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Biomedical subjects

N Brock

Publications and source records attributed to N Brock.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1982

Long-term follow-up of ambulatory management of osteomyelitis.

Over four years, 50 patients with osteomyelitis (32 classified as acute and 18 as subacute or chronic disease) were treated with oral antibiotics in an ambulatory setting. The profile of clinical and laboratory parameters, including etiologic agents, was similar to previous series. Forty-eight patients initially received parenteral drugs, mean duration 14 days (range 0-36). Oral agents administered at home included cephalosporins, clindamycin, dicloxacillin, penicillin VK, amoxicillin, and sulfa-trimethoprim. Mean duration of total therapy was 53.2 days (range 16-365). In follow-up, ranging from 12 to 60 months (mean 35), relapses occurred in one patient with acute and one with chronic disease. Both responded to oral treatment. No residual infection has resulted, although clinical and radiographic sequelae remain in six more patients initially termed subacute or chronic. Long-term follow-up of patients receiving high-dose oral antibiotic therapy for osteomyelitis due to sensitive organisms confirms the safety and efficacy of this mode of treatment and the feasibility of ambulatory management. The outcome after oral therapy is equivalent to that following parenteral therapy. Patients with subacute or chronic disease have a significantly poorer prognosis despite a milder initial illness and longer course of therapy.

Administration, Oral↗
PubMed1982

[Prevention of urotoxic actions of cyclophosphamide and ifosfamide by dimesna (preliminary communication) (author's transl)].

Sodium 2-mercaptoethane sulfonate (mesna, Uromitexan) is oxidized in the organism of rats to 2,2'-dithiodi-(ethane sodium sulfonate) (dimesna). Dimesna is partially reduced to the mercapto compound mesna (kidneys); both compounds are eliminated via the urine. Even after administration of dimesna mesna can be detected in the urine. Accordingly dimesna also proved to be an effective antidote against the urotoxic actions of cyclophosphamide and ifosfamide.

Animals↗
PubMed1981

Detoxification of urotoxic oxazaphosphorines by sulfhydryl compounds.

Urotoxic side effects, especially hemorrhagic cystitis, have so far been a limiting factor in the therapeutic use of cyclophosphamide (Endoxan), ifosfamide (Holoxan), and trofosfamide (Ixoten). The uroprotective agent mesna (Uromitexan) allows regional detoxification in the kidney and the urinary tract, and thus clinical prevention of the urotoxic side effects of the above cytostatics. The uroprotective mechanism of mesna is based on the formation of nontoxic additive compounds with acrolein and 4-hydroxy-metabolites. In the body, mesna is rapidly transformed into its biologically inert disulfide. After glomerular filtration mesna disulfide is rapidly reduced by reacting with the glutathion system and elimination in the urine as a free thiol compound, further detoxifying the aggressive oxazaphosphorine metabolites.

Animals↗
PubMed1980

The development of mesna for the inhibition of urotoxic side effects of cyclophosphamide, ifosfamide, and other oxazaphosphorine cytostatics.

Urotoxic side effects on the kidneys and urinary bladder are a limiting factor in chemotherapy with oxazaphosphorine cytostatics such as cyclophosphamide and ifosfamide. Acrolein was found to be the causative factor which is spontaneously formed in the urine from the primary metabolites eliminated via the kidneys. Sodium 2-mercaptoethanesulfonate (INN: mesna) enables regional detoxification of acrolein in the kidneys and deferent urinary tract. The author reports on the pharmacotherapeutic bases and the mechanism of action of this new combination therapy and its clinical results. The untoward urotoxic side effects can be avoided with mesna without interfering with the chemotherapeutic effect on the tumor.

Animals↗
PubMed1979

Controlled clinical studies with an antidote against the urotoxicity of oxazaphosphorines: preliminary results.

