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One day after unilateral nephrectomy (uNX), excretion of p-aminohippurate (PAH) reaches 80% of control values in rats. A stimulation of tubular transport by repeated administration of xenobiotics shortened the phase of diminished PAH excretion capacity following. The relative extent of compensation (%) after uNX is not affected significantly by inhibitors of protein synthesis. These inhibitors influence the time course of compensation after uNX. Administration of azauracil, fluorouracil and neomycin, respectively, causes a dose dependent reduction of PAH excretion in nephrectomized and sham operated animals. This effect is also provable following pretreatment with cyclopenthiazide, which can stimulate the PAH elimination. A stimulated renal function after uNX can also be suppressed by high doses of inhibitors of protein synthesis. In contrast to this, small doses of these substances produce a stimulation of renal PAH excretion. The extent of this stimulation reached the same degree as after cyclopenthiazide pretreatment found in preliminary experiments. An additional treatment with cyclopenthiazide does not additionally increase PAH excretion. These results indicate that processes of compensatory growth as well as induction of renal tubular transport are caused by increased protein synthesis.

A Phase I trial of acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid] has been performed on an escalating-dosage 24-hr continuous i.v. infusion schedule. Thirty-one patients received 77 courses of treatment, and all but one were evaluable for toxicity. Pharmacological monitoring in selected patients demonstrated that peak plasma levels correlated with dose. Postinfusion t1/2 beta was 6 to 9 hr, and urinary recovery of the administered dose was 14 to 19% as unchanged drug during the 24-hr infusion. Hematological and gastrointestinal toxicities were variable and not dose related. In contrast, neurotoxicity characterized by lethargy, fatigue, confusion, disorientation, hallucinations, nightmares, and truncal ataxia was dose limiting and related to plasma drug levels. A minimal antitumor response was observed in a patient with colorectal carcinoma, and a partial response occurred in a patient with liver metastases from gastric carcinoma. The recommended dose for Phase II trial by 24-hr infusion is 160 mg/sq m.

The disposition of [14C]-labeled 2-mercaptobenzimidazole (MBI) in male Fischer-344 rats dosed orally (49 or 0.5 mg/kg) or intravenously (0.5 mg/kg) was determined. Absorption of the oral dose was evident, since, in 72 h, most of the radioactivity administered by either route appeared in the urine. Smaller amounts appeared in the feces. In 4 h, 12% of the radioactivity from an intravenous dose of 0.5 mg/kg was excreted in the bile of rats with biliary cannulas. For rats dosed intravenously, the half-life for disappearance of unchanged MBI from plasma was 125 min. In contrast, the terminal half-life for loss of radioactivity from blood was 83 h. The concentration of total radioactivity was higher in liver and kidney tissue than in blood. One of the major urinary metabolites was identified as benzimidazole, and a minor component was tentatively identified as unchanged MBI. Neither of these could be detected in bile.

The effect of systemic glutathione (GSH) depletion on sensitization of bladder cancer cells to various antineoplastic agents was investigated using murine model, MBT-2. Subcutaneous injection(s) of buthionine sulfoximine (BSO) significantly depleted the GSH content in the tumor and organs. BSO pretreatment produced significant enhancement in the antitumor effect of cyclophosphamide (CY), though it failed to sensitize the tumors to doxorubicin hydrochloride (Adriamycin), cisplatin, mitomycin C, JM-8, methotrexate, vinblastine, and tumor necrosis factor. Mice tolerated cytotoxic agents alone and in combination with BSO except for cisplatin in combination with BSO. A 29 percent (4/14) mortality rate was observed in mice treated with BSO and divided schedule of cisplatin.

The direct injection of semicarbazide (SC), an antivitamin B6 (anti-B6), into the lateral ventricle of the mouse brain induced convulsion and tremors at a smaller dose after a shorter latent period than that in systemic administration. The symptoms were prevented by pyridoxine, aminooxyacetic acid or acetone, while they enhanced by pyridoxal, pyridoxal phosphate, or some other anti-B6. In mice fed a vitamin B6 (B6)-deficient diet, convulsion and tremors occurred at smaller doses of SC than those in mice given control food, and were counteracted by pyridoxine. On the other hand, mice into which SC had been injected in the neighboring site of the lambda first showed running fits, which was followed by convulsion and tremors.

Fifty-two patients with generalized Hodgkin's disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin's disease is strongly recommended.

Five patients received cholesterol-7alpha-(3)H intravenously during control periods. Specific activity of total serum cholesterol was determined serially during the 1st wk and weekly thereafter. 28-59 wk after the injection of the tracer, when no further radioactivity could be detected in serum cholesterol, 2 g of oral neomycin was given daily to four patients for the remainder of the experiment. Average total serum cholesterol concentrations were reduced by 20, 21, 26, and 29%, respectively, in these subjects. The fifth patient, given placebo, had no change in serum cholesterol. After a period of 12-26 wk of medication the intravenous injection of cholesterol-7alpha-(3)H was repeated, and while neomycin or placebo administration was continued, serum cholesterol specific activity was again determined serially during the 1st wk and weekly thereafter for 23-42 wk. The data were subjected to a two-compartment analysis. During the administration of neomycin, half-times of the cholesterol radio-activity decay curves were decreased in two patients and remained unchanged in two subjects. The size of the "intermediate" pool of cholesterol decreased in each patient during the administration of neomycin by 33, 36, 40, and 44%, respectively. The absolute decrease was much larger in each case than the concomitant reduction of serum cholesterol. There was no significant change in the data during the administration of placebo in one patient. The size of the "intermediate" pool can be calculated by compartmental analysis from the cholesterol decay curves. For the "slow" pool size and the other kinetic parameters only ranges of values can be deduced from the present experiment.