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Biomedical subjects

J Pohl

Publications and source records attributed to J Pohl.

At least 163 records · Page 9Linked to original sources
PubMed1985

[Urologic complications in Crohn disease].

The main urological complications of Crohn's disease are: vesico-intestinal fistula, ureteral obstruction, formation of urinary calculi and amyloidosis of the kidney. In the course of their illness nearly 4 to 10 per cent of patients with Crohn's disease suffer from these complications. The frequency of vesico-intestinal fistula is nearly 4 per cent; with great fluctuations, the frequency of ureteral obstruction is specified by 6 per cent. 10 per cent of all patients with Crohn's disease will suffer from secondary amyloidosis. In most cases the kidney is the organ of manifestation. In 5 per cent the formation of urinary calculi is complicating Crohn's disease. The specific complications are demonstrated in symptoms, diagnostic and therapy.

Amyloidosis↗
PubMed1985

[Urologic complications in 200 patients with Crohn disease].

The main urological complications of Crohn's disease are: vesico-intestinal fistula, ureteral obstruction, formation of urinary calculi and amyloidosis of the kidney. 200 patients suffering from Crohn's disease who had been treated in- or outpatient between 1973 and 1982 have been examined concerning urological complications. The frequency of complications was 14,5 per cent. Twenty patients developed fistulae, eleven had ureteral obstructions, two patients suffered from calculi and two from amyloidosis of the kidney. Due to this frequency a special urological diagnostic program is mandatory. A sonogram of the kidney and an i.v. urography should be made in case of pathological sonogram. This is as necessary as the control of kidney function and diagnosis of the urine. These specific urological complications are demonstrated in symptoms, diagnosis and therapy.

Adolescent↗
PubMed1984

Antineoplastic activity of ASTA Z 7557 (NSC-345842, INN mafosfamide) on transplantable murine tumors.

The antitumor activity of ASTA Z 7557, a stabilized primary metabolite of cyclophosphamide, was evaluated in comparison with cyclophosphamide (CP) against different rodent tumor systems. At equimolar doses, which corresponded in mg/kg to the optimal doses of each compound, Z 7557 showed a higher therapeutic activity than CP when both drugs were administered intraperitoneally (ip) during 5 consecutive days. The drug remained active against a P388 subline totally resistant to CP, but to a much lesser extent. The ip-implanted B16 melanoma was highly sensitive to 100 and 50 mg/kg administered during 9 consecutive days: an increase in lifespan (ILS) of 244% was produced and 5 mice out of 10 were cured. This treatment administered against Lewis lung carcinoma (LL) transplanted intravenously (iv) induced an ILS of 179% and 3 mice out of 10 survived on day 60. This effect was slightly inferior to that produced by 50 mg/kg of CP, but is balanced by the number of long-term survivors recorded after administration of low doses of Z 7557. When mice bearing the subcutaneously (sc) implanted colon 38 (C38) tumor were treated with 200 mg/kg on days 2 and 9, the tumor growth was inhibited by 83% in comparison to the control mice. The wide range of activity of Z 7557, its stability and its different chemical reactivity as compared to CP appear to justify interest in this activated oxazaphosphorine.

Animals↗
PubMed1984

Experimental toxicology of ASTA Z 7557 (INN mafosfamide).

The LD 50 of Z 7557 in mice was between 500 and 625 mg/kg after i.v. and around 2310 mg/kg after oral administration. The corresponding LD 10 was around 435 mg/kg (i.v.) or 1100-1250 mg/kg (p.o.), respectively. The LD 50 values in rats were in the range of 250-310 mg/kg after i.v. administration and around 1000-1250 mg/kg if given orally. With repeated daily i.v. injections only 70% of the daily dose contributed to lethality. A second administration of Z 7557 to rats after reversal of all toxic signs from the first administration induced the same symptoms and degree of toxicity as the initial injection. Reversible myelosuppression was the predominant feature of toxicity in mice and rats, but at equimolar doses this myelotoxicity was less than half that of cyclophosphamide (CP). First signs of immunosuppression were seen only at 100 mg/kg i.v.. No severe urotoxicity was observed in rats with single i.v. doses up to 192 mg/kg. This might be due to the fast and complete renal excretion of the thiol moiety of Z 7557, whereas the activated oxazaphosphorine component occurred in the urine only to a much smaller amount, as could be shown by a pilot pharmacokinetic study. In conclusion, Z 7557 appeared to have an overall tolerance in rats and mice similar to cyclophosphamide but was clearly less toxic with respect to the bone marrow, the immune system and the urinary tract.

Animals↗
PubMed1984

Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols.

