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Biomedical subjects

J J Lipsky

Publications and source records attributed to J J Lipsky.

At least 91 records · Page 5Linked to original sources
PubMed1986

Production of hypoprothrombinaemia by cefazolin and 2-methyl-1,3,4-thiadiazole-5-thiol in the rat.

Recent findings have suggested that the 1-methyltetrazole-5-thiol (MTT) group contained in several beta-lactam antibiotics may be responsible for the hypoprothrombinaemia associated with these drugs. In order to determine if the hypoprothrombinaemia associated with cefazolin is due to the presence of the structurally related 2-methyl-1,3,4,-thiadiazole-5-thiol (MTD) group which it possesses, the ability of MTD and cefazolin to produce hypoprothrombinaemia in rats was examined. Female rats maintained on a vitamin K-deficient diet for ten days developed hypoprothrombinaemia after the intravenous administration of cefazolin for two subsequent days. Hypoprothrombinaemia was also produced by the oral administration to vitamin K-deficient rats of either cefazolin or MTD, while the oral administration of cefotaxime, which does not contain a thiol group, had no effect. In a rat liver microsomal system, MTD was found to be a much more potent inhibitor than cefazolin of the vitamin K-dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid. These results suggest that the hypoprothrombinaemia associated with cefazolin may be due to the MTD group.

Administration, Oral↗
PubMed1985

Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5-thiol and 2-methyl-1,3,4-thiadiazole-5-thiol.

Heterocyclic thiol metabolites of cephalosporin antibiotics may play an important role in the pathophysiology of hypoprothrombinemia and hemorrhage in patients treated with these drugs. A heterocyclic thiol metabolite of moxalactam, 1-methyltetrazole-5-thiol (MTT), inhibits the gamma carboxylation of glutamic acid that is required for the formation of active clotting factors. One possible pathway for the biotransformation of thiol compounds such as MTT is S-methylation catalyzed by either thiopurine methyltransferase (TPMT), a soluble enzyme, or by thiol methyltransferase, a microsomal enzyme. Therefore, MTT and 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), a thiol "leaving group" structurally related to MTT that is present in cefazolin, were tested as possible substrates for S-methylation catalyzed by purified human kidney TPMT or by human liver microsomes, a source of thiol methyltransferase. MTT and MTD were methylated by both human kidney TPMT and human liver microsomes. The products of these reactions were shown by high-performance liquid chromatography to be S-methyl MTT and S-methyl MTD. Apparent Km constants for the methylation of MTT and MTD by TPMT were 0.26 and 0.068 mM, respectively. Apparent Km constants for the methylation of MTT and MTD by human liver microsomes were 0.60 and 0.20 mM, respectively. Maximal velocity (Vmax) values for the S-methylation of MTD catalyzed by TPMT and by human liver microsomes were 3.58- and 678-fold greater than were those for the thiol methylation of MTT. Finally, S-methyl derivatives of MTT and MTD were one to two orders of magnitude less potent as inhibitors of the in vitro gamma carboxylation of glutamic acid than were MTT and MTD themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Mechanism of the inhibition of the gamma-carboxylation of glutamic acid by N-methylthiotetrazole-containing antibiotics.

Antibiotics that contain a 1-N-methyl-5-thiotetrazole (MTT) side group have been associated with hypoprothrombinemia. In a detergent-treated rat liver microsomal system, MTT inhibited the carboxylation of the gamma carbon of glutamic acid, a necessary reaction in the synthesis of four of the clotting factors. In the present work, the inhibition by MTT was found to be slow in onset, with a lag time of 15 min before significant inhibition occurred. A preincubation of MTT with the microsomes decreased the lag time and increased the extent of inhibition. Glutathione at 1 mM was found to markedly decrease the ability of MTT to inhibit this reaction. The disulfide dimer of MTT was a more potent inhibitor of the system than was MTT, with inhibition detected as low as 1 microM dimer. Disulfiram also inhibited the carboxylation system. These results indicate that the sulfhydryl group of MTT is important for the inhibitory effect of MTT and suggest that a slowly formed metabolite of MTT may be directly responsible for the observed inhibition. The inhibitory mechanism of MTT may be analogous to that of disulfiram, which would explain some pharmacologic effects in common with disulfiram. In addition, the in vitro observations presented here and a closer examination of the clinical evidence raise the possibility that MTT-containing antibiotic-induced hypoprothrombinemia may not be a vitamin K reversible phenomenon.

