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Biomedical subjects

S Kacew

Publications and source records attributed to S Kacew.

At least 37 records · Page 2Linked to original sources

Adverse effects of drugs and chemicals in breast milk on the nursing infant.

Breastfeeding is an essential physiologic process that provides nutrition to the infant and protects the child against infection and immunologic disorders. The incidence of various diseases and metabolic disorders is known to be less in a breastfed infant compared with a child given a milk substitute. Psychologically, a breastfed infant forms a maternal bond that enables adaptation more readily to a social environment. It is well-established that all drugs are excreted into breast milk and are bioavailable to the infant. In general the majority of drugs do not pose a significant problem to the nursing infant and breastfeeding should be encouraged. The physician should be aware of which drugs are contraindicated during lactation and which drugs should be used with caution. There are also environmental chemicals that readily enter breast milk and may induce adverse effects. At present, the advantages of breastfeeding for infant development outweigh the potential adverse consequences and this physiologic process should be encouraged. With the use of available data on pharmacokinetics, milk-to-plasma ratio, excretion, etc. a supportive approach can be delineated by the pediatrician to reassure the nursing mother that they can safely breastfeed and continue therapy with minimal effects on the infant. It is thus imperative to document the extent to which a drug or chemical appears in breast milk and any apparent effects in the infant.

Alcohol Drinking↗

Bioavailability to rats of bound [14C] pirimiphos-methyl in stored wheat.

Stored wheat treated with radiolabelled pirimiphos-methyl (0-2-diethyl-amino-6-methyl-pyrimidin-4-yl 0,0-dimethyl phosphorothioate) formed bound (nonextractable) 14C residues. Supercritical fluid extraction, gas chromatography and mass spectrometric techniques were used to identify and quantitate the 14C bound residues in wheat grains. The amount of bound 14C residues present after 28 weeks of storage was about 9.9% of the applied radioactivity. Pirimiphos-methyl accounted for 80% of the bound residue. Grain-bound residues were fed to rats for 5 days. After a total period of 8 days a substantially large percentage of the administered bound 14C residues (72.9%) was eliminated in urine while feces contained only 17.9%. Bound pirimiphos-methyl in wheat grain was metabolized in rats by processes involving hydrolysis, N-dealkylation and 0-demethylation. The results indicate that wheat-bound residues of pirimiphos-methyl are highly bioavailable to the rat and may possess a toxicological potential as manifested by a significant reduction in body weight gain.

Animals↗

Plasma elimination and urinary excretion of procaine after administration of different products to standardbred mares.

Plasma and urinary concentrations of procaine were examined in Standardbred mares after subcutaneous administration of various doses (80 mg to 1600 mg) of procaine hydrochloride. Regardless of dose, peak plasma procaine values occurred within 1 h, but remained detectable in a dose-dependent manner, with procaine present at 1 h with the 80 mg dose and 6 h at the 1600 mg dose. Similarly, peak urinary procaine concentrations were attained within 1.5 to 3 h, irrespective of dose, while detection time was dose-dependent, being 23 h for 80-200 mg doses but as long as 30-54 h with the 1600 mg dose. When mares were given a single intramuscular injection of a penicillin G-procaine preparation (Ethacillin, Cillimycin, Penamycin, Derapen A, Azimycin or Diathal), peak plasma procaine concentrations varied and were reached from 10 min to 3 h in all cases, with detection from 3 to 20 h after drug administration. Although the peak urinary levels of procaine occurred between 30 mins and 6 h, detection in urine in most cases was as long as 78-120 h except for Diathal for which detection was limited to 54 h. Daily administration of a penicillin G-procaine preparation (Pen-Di-Strep) for 5 days produced a biphasic peak in plasma procaine at 3 and at 6-9 h with detection from 16 to 23 h after drug treatment. Although peak urinary procaine values were reached at similar times after single or multiple injections, the duration of detection was markedly longer (425 h) after the multiple-dose regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effect of interaction between gentamicin and pyridoxal-5-phosphate on functional and metabolic parameters in kidneys of female Sprague-Dawley rats.

