 14C label was tentatively identified as this metabolite in blood. The relative amount of the metabolites present in blood was highest for low concentrations of inhaled isoprene and for shorter exposure durations. Body fat appeared to be a reservoir for both isoprene metabolites and isoprene itself. The appearance of metabolites in the respiratory tract after short exposure durations together with low blood concentrations of isoprene indicated that substantial metabolism of inhaled isoprene in the respiratory tract may occur.     

Familial long thoracic nerve palsy: a manifestation of brachial plexus neuropathy

Long thoracic nerve palsy causes weakness of the serratus anterior muscle and winging of the scapula. It is usually traumatic in origin. Isolated long thoracic nerve palsy has not been recognized as the major manifestation of familial brachial plexus neuropathy, but I have studied the syndrome in four members of three generations of one family. One individual suffered an episode of facial paresis. The inheritance pattern was autosomal dominant.     

Intra-urban variations of neonatal and post-neonatal mortality in a developing city

Numerous surveys at the national and regional level have demonstrated that large inequalities in infant health status exist in Southern Africa. Few studies have assessed infant mortality at the intra-urban scale of geographic analysis. Comparisons between infant mortality rates from different areas are made even more meaningful if the data are divided into two primary categories based on period-of-death; these being the neonatal and post-neonatal components. This study presents the results of a survey undertaken in Metropolitan Cape Town (population 1.6 million) during 1982. The aim was to determine the spatial variation of neonatal and post-neonatal mortality at the suburb (or community) level within the city. Overall, a total of 36,789 live births and 928 infant deaths were recorded; 53.4% in the neonatal period and 46.6% in the post-neonatal period. The mean infant mortality rate was 25.2 per 1000 live births; the neonatal mortality rate and post-neonatal mortality rate being 13.5/1000 and 11.7/1000, respectively. A marked range in death rates was evident for both components. For the neonatal category it was 0.0-49.9/1000 and 0.0-40.0/1000 for the post-neonatal period. The generally low post-neonatal mortality rate among the 69 suburbs studied has made the neonatal component the dominant contributor to the infant mortality rate. However, in the lowest socio-economic areas the post-neonatal mortality rate was responsible for over 60% of infant deaths.(ABSTRACT TRUNCATED AT 250 WORDS)     

Health risks among submarine personnel in the U.S. Navy, 1974-1979

This study evaluated health risks associated with U.S. Navy submarine duty by comparing hospitalization rates of submariners with surface ship personnel. The groups were compared using age-adjusted hospitalization rates for 16 major diagnostic categories and several specific diagnoses postulated to be submarine associated. Submarine personnel did not have significantly higher hospitalization rates for any diagnostic categories nor for any of the submarine-associated illnesses. Submariner relative risk of hospital admissions was greater for a few selected diagnoses but statistical significance was not attained. Submarine personnel had lower hospitalization rates for nearly all of the diagnostic categories examined. Reasons for these lower rates may be stringent screening of submariners, higher levels of education among submariners, difficulty of evacuation from a submarine, and the healthy-worker effect. The health status of U.S. Navy personnel does not seem to be adversely affected by submarine duty.     

Methods of ultrasonic angiography and spectrum analysis of the Doppler signal in the diagnosis of the degree of occlusive lesions of the brachiocephalic arteries

Results of an examination of 39 patients are described and critically assessed. An analysis of the resolving power of the method of ultrasonic angiography in pathological formations of major vessels of the neck is given.     

Transferrin receptors and natural killer cell lysis. A study using Colo 205 cells exposed to 60 Hz electromagnetic fields

The role of target cell transferrin receptors (TfR) in natural killer (NK) cell-induced cytolysis has been studied using Colo 205 cells in which prior exposure to 60 Hz electromagnetic fields produced constitutive expression of maximum numbers of TfR. It was found that NK cell cytolysis was decreased in those cells expressing the highest levels of TfR, while cells expressing the lowest level of TfR were lysed to the greatest extent. Furthermore, pretreatment of target cells with, and the continued presence in the assay medium of, iron transferrin produced, in general, only a slight decrease in cytolysis. Incubation of cells with apotransferrin also produced only a slight decrease in cytolysis, while incubation with zinc transferrin produced a greater decrease in cytolysis. This latter effect was particularly dramatic for cells that had been exposed previously to either a 60 Hz magnetic field alone (1.0 gauss) or to a combined electric + magnetic field (current density 300 mA/m2, 1.0 gauss). In addition to indicating a discordance between TfR expression on target cells and their sensitivity to NK cell cytolysis, the data presented provide a further indication of cellular membrane changes produced by exposure to 60 Hz electromagnetic fields.     

Liquid crystalline phases in concentrated aqueous solutions of Na+ DNA.

Concentrated aqueous saline solutions of short (146-base-pair) DNA fragments suddenly become turbid and iridescent when the DNA concentration is slightly increased or the temperature is decreased. Microscopic examination through crossed polarizing filters shows that turbidity and iridescence is due to formation of a liquid crystalline DNA phase similar to cholesteric liquid crystals formed by other semirigid, but nonelectrolyte, chiral polymers. Several distinct textures of the liquid crystalline phase or phases are observed depending on DNA concentration, temperature, and method of sample preparation. Textures observed include spherulites with Maltese crosses, striated and highly colored ribbons, whorls of periodic interference fringes, and colored flakes. The liquid crystalline DNA phase coexists in metastable equilibrium with the isotropic phase over a relatively narrow temperature/concentration range--approximately 175-250 mg/ml and 25-62 degrees C (limit of measurements). At higher concentrations and temperatures above approximately equal to 25 degrees C, the solutions appear fully liquid crystalline. When concentrated solutions are cooled below room temperature, crystals form due to precipitation of supporting electrolyte. A partial phase diagram is reported for the isotropic----liquid crystal----crystal transitions of solutions of DNA in buffered saline (2 M Na+). The general features of this phase diagram and the critical DNA volume fraction for formation of the anisotropic phase are consistent with the observed and theoretically predicted phase behavior of rodlike or semirigid nonelectrolyte polymers.