Animals↗
PubMed1984

Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats.

To determine whether the hypoprothrombinemia associated with antibiotics containing a 1-methyl-5-thiotetrazole (MTT) group is a result of the presence of the MTT group, rats were maintained on a vitamin K-deficient diet for 10 days and then received either intravenous moxalactam or cefotaxime or oral MTT for two additional days. MTT and moxalactam, which contains the MTT group, prolonged prothrombin time. Cefotaxime, which lacks the MTT group, had no effect.

Administration, Oral↗
PubMed1984

Risk factors for nephrotoxicity in patients treated with aminoglycosides.

Risk factors for nephrotoxicity in patients treated with aminoglycosides were determined from the case records of 214 patients in two prospective, randomized clinical trials of gentamicin and tobramycin. Nephrotoxicity, defined as a 50% or greater fall in calculated creatinine clearance, developed in 30 patients (14.1%). Patients with nephrotoxicity had higher initial calculated creatinine clearances, were more often women, and were more likely to have liver disease. Using stepwise discriminant analysis, these factors were selected with the initial 1-hour post-dose aminoglycoside level, patient age, and shock. An equation was generated that was accurate in discriminating between patients with and without nephrotoxicity when validated in an independent population. Factors that did not add significantly to the equation were diabetes, dehydration, serum bicarbonate, bacteremia, urinary tract infection, gentamicin or tobramycin use, duration of therapy, total aminoglycoside dose, or the use of clindamycin, furosemide, or cephalothin.

Aged↗
PubMed1984

Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double-blind trial.

In a prospective, randomized, double-blind study, we compared cefotaxime with nafcillin plus tobramycin in the treatment of serious bacterial infections. Of 195 patients with suspected or proven infections who were not neutropenic, definite bacterial infections were identified in 81; 34 of 38 patients given cefotaxime and 26 of 43 given nafcillin plus tobramycin (p less than 0.01) responded to treatment. The difference in response rates occurred primarily in patients with rapidly fatal underlying disease or with an infection outside the urinary tract. A logistic regression analysis showed that treatment with cefotaxime was still associated with a higher response rate after adjusting for several potential confounding factors. Among patients treated for 3 days or more, our criteria for nephrotoxicity were met in 2 of 68 (2.9%) given cefotaxime and 16 of 57 (28.1%) given nafcillin plus tobramycin (p less than 0.001). Prolongation of the prothrombin time and enterococcal colonization did not occur more frequently with cefotaxime. We conclude that cefotaxime may be more effective and less toxic than nafcillin plus tobramycin for patients with serious bacterial infections.

Adult↗
PubMed1983

N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinaemia.

Several new antibiotics which contain an N-methyl-thio-tetrazole side chain have been associated with the development of hypoprothrombinaemia. This side chain was found to be capable of the in-vitro inhibition of a necessary reaction in the synthesis of prothrombin, the gamma carboxylation of glutamic acid. The 50% inhibitory concentration was 1.1 mmol/l. The intact antibiotics latamoxef, cephamandole, and cefoperazone, which contain the side chain, did not inhibit the reaction at concentrations up to 2 mmol/l. These results suggest that hypoprothrombinaemia associated with antibiotics containing N-methyl-thio-tetrazole side chains may be a consequence of the in-vivo degradation of these antibiotics and the subsequent inhibition of the gamma carboxylation of glutamic acid by the side chain.