Daily intraperitoneal (i.p.) injection of genatmicin at a dose of 70 mg/kg for 11 days produced nephrotoxicity in female Sprague-Dawley rats as evidenced by increased excretion of urinary protein and trypsin inhibitory activity as well as rise in renal individual class and total phospholipid. The observed proteinuria was associated with a significant twofold fall in creatinine clearance and histopathological changes, including the presence of hyaline casts and flattened epithelial cells within the lumen of proximal convoluted tubules. Although pyridoxal-5-phosphate (50 mg/kg) administered i.p. did not significantly alter creatinine clearance, histopathology, proteinuria, and urinary trypsin inhibitory activity, an increase in individual class and total phospholipid was noted in kidney. In rats simultaneously administered gentamicin and pyridoxal-5-phosphate, the observed fall in renal gentamicin content was associated with a return of individual class and total phospholipid to control values. However, the decline in creatinine clearance, enhanced proteinuria, and increase in urinary trypsin inhibitory activity in the simultaneous-treated group was similar or greater than that seen in the gentamicin-only injected rats. Morphological examination of simultaneous-treated rats revealed extensive alterations in proximal tubules including numerous mitotic figures, large vesicular nucleii, and prominent nucleoli in epithelial cells as well as hyaline casts within the lumen. Our data combined with results of previous studies suggest that sex and type of rat strain are important factors in aminoglycoside-induced nephrotoxicity. It is evident that a specific concentration of pyridoxal-5-phosphate may be necessary to provide protection against all manifestations of aminoglycoside-induced renal damage.

Animals↗

Changes in saccharide and phospholipid content associated with drug storage in cultured rabbit aorta muscle cells.

In the investigation of cellular changes associated with intracellular drug storage, we incubated cultured rabbit aorta muscle cells with various amphiphilic agents. Disobutamide, chloroquine, and desipramine each increased cellular content of rhamnose, arabinose, mannose, glucose, and total saccharides; these agents also elevated total and individual phospholipid of all classes. Amiodarone did not alter total saccharide content, but increased total phospholipid. Tilorone, in contrast, decreased total saccharides, but phospholipid content was unchanged. All test agents decreased xylose content. By light microscopy, disobutamide, chloroquine, and tilorone induced clear cytoplasmic vacuoles; desipramine induced dense cytoplasmic granules; and amiodarone induced both cytoplasmic changes. By electron microscopy, the content of the cellular alterations induced by disobutamide was primarily electron lucent; that of the alterations induced by desipramine was primarily concentric lamellar bodies/flocculent electron-dense structures; and that of the alterations induced by amiodarone was a mixture of both. There was no correlation, therefore, between the induced cellular chemical contents and morphologic changes. Despite the physicochemical similarity of the amphiphilic drugs (all have cationic and lipophilic moieties), the chemical responses they induced were different. The results suggest that amphiphilic drugs alter processes involving saccharides as well as those of phospholipid metabolism. The origin of the saccharide moieties associated with the induced changes in monosaccharide contents is not known. Increased content of phosphatidylinositol, mannose, and glycosyl residues is consistent with the suggestion that amphiphilic drugs may cause an increase in membrane anchor synthesis. The inhibition of lysosomal enzyme activities responsible for the degradation of phospholipid and other anchors may also account for the observed increase in monosaccharides and phosphatidylinositol content.

Amines↗

Pathogenic factors in aminoglycoside-induced nephrotoxicity.

Aminoglycoside antibiotics play an integral role in antimicrobial chemotherapy. Unfortunately, these drugs are known to cause nephrotoxicity in man and experimental animals. In fact, the incidence of renal dysfunction during the course of clinical treatment with aminoglycoside antibiotics is approximately 10%. Over the past two decades the elucidation of the pathogenesis of aminoglycoside-induced nephrotoxicity has been the subject of numerous investigations. This review describes the recent theories postulated to play a role in the pathogenesis of antibiotic-induced renal damage. In particular, the importance of amino-glycoside levels in the renal cortex or at the membrane binding site is examined in detail. The relevance of antibiotic tissue levels is reflected in the ability of other drugs to modify nephrotoxicity through an alteration in renal aminoglycoside content. The role of factors including age and diet in drug-induced nephrotoxicity is described. In clinical practice, aminoglycoside antibiotics may often be with other agents. The influence of aminoglycoside interaction with other drugs including vancomycin, cephalosporins and cytotoxic drugs is examined in the light of reports that nephrotoxicity is potentiated in these situations. In addition, this review focuses on the role of infection (pyelonephritis and septicemia) and bacterial endotoxin as pathogenic factors involved in aminoglycoside nephrotoxicity. Both the direct influence of endotoxin and the indirect effects of vasoactive mediators and inflammatory processes will be discussed. A multiplicity of factors is involved in the pathogenesis of aminoglycoside-induced nephrotoxicity and these are further amplified in the presence of infection.

Aminoglycosides↗

Gentamicin-induced renal metabolic alterations in newborn rat kidney: lack of potentiation by vancomycin.

