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M Schleimer

Publications and source records attributed to M Schleimer.

7 recordsLinked to original sources
PubMed2004

Efficacy of BAL5788, a prodrug of cephalosporin BAL9141, in a mouse model of acute pneumococcal pneumonia.

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

Animals↗
PubMed2000

Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450.

The use of common formulation ingredients (categorized into six groups) for preclinical animal studies has been assessed with respect to cytochrome P450 (CYP) inhibition, specifically CYP3A inhibition, in expressed human CYP3A4, human liver microsomes, dog- and cynomolgus monkey intestinal microsomes. Results indicated a wide range of inhibition potentials and there appeared to be species differences with inhibition of CYP3A activity. Generally, greater inhibition of CYP3A activity was observed with amphiphilic ingredients (for example mixed micellar solutions, Tween 80, and oleic acid). From the data presented, it can be predicted that the majority of the ingredients tested would not have a significant impact on the potential inhibition, by the formulation, on any apparent first pass metabolism in the intestinal tract for new drug entities being tested in the preclinical environment. However a number of common ingredients will require further investigation based on the estimated concentration within the gastrointestinal tract.

Animals↗
PubMed1999

The effect of tolcapone on the pharmacokinetics of benserazide.

This study investigated the potential interaction between tolcapone, a catechol-O-methyltransferase (COMT) inhibitor, and the decarboxylase inhibitor, benserazide. In an open-labelled six-week study, patients with Parkinson's disease (PD), treated with levodopa/benserazide, were given tolcapone at 200 mg t.i.d. Blood samples for analysis of benserazide, its main active metabolite, trihydroxybenzylhydrazine, levodopa and 3-O- methyldopa (3-OMD) were collected immediately before and repeatedly after the first drug intake of the day at baseline and after 1-2 and 6 weeks of treatment. Furthermore, animal experiments were performed to determine the levels of benserazide and trihydroxybenzylhydrazine at doses for which safety had previously been established. It was shown that tolcapone can cause an increase in benserazide plasma concentrations and that this effect is dependent on the benserazide dose. When tolcapone was combined with 25 mg benserazide the elevation was small. Although the increase was more pronounced when tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals. The safety margin derived from this study, together with the absence of any organic toxic effects in clinical trials, show that the observed interaction between tolcapone and benserazide does not represent a safety concern for PD patients treated with this combination.

Aged↗
PubMed1996

Quantitative determination of heparinoid mimetics in human and rat plasma by micellar electrokinetic chromatography.

The investigated new class of heparinoid mimetics are spaced persulfated carbohydrates designed to increase the success rate of angioplasty and bypass surgery by preventing restenosis without increasing the risk of bleeding. Due to the presence of sulfate groups, these compounds are highly charged and, for preclinical kinetic investigations only small sample volumes of rat plasma were available. Therefore, capillary electrophoresis (CE) was applied. A bioanalytical method based on micellar elektrokinetic chromatography (MEKC) with UV-detection was developed for the selective quantitation of heparinoid mimetics (e.g., Ro 48-0843, Ro 48-3151, Ro 47-6199 and Ro 48-8722) in plasma. Using this method, only small volumes of plasma were required, which could be introduced directly into the separation capillary after 1:1 dilution with 100 mM aqueous sodium dodecyl sulfate (SDS). For increased sample throughput, an additional ultrafiltration step was performed after SDS-dilution of the plasma sample, improving both reproducibility and robustness of the method considerably. The sensitivity of the new method (3 micrograms/ml) was sufficient to follow plasma levels in pharmacokinetic studies. The practicability of this easy and rapid assay was demonstrated by the analysis of more than 350 plasma samples from pharmacokinetic studies performed in rats.

Animals↗
PubMedDate not supplied

Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

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