Animals↗
PubMed1983

Prospective randomized double-blind comparison of moxalactam and tobramycin in treatment of urinary tract infections.

In a prospective, randomized, double-blind trial, a regimen of 250 mg of moxalactam every 12 hours was compared with 1.0 mg/kg of tobramycin every eight hours in the treatment of urinary tract infections. One hundred and eleven patients were entered into the study; results in 63 (18 men and 45 women) were evaluable for both efficacy and toxicity. Thirty evaluable patients received moxalactam, and 33 received tobramycin. The mean duration of therapy in each group was seven days. There were six treatment failures in the moxalactam group and 10 failures in the tobramycin group (p greater than 0.4). Nephrotoxicity, defined as an increase in serum creatinine levels to 0.5 mg/dl or more, did not occur in either group. Thirteen patients in the moxalactam group and one in the tobramycin group had enterococci isolated from a urine culture specimen during or after therapy. It is concluded that use of the moxalactam regimen is as effective and safe as use of the tobramycin regimen in the treatment of urinary tract infections. The clinical significance of the enterococcal isolates associated with moxalactam therapy is yet to be determined.

Adult↗
PubMed1983

Initial aminoglycoside levels in the critically ill.

Twenty-six consecutive patients admitted to the medical ICU with presumed sepsis or septic shock had their initial serum aminoglycoside level determined 1 h after completion of a 20-min infusion of tobramycin, 2 mg/kg. There was a poor correlation between the dose received and the measured aminoglycoside level; 59% of the patients had initial blood aminoglycoside concentrations below the recommended peak level of 5 micrograms/ml. An underestimation of the volume of distribution in critically ill patients best explains the low serum aminoglycoside levels produced by the currently recommended dosage schedule.

Aminoglycosides↗
PubMed1982

Aminoglycoside inhibition of a renal phosphatidylinositol phospholipase C.

Aminoglycosides are able to inhibit phosphatidylinositol phospholipase C activity in a soluble fraction of rat renal tissue. The Km of the enzyme with respect to phosphatidylinositol is 0.53 mM and Vmax was 0.671 mumol of phosphatidylinositol cleaved per hr per mg of protein. The enzyme is calcium activated and inhibited by ethylene glycol bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid. Streptomycin, amikacin, kanamycin, tobramycin, gentamicin and neomycin inhibit enzyme activity in the same rank order as their ability to produce nephrotoxicity. The 50% inhibitory concentrations ranged from 0.03 mM for neomycin to 0.38 mM for streptomycin. Lineweaver Burk plots indicate competitive inhibition with a possible relation to the calcium activation. It is possible that aminoglycosides may inhibit phosphatidylinositol phospholipase C in vivo and that this inhibition may be related to the nephrotoxicity of aminoglycosides.

Aminoglycosides↗
PubMed1980

Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin.

Two hundred fifty-eight patients with suspected sepsis were treated with tobramycin or gentamicin in a prospective, randomized, double-blind trial. One hundred forty-six patients received nine or more doses, had serial determinations of serum creatinine, and were evaluated for nephrotoxicity; 91 were able to cooperate with audiometry and were evaluated for auditory toxicity. Auditory toxicity developed in five of 47 (10 per cent) given gentamicin and five of 44 (11 per cent) given tobramycin. Nephrotoxicity developed in 19 of 72 (26 per cent) given gentamicin and nine of 74 (12 per cent) given tobramycin (P less than 0.025). The severity of the nephrotoxicity was not different; the mean increase in creatinine was 1.3 mg per 100 ml (114.9 mumol per liter) in both groups. Both the tobramycin and gentamicin groups had a similar mean age, initial serum creatinine level, total dose, serum aminoglycoside level, and duration of therapy. We conclude that tobramycin causes nephrotoxicity less frequently than does gentamicin.