A number of thiol compounds have been studied with reference to their selective protective action against urotoxic side-effects of oxazaphosphorine cytostatics. The uroprotective capacity is determined exclusively by the pharmacokinetic behavior of the compound. When given PO, all compounds tested were absorbable from the gut. Both thiols and disulfides are rapidly eliminated from the blood, but during their short half-life a number of unknown chemical reactions probably take place to maintain a physiological redox equilibrium. Elimination from the blood plasma occurs via two fundamentally different mechanisms: by distribution throughout the tissues and intracellular uptake or, alternatively, by rapid renal excretion. Most of the compounds tested belong to the first group: N-acetylcysteine, carboxycysteine, disulfiram and its metabolite DDTC, glutathione, WR 2721, etc. Few compounds are quantitatively excreted through the urine: mesna, dimesna, and DA 12. Only these compounds were suitable for selective regional detoxification and for the prevention of oxazaphosphorine-induced urotoxic lesions.

Animals↗
PubMed1984

Purification of pepsins and cathepsin D by affinity chromatography on Sepharose 4B with an immobilized synthetic inhibitor.

Val-D-Leu-Pro-Phe-Phe-Val-D-Leu, a specific inhibitor of aspartate proteinases of the pepsin type, was synthesized. Its bonding to activated 6-aminohexanoic acid-Sepharose 4B afforded an affinity support suitable for the purification of human, porcine, and chicken pepsin, human gastricsin, and bovine cathepsin D. These enzymes bind to the support over the pH range 2-5 at 0-1.5 M concentration of NaCl. A buffer at pH greater than or equal to 6, low ionic strength, and containing 20% dioxane can serve as a general desorption agent. The proteinases were isolated from the crude extracts by a single-step procedure in a high degree of purity and in yields exceeding 70%; human pepsin, however, was not separated from human gastricsin. The support does not show any binding capacity for rat plasma renin at pH 7.4 and for some cysteine endopeptidases (cathepsin B, H, and L) at pH 3-5. The cathepsin D preparations isolated by affinity chromatography on the new support and on pepstatin-Sepharose were of the same degree of purity as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, N-terminal amino acid sequences, and specific activity.

Animals↗
PubMed1984

alpha-/beta-Triglycidyl-urazol (TGU, NSC 332488, I.N.N.: ANAXIRONE): a new chemotherapeutic agent.

Triglycidyl-urazol (TGU) was a rational drug development from the original triepoxide triglycidyl-triazinetrione (TGT). It was selected for further studies because of its superior physico-chemical properties as well as its improved therapeutic range in animals. Like the parent compound, TGU exerts antitumour activity in a wide spectrum of experimental tumours, including those resistant to cyclophosphamide. Its biochemical reactivity is very high, a fact which may contribute to its rapid plasma clearance after parenteral administration. Bone marrow suppression constitutes the dose-limiting toxicity in animals and man with a vague suggestion of cumulative effects. Other toxicities are generally mild and rapidly reversible. The new chemical structure, its reproducible experimental antitumour activity combined with an acceptable and manageable toxicology warranted the introduction of the compound into the clinic. Phase I studies in patients have largely confirmed the predicted toxicities and probable antitumour activity in man (7, 12, 13). Consequently, clinical phase II studies in various tumour types are now under way.

Alkylating Agents↗
PubMed1984

Effect of the uroprotector sodium 2-mercaptoethane sulfonate (Mesna) on the proliferation of the bladder urothelium in the rat after administration of cyclophosphamide.

The chemotherapy of malignant tumors with oxazaphosphorine cytostatics, e.g., cyclophosphamide (CP) and ifosfamide, is limited by their severe urotoxic side effects. As a result of cytotoxic damage, the proliferation of the urinary bladder urothelium is considerably stimulated during an intensive reparative regeneration. The recently developed uroprotector sodium 2-mercaptoethane sulfonate (Mesna) allows regional detoxification limited to the kidneys and lower urinary tract and thus protects against damage by aggressive oxazaphosphorine metabolites. The object of the present quantitative autoradiographic investigation was to study urothelial proliferation in the bladder of rats after administration of CP alone and in combination with Mesna. 20 h after intraperitoneal injection of a single dose of CP alone (100 mg/kg), the urothelium showed a steep rise of the 3H-thymidine (3H-TdR) labeling index which reached a peak of 17.6% at 30 h. Thereafter, the 3H-TdR index rapidly dropped. A second peak of 4.4% was observed after 7 days. With supplementary intravenous administration of a single dose of Mesna (100 mg/kg) 15 min before treatment with CP, the labeling index was substantially lower than after administration of CP alone. Thus, maximal values of only 1.6 and 1.9% were observed at 35 h and 7 days, respectively. Histopathological examination of the bladders showed severe necrotizing and ulcerative cystitis, 10, 20 and 25 h after administration of CP alone whereas with additional treatment with Mesna only slight edema of the lamina propria developed. The results obtained clearly demonstrate the protective action of Mesna on the urothelium of the lower urinary tract against the urotoxic effects of CP.

