Biomedical subjects

H Kropp

Publications and source records attributed to H Kropp.

At least 37 records · Page 2Linked to original sources

PubMed1992

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice.

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was less than 4% for both compounds.

Animals↗

PubMed1986

[Selection of resistant variants by broad spectrum beta-lactam antibiotics: to what extent is there cross resistance between imipenem and other beta-lactam antibiotics?].

Resistant variants can be selected in the presence of most of the recently developed beta-lactam antibiotics thus resulting in cross resistance between penicillin-, cephalosporin- and monocyclic derivatives except for imipenem. Among the Enterobacteriaceae-resistant so-called beta-lactamase-overproducing variants can be selected in some species in the presence of various broad-spectrum beta-lactams except for imipenem. However, imipenem-resistant variants can be selected from clinical Pseudomonas aeruginosa isolates in a frequency comparable to those obtained for other beta-lactams. Imipenem resistance in Pseudomonas aeruginosa is presently understood to be independent of either enzymatic degradation or an alteration of the penicillin-binding proteins; moreover, it has to be attributed to characteristic changes of the outer membrane proteins, thus explaining imipenem resistance due to impaired penetration. Consequently, resistance to imipenem in Pseudomonas aeruginosa has to be considered independent of resistance to other beta-lactams.

Anti-Bacterial Agents↗

PubMed1985

Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin.

The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcome by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Coadministered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its coadministration prevents proximal tubular necrosis which has been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics.

Animals↗

PubMed1983

Thienamycin: development of imipenen-cilastatin.

Thienamycin, a natural product produced by Streptomyces cattleya is the first representative of a unique class of beta-lactam antibiotics, the carbapenems. Despite its outstanding potency and antibacterial spectrum, thienamycin was itself unsuited for further development because of its chemical instability in concentrated solution and in the solid state. Synthesis of the amidine derivative, N-formimidoyl thienamycin (imipenem, MK0787) resulted in a crystalline product with much improved stability and with antibacterial properties significantly superior to thienamycin. Imipenem has an unusually broad antimicrobial spectrum. A high order of bactericidal activity is found against Pseudomonas aeruginosa, Serratia, Bacteroides fragilis, enterococci and numerous other species intrinsically resistant to other antibiotics. Imipenem is refractory to hydrolysis by all important classes of bacterial beta-lactamases and thus exhibits no cross-resistance with penicillins or cephalosporins. Imipenem is distinguished from the new generation of extended-spectrum cephems by its unusually high potency against Gram-positive as well as Gram-negative organisms. Offsetting these excellent antimicrobial properties was an unusual susceptibility exhibited by imipenem to renal metabolism in animal species and in man. Very low urinary recoveries resulted without, however, any significant reduction in the serum half-life of imipenem. A brush-border dipeptidase, dehydropeptidase-I, was shown to be responsible for renal metabolism. Metabolism has been countered with the development of cilastatin (MK0791), a substituted amino-propenoate inhibitor of dehydropeptidase which is specific, potent and well matched in its pharmacokinetic properties for co-administration with imipenem. With the imipenem/cilastatin combination, uniformly high urinary concentrations and recovery are obtained regardless of the varying but often extensive metabolism suffered by imipenem in human populations. An additional benefit conferred by cilastatin results from its ability to exclude imipenem competitively from entry into and subsequent metabolism within the proximal tubular epithelium of the kidney. The tubular necrosis induced by imipenem alone when it is administered at very high doses to susceptible mammalian species is thereby eliminated. Thus the imipenem/cilastatin combination affords reliability and enhanced safety in the application of the antibiotic's unusual antibacterial potential in the treatment of difficult infections regardless of the site of disease.

Animals↗

PubMed1983

Urinary recovery of N-formimidoyl thienamycin (MK0787) as affected by coadministration of N-formimidoyl thienamycin dehydropeptidase inhibitors.

N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an N-formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N-formimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.

Adult↗

PubMed1982

Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase.

Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787, and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys, and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I was found to catalyze the hydrolysis of the beta-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic N-acylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4- to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic infections in animals remain satisfactory.

Animals↗

PubMed1982

[Varicella-zoster-immunoglobulin as a safe prophylaxis of varicella (author's transl)].