Acute Kidney Injury↗
PubMed1980

Neomycin inhibition of adenosine triphosphatase: evidence for a neomycin-phospholipid interaction.

The inhibition of canine renal sodium potassium adenosine triphosphatase (ATPase) by neomycin was examined. Neomycin inhibited ATPase nearly maximally at 0.02 mM. The inhibition was temperature dependent with a decrease in inhibition occurring at temperatures below 21 degrees C, a temperature which corresponded to a change in activation energy of the ATPase as determined by Arrhenius plot. Preincubation of the ATPase with phosphoinositides was found to prevent the inhibition by neomycin. Other phospholipids were not found to prevent the inhibition. These results indicate a possible interaction between neomycin and the phosphoinositides of the ATPase complex.

Adenosine Triphosphatases↗
PubMed1980

Iron and deferoxamine in lymphocyte blastogenesis.

Murine lymphocytes in tissue culture accumulate 59Fe during the blastogenic process. The accumulation of iron is related to the time of maximal activity of DNA synthesis. A chelator of iron, deferoxamine, inhibits blastogenesis with 50% inhibitory concentration of 5 microM. These results suggest that iron is necessary for the blastogenic response and may partially explain the immune deficiency associated with iron deficiency anemia.

Animals↗
PubMed1980

Gentamicin uptake by renal tubule brush border membrane vesicles.

The uptake of [3H]gentamicin by isolated rabbit renal proximal tubule brush border membrane vesicles was studied. Uptake was biphasic, with an initial rapid uptake followed by a prolonged slower phase. Approximately half of the total uptake represented binding; the other half represented transport into an intravesicular space. Scatchard analysis indicated the presence of two binding sites, differing in affinity (8 X 10(3) and 0.9 X 10(3) M-1) and number of sites per milligram of protein (1.2 and 3.7 nmol/mg of membrane protein, respectively). [3H]Gentamicin uptake was not affected by a Na+ electrochemical gradient, a valinomycin-generated (inside negative) K+ diffusion potential or the presence of phlorizin and D- of L-glucose. These findings indicate that the mechanism of uptake of the aminoglycoside was distinct from those of sugar and amino acids. Uptake of [3H]gentamicin was inhibited and reversed by the unlabeled aminoglycoside and by spermine. Spermine, on a molar basis, was as effective as gentamicin. These results suggest that gentamicin and spermine may have a common polyamine transport system and demonstrate the feasibility of further investigations to prevent aminoglycoside accumulation and possibly subsequent nephrotoxicity.

Animals↗
PubMed1979

Relationship between aminoglycoside-induced nephrotoxicity and auditory toxicity.

We have reviewed our data from 391 patients entered into three prospective, double-blind studies of aminoglycosides and evaluated 127 cases to determine whether aminoglycoside-induced auditory toxicity and nephrotoxicity are independent events. The cases selected for evaluation included all patients treated for greater than 3 days (mean, 7.7 days) who had serial creatinine determinations and were able to cooperate with serial bedside audiograms (250 to 8,000 Hz). Patients received either gentamicin, tobramycin, or amikacin. Drug dosage was altered to keep serum levels 1 h after administration between 5 and 10 mug/ml (gentamicin or tobramycin) or 20 and 40 mug/ml (amikacin). The investigators evaluating auditory toxicity and nephrotoxicity were blind to the aminoglycoside being administered. The incidence of auditory toxicity in the nephrotoxic group (18.2%) was not significantly different from that in the nonnephrotoxic group (15.2%) (P = 0.75; Fisher exact test). There was no statistical difference between the nephrotoxic and auditory toxic groups in patient age, total dose of aminoglycoside, initial creatinine level, duration of therapy, or concurrent use of furosemide or cephalothin. We conclude that aminoglycoside-induced auditory toxicity and nephrotoxicity are independent events when the drug is administered for approximately 7 days and when aminoglycoside levels are maintained within a predefined range.

Amikacin↗