Animals↗
PubMed1983

Chromophoric peptide substrates for activity determination of animal aspartic proteinases in the presence of their zymogens: a novel assay.

Solid-phase synthesis was used for the preparation of pyroglutamyl-histidyl-p-nitrophenylalanyl-phenylalanyl-alanyl-leucine amide (I) and glycyl-glycyl-histidyl-p-nitrophenylalanyl-phenylalanyl-alanyl-leucine amide (II), two water-soluble and sensitive chromophoric substrates of chicken pepsin, hog pepsin A, and bovine spleen cathepsin D. The kinetic constants of hydrolysis of the p-nitrophenylalanyl-phenylalanyl bond of the substrates were measured by difference spectrophotometry at 308 nm (delta epsilon = 860 M-1 cm-1) and by ninhydrin colorimetry (substrate I, epsilon 570 = 2.31 X 10(4) M-1 cm-1). The pH optimum of cleavage is 5 for the pepsins and 3.7 for cathepsin D. Since all three proteinases still have a significant activity at pH 5.5-6 a new, simple assay was designed for submicrogram quantities of pepsins in the presence of pepsinogens without interference of the latter. The method is particularly suitable for the analyses of the zymogen activation mixtures.

Animals↗
PubMed1983

Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat.

The synthetic low-molecular-weight thiol, 2-mercaptoethanesulfonate (mesna), exerts efficient protection against oxazaphosphorine-induced urothelial toxicity by binding the renally excreted and concentrated toxic metabolite(s). In this study, the pharmacokinetics and metabolism of mesna and its disulfide form (dimesna) have been investigated in the intact rat and in several in vitro systems, including isolated perfused organs, freshly isolated cells, and subcellular fractions; the mechanism of reduction of dimesna to form the pharmacologically active thiol mesna has been further studied with purified enzyme preparations. The results may be summarized as follows: (a) After p.o. administration, mesna and dimesna are both absorbed from the intestine, and dimesna undergoes reduction to mesna during intestinal absorption; (b) when present in plasma, mesna is rapidly oxidized to dimesna by a metal-dependent reaction; (c) mesna and dimesna pass unchanged through the hepatic vasculature, are not taken up into liver cells, and are not excreted in bile; (d) in the kidney, dimesna is filtered through the glomeruli and subsequently reabsorbed, whereupon reduction to the pharmacologically active thiol form occurs in the renal tubular epithelium, and the thiol is then reexcreted into the tubular lumen; (e) reduction of dimesna to mesna occurs in intestinal and renal epithelial cells by a mechanism involving the cytosolic enzymes thiol transferase and glutathione reductase. Thus, the formation of the pharmacologically active thiol form from dimesna is associated with the consumption of equimolar concentrations of reduced glutathione.

Animals↗
PubMed1983

[Autoradiographic studies on the protective effect of mesna in the urinary bladder mucosa of the rat during administration of cyclophosphamide (preliminary communication)].

Cyclophosphamide (100 mg/kg i.p.) produces severe bladder lesions in rats and induces an intense regeneration of the urothelium which can be followed up by 3H-thymidine incorporation. Simultaneously administered mesna (100 mg/kg i.v.) prevents these bladder lesions and no increased regeneration with 3H-thymidine incorporation can be observed.

Animals↗
PubMed1982

Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention--III. Profile of action of sodium 2-mercaptoethane sulfonate (mesna).

Mesna is a pharmacologically unremarkable, physiologically largely inert and almost totally non-toxic thio compound. It is rapidly eliminated renally and only slightly permeates into tissues. It has been shown experimentally that the bladder damage inducible in the rat by administration of oxazaphosphorine cytostatics can be successfully prevented by quite small doses of mesna. The detoxifying action of mesna is limited to the kidneys and the efferent urinary tract. The systemic effects of the oxazaphosphorines, however, remain unaffected. This applies particularly to the curative oncocidal efficacy of these compounds. It has also been shown experimentally that mesna does not affect the curative effects of other cytostatic drugs (doxorubicin, BCNU, methotrexate, vincristine). The efficacy of the cardiac glycoside proscillaridin is also not impaired by mesna.

Animals↗