Daily subcutaneous administration of 20 or 100 mg/kg gentamicin for 4 days significantly decreased pyridoxal-5'-phosphate and lysosomal specific phosphatidylinositol-phospholipase C (PI-PLC) in newborn rat kidney. The fall in PI-PLC was associated with an elevation in renal phosphatidylinositol, phosphatidylserine, and phosphatidylcholine. The 100 mg/kg gentamicin dose also produced a rise in renal sphingomyelin, phosphatidylethanolamine, phosphatidylglycerol, and total phospholipid (TPL) accompanied by inhibition in the activities of Na+,K+-ATPase and alkaline phosphatase. In contrast, daily intraperitoneal injection of 100 mg/kg vancomycin for 4 days failed to markedly alter renal metabolic parameters. However, the 500 mg/kg vancomycin dose increased kidney weight, TPL, and all individual phospholipid class concentrations accompanied by inhibition of lysosomal specific PI-PLC activity and reduced pyridoxal-5'-phosphate levels. Simultaneous administration of 20 mg/kg gentamicin with either vancomycin dose resulted in renal alterations similar to those produced by gentamicin alone. Concurrent treatment with 100 mg/kg aminoglycoside and either vancomycin dose produced changes in kidney which were similar to those produced by gentamicin alone, except for a synergistic rise in PI as well as a greater fall in alkaline phosphatase and pyridoxal-5'-phosphate. Surprisingly, the concentration of gentamicin and vancomycin was less in newborn kidneys of rats receiving a simultaneous high dose of vancomycin and aminoglycoside treatment compared to levels found in animals given either antibiotic separately. The lack of potentiation of nephrotoxicity in newborns administered a combination of vancomycin and gentamicin may be due to decreased accumulation of either antibiotic in kidney.

Adenosine Triphosphatases↗

Amiodarone-induced pulmonary toxicity in rats: biochemical and pharmacological characteristics.

Treatment of humans with the antiarrhythmic drug, amiodarone (AD), may result in the development of pulmonary toxicity. To characterize this response, male Fischer 344 rats were treated with AD for 1, 3, 9, and 16 weeks. AD induces a twofold increase in the level of pulmonary phospholipid after 3 weeks of treatment. Continued administration results in only a small increase above this level. All classes of phospholipids are elevated; phosphatidylcholine displays the largest increase, both quantitatively and as a relative increase over the control level. Both AD and its principal metabolite, desethylAD, are sequestered in the lungs following AD treatment. The relative levels are similar at all time points except 16 weeks, where the relative amount of AD is decreased. After 3 weeks of AD, female 344 rats show the same increase in pulmonary phospholipid as males. While similar levels of desethyAD are sequestered in the lungs of both sexes, AD levels are much lower in female lungs. Evidence is presented to suggest that desethylAD may play an important role in the induction of the phospholipidosis. The activity of Na+,K+-ATPase in the lungs is inhibited by 75% after 9 weeks of AD while the activity of the acid hydrolase, beta-N-acetylglucosaminidase is increased significantly at this time point. All biochemical changes are reversible with values returning to control levels 2 weeks after termination of a 3-week AD treatment protocol. Measurable levels of AD and desethylAD are present in lung tissue after 5 weeks of recovery.

Acetylglucosaminidase↗

Inhibition of gentamicin-induced nephrotoxicity by pyridoxal-5'-phosphate in the rat.

Daily s.c. injection of gentamicin at either 100 mg/kg for 4 days or 60 mg/kg for 2 weeks produced nephrotoxicity in the adult rat as judged by an increase in urinary excretion of beta-galactosidase, beta-glucuronidase and beta-N-acetylglucosaminidase. The observed enzymuria was associated with significant elevation in total renal phospholipid, phosphatidylinositol, phosphatidylcholine and phosphatidylserine. In addition, gentamicin decreased the activities of renal cortical Na+-K+-adenosine triphosphatase, alkaline phosphatase as well as phospholipase C. Pyridoxal-5'-phosphate (250 mg/kg/day) administered i.p. for 4 or 14 days did not markedly alter the metabolic markers of kidney function. In rats simultaneously given pyridoxal-5'-phosphate and gentamicin for 4 days the vitamin failed to prevent either the antibiotic-induced decrease in renal phospholipase C and alkaline phosphatase or the increase in total renal phospholipid, phosphatidylinositol, phosphatidylcholine and phosphatidylserine. However, simultaneous pyridoxal-5'-phosphate and aminoglycoside treatment for 2 weeks proved effective in blockade of the gentamicin-induced kidney phospholipidosis, elevation in urinary beta-galactosidase, beta-glucuronidase and beta-N-acetylglucosaminidase, as well as reduction in renal phospholipase C and alkaline phosphatase. The gentamicin-induced nephrotoxicity was associated with a decrease in renal pyridoxal-5'-phosphate levels. In the simultaneous 4-day-treated rat the renal concentration of pyridoxal-5'-phosphate returned to approximate control values, whereas after 2 weeks the level of vitamin B6 was approximately 2-fold higher than control. Although pyridoxal-5'-phosphate in the simultaneous group lowered kidney gentamicin content by 40% after 4 or 14 days, protection from aminoglycoside-induced nephrotoxicity was apparent only after 2 weeks in our study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Inability of nitrendipine to protect against gentamicin nephrotoxicity in the rat.

