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At least 685 records · Page 38Linked to original sources
PubMed1994

Relevance of drug-melanin interactions to ocular pharmacology and toxicology.

In melanocytes, the biosynthesis of L-dopa derived indole polymer, melanin, is accelerated by tyrosinase and related enzymes. The brown to black pigment is characterized by a stable free-radical property. In humans, a pigment dependent slow onset of ocular actions of ephedrine, atropine, cocaine, pilocarpine and related medications was observed. Extensive accumulation of drugs by melanin appears to be the most important factor governing the long term therapeutic/toxicological activities. Drugs crossing placental circulation are localized in the mouse fetal eye. Thus, drugs exhibit a high binding capacity for melanin containing tissues. Studies on synthetic melanin and melanin granules also indicated a high binding capacity of many therapeutic classes of drugs, including psychotropics. In addition to the liposoluble property of the molecule, there is a definite relationship between chemical structure and the affinity of drugs for melanin. For example, the affinity of chlorpromazine for melanin is higher than that of chlorprothixene. NMR studies, with soluble melanins indicate that there is a steric preference among ephedrine enantiomers. A high binding capacity indicates that more than two molecules of (-)-ephedrine may complex with one indole unit of melanin. Ocular drug development calls for the study of qualitative and quantitative aspects of drug-melanin interaction.

Animals↗
PubMed1992

Severe streptococcal infections in historical perspective.

The recent unexplained increase in severe streptococcal diseases in the United States and Great Britain is compared to the 1825-1885 pandemic of fatal scarlet fever. Although scarlet fever may not be representative of all severe streptococcal disease, it was the only one reliably identified in the 19th century. The epidemiology of scarlet fever during the 19th century pandemic suggests the following features of the disease; cocirculation of both virulent and less-virulent streptococcal strains eliciting cross-immunity; circulation of hyperendemic prevalent strains in urban centers of developed nations, with periodic spillovers to rural areas and developing nations; and protection of infants from infection (but not from fatal disease once infection occurred) by the transfer of maternal antibodies via the placenta, breast milk, or both. The 19th century data suggest that efforts to prevent severe streptococcal diseases should begin with better characterization of the epidemiology of streptococcal disease, a task entailing identification of streptococcal virulence factors and measurement of their distribution among isolates from individuals with streptococcal diseases and in open populations.

Global Health↗
PubMed1985

An increase in afterload augments ventricular relaxation rate in isolated perfused canine hearts.

The afterload dependency of relaxation rate was reappraised in isolated canine hearts both in isovolumic and isobaric contractions by using the reliable exponential method in which the asymptote LV pressure (P chi) is variable. This method provided a closer correlation (r = 0.999 +/- 0.001) between the measured LV pressure decay and the model estimate than the semilogarithmic method assuming P chi = 0 (r = 0.992 +/- 0.001). Time constants of isovolumic LV pressure decay obtained by the exponential method demonstrated a significant (p less than 0.01) decrease during volume loading both in isovolumic and isobaric contractions, indicating that the relaxation rate is augmented as afterload increases. In contrast, if we assume P chi = 0, the time constant of LV pressure decay was independent of peak LV pressure as previously reported. Thus, we conclude that the load insensitive relaxation rate implied by the semilogarithmic method (P chi = 0) may be erroneous due to an invalid assumption, ie, P chi = 0, but the relaxation rate is augmented as afterload increases both in isovolumically contracting and isobarically ejecting isolated canine hearts.

Animals↗
PubMed1983

Comparison of large-pore membrane haemodialysis and cross-dialysis in acute hepatic insufficiency in pigs.

We studied the duration of survival and the removal of putative toxins in forty pigs with ischaemic hepatic necrosis, undergoing haemodialysis or cross-dialysis with a large-pore membrane. Ischaemic hepatic necrosis was induced in conscious animals by tightening a loop around the hepatic artery 3 days after construction of a portocaval shunt. Pigs treated by a dialysis procedure survived significantly longer (45.2 +/- 11.9 h) than controls (26.3 +/- 5.4 h). There was no difference between haemodialysis and cross-dialysis. Blood ammonia initially dropped significantly (P less than 0.05) more during haemodialysis (560 +/- 107 leads to 210 +/- 51 mumol/l) than during cross-dialysis (596 +/- 131 leads to 398 +/- 81 mumol/l) but it subsequently increased beyond initial values despite efficient removal during continuous dialysis. Removal of ammonia was greater during cross-dialysis than during haemodialysis, but haemodialysis was more effective in the removal of the ammonia precursors glutamine and urea. We conclude that dialysis procedures can prolong survival in pigs with ischaemic hepatic necrosis. The removal of ammonia-precursors is more effective in the prevention of hyperammonaemia than the removal of ammonia itself. Since dialysis cannot prevent progressive hyperammonaemia, control of excessive toxin production seems mandatory for effective hepatic support.