The occurrence of varicella in the course of immunosuppressive therapy is always a hazard to life. Up till now, passive immunization is the only method which provides reliable protection. We have had an immunoglobulin compound at our disposal during the last 5 years. This compound was obtained by screening a plasmapool for high-titre varicella antibodies, which were then fractionated. Varicella immunoglobulin was injected on 298 occasions to children incubated with varicella. There were no serious side effects after i.v. administration. These children were on polychemotherapy because of malignant diseases. Only 4 children developed varicella, 3 of them very mildly and none of them was later disabled due to varicella in any form. The protective value of this varicella-immunoglobulin compound is much greater than any other known so far [16].

Adolescent↗

PubMed1980

Use of acetylacetone to prepare a prodrug of cycloserine.

Several derivatives of cycloserine (1) were prepared and it was found that (R)-4-[(1-methyl-3-oxo-1-butenyl)-amino]-3-isoxazolidinone (11), the condensation product of acetylacetone and cycloserine (1), was an efficacious prodrug of increased stability under aqueous conditions.

Animals↗

PubMed1980

[Prevention of varicella in children on immunosuppressive therapy (author's transl)].

The mortality rate due to varicella in patients on cytostatic therapy is high. However, during the first 72 hours after infection, an effective protection can be given with Varicella/Zoster-Immunoglobulin (ZIG). This article deals with 172 cases with malignant diseases. These children who were on polychemotherapy contacted varicella. They were treated with ZIG 0,2 ml/kg per body weight in 15% concentration. After triple dilution ZIG was administered intravenous to 151 patients and undiluted intramuscular to 21 patients. ZIG was well tolerated. Only 3 children had varicella and even this was in a mild form. The donors of ZIG were selected through a screening program.

Chickenpox↗

PubMed1980

MK0787 (N-formimidoyl thienamycin): evaluation of in vitro and in vivo activities.

The practical application of thienamycin, a novel beta-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most beta-lactam antibiotics, such as Pseudomonas aeurginosa, Serratis, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal activity usually occurs at the minimal inhibitory concentration endpoint. Activity was reduced only at the highest inoculum densities tested and by a lessor factor than was observed with reference beta-lactam antibiotic active against P. aeruginosa and beta-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo activity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference beta-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.

Animals↗

PubMed1979

[Clinical trials with mercapto polycytidylic acid in the treatment of acute childhood leukemia (author's transl)].

Mercapto Polycytidylic acid (MPC) is a potent inhibitor of oncornaviral reverse transcriptase. The fact that this enzyme has been found in human leukemic cells, has let to the clinical trials of MPC in the treatment of childhood acute leukemia. This report discribes the first pilot clinical trial on 23 patients. The results are encouraging, and have let to a second pilot study including other clinical centers on the clinical efficacy of MPC in the treatment of leukemia.

Acute Disease↗

PubMed1978

[Interstitial pneumonia in children with malignancies during cytotoxic therapie. Clinical picture, analysis of promoting factors, and detailed discussion of etiology (author's transl)].

This communication documents a study of 35 patients with systemic malignant diseases between 1964 and 1973. All these patients developed interstitial pneumonia (int.pn.), and in two cases recurrence of int.pn. was observed after several months. Of these 35 patients 29 were diagnosed of acute lymphoblastic leukemia (ALL). In particular the occurrence of int.pn. was very frequently noticed under the more aggressive therapeutic regimes mentioned in the Memphis protocol VII. The statistical analysis revealed that the most critical period of occurrence is between 8 and 11 weeks after the induction therapy or 6-9 weeks after the reinduction or relapse therapy. These observations indicate the dependency of this disease during the intensive phase of therapy. The prognosis of int.pn. was improved significantly after the pentamidine treatment. The etiology of the int.pn. is discussed in detail. The post mortem examination of 6 patients revealed that 5 of them had pneumocystes carinii.

Adolescent↗

PubMed1975

[Interstitial pneumonia in children on cystostatic treatment for malignant systematic disease (author's transl)].

The radiologic appearances of interstitial pneumonia are described as they appeared in 39 children treated with immunosuppressive and cytostatic substances given for malignant systemic disease. At the time most of the children were in a stage of remission of their basic illness. In most of them there may have been a pneumocystis carinii infection. 15 children died of this pneumonia. In the majority of post-mortem examinations pneumocysts could be detected.

Adrenal Cortex Hormones↗

PubMed1974