Daily sc injection of gentamicin (100 mg/kg) for 4 days produced a significant decrease in the activities of renal cortical Na+,K+-ATPase and alkaline phosphatase. The observed reduction in renal functional enzymatic markers was associated with significant elevation in sphingomyelin, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine, and total phospholipid. Gentamicin significantly decreased the activity of renal phospholipase C. Nitrendipine (25 mg/kg/day) for 7 days po for 4 days alone did not markedly alter the activities of kidney phospholipase C, alkaline phosphatase, and Na+,K+-ATPase or tissue phospholipid levels. Daily administration of nitrendipine for 3 days followed by concurrent treatment of nitrendipine and gentamicin failed to prevent antibiotic-induced renal histopathologic changes, phospholipidosis, or decrease in alkaline phosphatase. However, in rats simultaneously given nitrendipine and gentamicin the activity of Na+,K+-ATPase returned to control values, indicating a selective blocking action for nitrendipine. The inability of nitrendipine to prevent gentamicin-induced renal phospholipidosis or decreases in enzymatic function markers was associated with significantly elevated tissue aminoglycoside levels when compared to values seen in rats given only the antibiotic. Evidence suggests that nitrendipine is not effective in lowering the concentration of gentamicin in renal cortex. The effectiveness of an agent in providing protection against aminoglycoside nephrotoxicity may be associated with the ability of the drug to lower renal gentamicin content.

Animals↗

Platinum concentrations in human autopsy tumor samples.

Platinum concentrations were determined in autopsy tumor samples obtained from 27 patients who had received cisplatin 40-1,029 mg/m2 from 0 to 240 days antemortem. Liver metastases had significantly higher platinum concentrations than did tumors in other sites (p less than 0.005). Platinum concentrations in liver metastases were similar to platinum concentrations in normal liver. Platinum concentrations in gliomas and brain metastases were similar to platinum concentrations in other extrahepatic tumors. Platinum concentration generally decreased with increasing distance into brain from tumor. By multiple stepwise linear regression analysis, the factors that were independently most closely associated with tumor platinum concentration were time from last cisplatin treatment, cumulative lifetime dose of cisplatin, route of cisplatin administration (intraarterial vs. other), and site of tumor deposit (liver vs. other) (r = 0.69, p less than 0.001). Patients whose tumors had responded to cisplatin-containing regimens had mean tumor platinum concentrations that were higher than the mean tumor platinum concentrations in patients whose tumors had not responded to cisplatin (p less than 0.05).

Autopsy↗

Amiodarone-induced phospholipidosis in rat alveolar macrophages.

Humans treated with the antiarrhythmic drug amiodarone may develop pulmonary toxicity accompanied by the presence of alveolar macrophages (AM) containing lamellar inclusions. This cellular response is indicative of the development of a drug-induced phospholipidosis. To characterize this response of the AM, Fischer-344 rats were treated with amiodarone, and the macrophages were recovered by pulmonary lavage. The development of phospholipidosis was dose- and time-dependent and was reversible. Daily treatment for 1 wk (5 days/wk) at 150 mg/kg resulted in a 5-fold increase in total phospholipid in the cells. Phospholipid levels were increased only slightly more through 9 wk of treatment. Cells were filled with lamellar inclusions and contained areas of amorphous granular and membranous material. Individual classes of phospholipids were all increased during the development of phospholipidosis. When expressed as mumol/10(7) cells, phosphatidylcholine demonstrated the largest increase. Levels of amiodarone and its major metabolite, desethylamiodarone, increased in AM in parallel with the increase in phospholipid. From 3 days through 9 wk of treatment, the level of desethylamiodarone was always higher than that of amiodarone. Treatment with desethylamiodarone also induced phospholipidosis in AM. Administration of phenobarbital along with amiodarone for 1 wk caused a reduction in the levels of amiodarone, desethylamiodarone, and phospholipid in the cells. The molar ratio of amiodarone to phospholipid was decreased, whereas the molar ratio of desethylamiodarone to phospholipid remained unchanged. Taken together, the results indicate that, along with amiodarone, desethylamiodarone and/or its metabolites may play an important role in the phospholipidosis induced in AM when rats are treated with amiodarone.