Acrylonitrile↗
PubMed2004

Liver invasion by malarial parasites--how do malarial parasites break through the host barrier?

Malarial transmission to the human host is established by sporozoite infection of the liver. Sporozoites are released from the mosquito salivary glands and carried by the blood flow to the liver sinusoid. In the sinusoid, sporozoites leave the blood circulation by crossing the sinusoidal cell layer to infect hepatocytes, the site for their development into the erythrocyte-invasive forms. Traversal of the sinusoidal cell layer and subsequent hepatocyte infection are the most important events in sporozoite liver invasion, but the molecular basis of both events remains to be elucidated. The present review of sporozoite liver invasion focuses on recent advances in this topic obtained by application of reverse genetics. Sporozoites traverse host cells, rupturing the host cell membrane in the process. Three microneme proteins have important roles in this motility. Disruption of one of these genes abolishes or severely impairs cell traversal without affecting other types of invasive motility. Studies using these disruptant parasites indicate that cell-traversal ability is required for crossing the sinusoidal cell layer and accessing the hepatocytes for infection. This process is homologous to midgut epithelium penetration by the malarial ookinete, because identical or paralogous genes are critically involved in both processes. After arrival at the hepatocyte, the invasion mode of the sporozoites switches from cell traversal to hepatocyte infection.

Animals↗
PubMed1986

Nitrate tolerance. State of the art--chairman's summary.

The development of tolerance to the effects of nitrates is well documented in the literature. It can be induced and rapidly reversed with all types of nitrates and it is more pronounced in the arterial as compared to the venous circulation. Cross-tolerance between different nitrates exists. Furthermore, tolerance seems more related to high and continuous plasma concentrations and may possibly be avoided by intermittent dosing. The importance of such factors as patient selection, type of nitrate preparation, duration of therapy, the significance of target organs, methods of evaluating the development of nitrate tolerance as well as a summary of the discussions during the workshop is presented.

Drug Tolerance↗
PubMed1977

Step function input to the rat kidney by shifting between auto- and alloperfusion.

A technique is described that permits instantaneous shifts from autoperfusion of the left kidney of an "experimental" rat to alloperfusion of the same kidney from a "pump" rat (or vice versa). Renal arterial and venous pressures are maintained at normal levels during alloperfusion. The kidney has proved to work satisfactorily during both auto- and alloperfusion as judged from measurements of renal blood flow, urine volume flow, urine osmolality, and fractional extraction of inulin and PAH. The vascular dead space of the system is extremely small. If the blood of the pump rat-experimental rat has been equilibrated with indicator, shifting from auto- to alloperfusion constitutes a practically pure step washin to/washout from the kidney. Reverse effects are obtained by shifting from allo- to autoperfusion. Compared with the bolus injection technique, recirculation problems are minimized because the perfused vascular volume of a single kidney is small compared with the whole-blood volume of the rat.

Animals↗
PubMed1981

Regression of cardiac oxygen consumption on ventricular pressure-volume area in dog.

Left ventricular systolic pressure-volume area (PVA) has been reported to be a reliable predictor of cardiac oxygen consumption rate per beat (VO2) in a given heart with a stable inotropic background. PVA is the specific area in the pressure-volume (PV) diagram, consisting of the area (EW) within the PV loop and the area (PE) bound by the end-systolic and end-diastolic PV lines and the relaxation segment of the PV loop. EW and PE correspond to the external mechanical work and the end-systolic elastic potential energy in the ventricular wall, respectively. We determined the optimal combination of EW and PE for the best prediction of VO2, using the linear multiple regression analysis. From EW, PE, and VO2, data of many isovolumic and ejecting contractions, the optimal coefficients of EW and PE were 1.67 +/- 0.43 (SD; 7 hearts) and 1.74 +/- 0.49 (10(-5) ml O2/mmHg . ml), virtually identical to each other, corroborating that PVA, i.e., a simple sum of EW and PE, can reliably predict VO2 of a given heart in a stable contractile state.

Animals↗
PubMed1975

Mesenteric baroreceptors.

Occlusion of the mesenteric vessels in the cat and injection of catecholamines produced significant changes in skin and muscle blood flows. These were abolished by cutting the mesenteric nerves. The occurrence of systemic pressure and peripheral resistance changes in cross-perfused mesenteric preparations indicates that hemodynamic factors alone, such as might result from occlusion of a large vascular region, were not initiating the reflex. This also excludes extramesenteric receptors within the heart and large vessels from the reflex. Since both intravascular pressure and catecholamines have been shown to modify Pacinian receptor discharge in vivo, the evidence suggests that the mesenteric Pacinian corpuscle is the baroreceptor probably initiating the vasomotor reflexes in skin and muscle. The net effect of mesenteric receptor activity appears to be an inhibition of vasomotor neurons supplying skin and muscle.

Animals↗