A randomized study in 20 patients with cancer was carried out to test the clinical efficacy of sodium-2-mercaptoethane sulfonate (ASTA D-7093; mesnum) as an agent to prevent urotoxic side effects (in particular, hemorrhagic cystitis) during cytostatic therapy with the oxazaphosphorines cyclophosphamide and ifosfamide. Eleven patients received mesnum iv and nine patients received a standard prophylaxis. The frequency of microhematuria was significantly lower in the patients receiving mesnum. A slight microhematuria was observed in one patient. With the standard prophylaxis, all nine patients receiving single-agent therapy with ifosfamide or cyclophosphamide had hematuria and three of these had macrohematuria. According to the available results, a daily mesnum dose of 60% (wt/wt) of the ifosfamide or cyclophosphamide dose is recommended. This dose should be divided into three equal fractions. The first administration should be given concurrently with the cytostatic agent and the subsequent two administrations at 4 and 8 hours after administration of the cytostatic agent. Significantly higher doses of mesnum (eg, 133% of the cyclophosphamide or ifosfamide doses) lead to gastrointestinal disorders, which are easily reversible.

Clinical Trials as Topic↗
PubMed1979

Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide.

The urotoxicity of oxazaphosphorine cytostatics is not based on their alkylating activity but on the presence of acrolein, which is spontaneously formed in the urine from the primary metabolites eliminated via the kidneys. Thus, acrolein proved to be the causative factor in the urotoxicity of oxazaphosphorines. The mechanism of action of the uroprotector sodium 2-mercaptoethane-sulfonate (mesnum, Mitexan) is mainly based on the formation of a non-toxic additive compound with acrolein.

Acrolein↗
PubMed1976

Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds.

This paper deals with the problem of the relative selectivity of the antitumor effect of cyclophosphamide (CP). CP and its metabolites are pharmacologically characterized by determining their chemical and biological activities in vitro and their pharmacotherapeutic properties in vivo. Of particular importance is the specificity of the cytotoxic activity (cytostatic units/mumol) in vitro and the margin of safety (therapeutic index) in vivo. The pharmacologic data reveal: a. Of the various metabolites of CP only 4-hydroxycyclophosphamide, the primary activation product, exerts a highly specific cytotoxic activity in vitro and has a wide margin of safety in vivo. b. The decisive step in toxication is the formation of the alkylating N,N-bis(2-chloroethyl)phosphorodiamidic acid after acrolein has been split off.

Acrolein↗
PubMed1976

Evaluation of a cooperative clinical study of the cytostatic agent ifosfamide.

In cooperative studies performed in 21 German clinics, the new cytostatic agent 3-(2-chloroethyl)-2-[(2-chloroethyl)-amino]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (ifosfamide; trade name: Holoxan) was administered as massive-dose treatment. The studies aimed at confirming the results obtained in pharmacological and Phase I clinical trials with a fractionated administration of ifosfamide on a large scale. The study was carried out in 390 patients suffering from various malignant conditions. The majority of patients had had pretreatment without response or were admitted at an advanced stage of disease. Despite this negative selection, 25.5% of the patients showed an initial full remission and 42.3% partial remission; in 32.2% of the patients, reduction of the tumour signs by at least 50% was not attained. After an average observation period of 6 1/2 months, 53.8% of the patients were still alive. The study clearly shows the superiority of fractionated administration of ifosfamide when compared to its use as a single administration. In addition, the rates of remission and survival, and of survival times, were clearly dependent on dosage, independent of the tumour type. A daily dosage of 50 to 60 mg/kg ifosfamide on 5 consecutive days produced the best results. In spite of the fact that ifosfamide was not always given at optimum dosage, it proved to be definitely superior to conventional chemotherapy in testicular tumours, particularly teratomas and also in hypernephromas. Retrospective comparison with results of conventional chemotherapy for ovarian, bronchial and mammary cancer has shown ifosfamide to produce the same therapeutic effect in these tumour types. In this study group, leukopenia was not regarded as a limiting factor to the administration of ifosfamide. Side effects in the efferent urinary tract, particularly cystitis, were controlled with adequate preventive measures.

Adenocarcinoma↗