Amiodarone↗

Role of phospholipase C in chlorphentermine-induced pulmonary phospholipidosis in rat.

Daily, oral administration of chlorphentermine (60 mg/kg) for 5 days to rats produced a significant increase in the concentration of whole lung total phospholipid as well as sphingomyelin, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. Similarly, a significant elevation in total and all individual phospholipid components was found in the lysosomal fraction of chlorphentermine-treated rat lung. In contrast, the activities of pulmonary Na+,K+-ATPase and alkaline phosphatase, enzymatic markers of membrane function, were not markedly affected by chlorphentermine treatment. The observed lung phospholipidosis was accompanied by inhibition of phospholipase C activity. Regardless of the phospholipid substrate, chlorphentermine significantly decreased pulmonary phospholipase C to approximately the same extent. Our data show that accumulation of phospholipid in whole lung and lysosomes is associated with an inhibition of phospholipase C activity.

Alkaline Phosphatase↗

Cationic amphiphilic drug-induced renal cortical lysosomal phospholipidosis: an in vivo comparative study with gentamicin and chlorphentermine.

Daily subcutaneous injection of gentamicin (100 mg/kg) for 2 days produced a significant decrease in the activities of alkaline phosphatase, a brush-border membrane marker, and Na+-K+ ATPase, a basolateral membrane marker, in adult rat kidney cortex. Analysis of homogenate and lysosomal fractions revealed a significant rise in the concentration of total renal cortical phospholipid, phosphatidylserine, phosphatidylcholine, and phosphatidylinositol. In the lysosomal fraction, an increase in the levels of phosphatidylglycerol and phosphatidylethanolamine was also noted. Daily, oral chlorphentermine (60 mg/kg) administration for 5 days significantly reduced renal Na+-K+ ATPase without a marked change in alkaline phosphatase. As in the case of gentamicin, chlorphentermine produced a significant elevation in phosphatidylserine, phosphatidylcholine, and phosphatidylinositol as well as total phospholipid in both the homogenate and lysosomal fractions of kidney cortex. The observed chlorphentermine- or gentamicin-induced renal phospholipidosis was associated with a significant reduction in the activity of phosphatidylinositol-specific phospholipase C. The drug-induced inhibition of phospholipase C was quantitatively equal in the renal cortical homogenate and lysosomal fractions. In addition, gentamicin significantly inhibited the activity of phosphatidylserine-phospholipase C and phosphatidylcholine-phospholipase C in renal cortical homogenate. In contrast, only the activity of phosphatidylinositol-specific phospholipase C was decreased in chlorphentermine-treated kidneys. Evidence thus indicates that the gentamicin-induced accumulation of phospholipid in renal cortical lysosomes is associated with inhibition of various forms of phospholipase C, while in the case of chlorphentermine the inhibition of different phospholipases may be involved in phospholipid accumulation.

Animals↗

Systematically applied chemicals that damage lung tissue.

A large, and increasing number of drugs and chemicals have been found which are toxic to lung following systemic administration. These agents damage lung tissue specifically, or in addition to damage to other tissues. Mechanisms explaining the pulmonary damage produced by some lung toxins have been uncovered. These include concentration of the agent within lung, the absence of adequate pulmonary detoxication systems, and bioactivation to a toxic species within specific lung cells or at distant sites followed by transport to the lung. The basic biochemical lesions underlying lung damage, responses of individual lung cells and pulmonary repair processes to the toxic agent, and species and age differences in susceptibility to lung damage have not, however, been well defined for most lung toxins. This review describes the information available on pulmonary biochemical and pathological changes associated with some of these lung-toxic agents. In addition, mechanisms proposed to explain the lung damage are discussed. The agents covered include: paraquat, the thioureas, butylated hydroxytoluene, the trialkylphosphorothioates, various lung-toxic furans and antineoplastic agents, the pyrrolizidine alkaloids, metals and organometallic compounds, amphiphilic agents, hydrocarbons, oleic acid, 3-methylindole, and diabetogenic agents. Detailed reviews on the overall toxicity of many of these agents have been published elsewhere. This review concentrates on their pulmonary toxicity. Information is presented as an overview to illustrate both the extensive literature that is available and the important questions that remain to be answered about systemic chemicals that damage lung tissue.

Animals↗