The CMF-regimen. Toxicity patterns following stepwise combinations of cyclophosphamide, methotrexate and fluorouracil.

The contribution of the agents used in the CMF regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), to the development of toxicity was determined in tumor-bearing WAG/Rij rats. Data from untreated (U) rats were compared with data from rats treated with single-agent therapy (C-, M- and F-treatment groups), with data from double-agent therapy (CM-, MF- and CF-treatment groups) and with data from the triple combination: the CMF-treatment group. Doses of agents of interest were the same in all treatment groups. The sequence of administration was (1) CY; (2) MTX and (3) FUra which is similar to clinical treatment with CMF. Systemic levels of CY, MTX and FUra were comparable to those found in patients treated according to the CMF regimen. Toxicity was evaluated by body-weight changes, water and food consumption, white blood cell (WBC) and platelet cell (Pts) counts. With the exception of WBC and Pts nadirs, estimated toxicity parameters reflected toxicity over the whole treatment period of 14 days. The toxicity was generally mild and well tolerated, with one fatality in the M-treatment group. CY was the main contributor to toxicity; it caused both myelotoxicity and gastro-intestinal toxicity. The contribution of FUra was judged to be negligible. MTX + FUra did not increase host toxicity in a synergistic or even an additional fashion. The absence of addition or synergism of toxic side-effects can be explained both by site-specific interactions at the pharmacodynamic level and by interactions at the pharmacokinetic level.

Pharmacokinetics of antimicrobial drugs in cystic fibrosis. Aminoglycoside antibiotics.

Patients with cystic fibrosis (CF) show abnormal aminoglycoside pharmacokinetics. After a conventional dose, the serum concentrations in CF patients are lower than those in nonCF patients. The lower serum concentrations in CF might be explained by increased total body clearance and/or a larger volume of distribution. The therapeutic range of aminoglycosides is narrow due to oto- and nephrotoxicity. The changed pharmacokinetics and the narrow therapeutic range make it difficult to ensure that patients with CF are adequately and safely treated with aminoglycosides. The mode of administration of aminoglycosides influences the antibacterial effect of these agents on Pseudomonas aeruginosa and the development of possible side effects. The therapeutic implications of these facts are discussed.

pH modulates cisplatin toxicity.

Cisplatin in normal saline of pH 2.5 caused haemolysis of rat erythrocytes, whereas cisplatin in normal saline of pH 3.5 did not. Even a difference of 0.2 pH units appeared to be of significant importance: haemolysis of rat erythrocytes was observed with cisplatin in saline of pH 3.0 but not with cisplatin in saline of pH 3.2. The LD in mice was 15.4 mg/kg for cisplatin in saline of pH 2.5 versus 24.0 mg/kg for cisplatin in saline of pH 3.5. Experiments with cisplatin should include careful control of pH.

Pharmacokinetics of the cytostatic drugs used in the CMF-regimen.

Forty-one clinical patients were studied on the first day of the first course of the CMF-regimen; administered by a fixed dosage scheme depending solely on body surface area of the patient in question. Parmacokinetic parameters were calculated for each drug: the data were analysed in conformity with the usual pharmacokinetic models. The results indicate a large pharmacokinetic variability, especially for cyclophosphamide (C). The large variability in plasma concentrations of C is presumed to be substantially attributable to the drug formula used.

Variability and predictability of the plasma concentration of ampicillin and kanamycin in new-born infants.

The variability and predictability of the plasma concentration of ampicillin and kanamycin in new-born infants being treated for infections are discussed. For kanamycin a standard dose regimen of 7.5 mg/kg/12h is recommended.

Accumulation and localization of gallium-67 in various types of primary lung carcinoma.

The uptake and location of Ga-67 were investigated in 15 primary pulmonary carcinomas. The accumulation in the tumor was determined by scintigraphy of the patient, grain counts over fields of tumor cells in autoradiographs of tumor-tissue samples, and gamma counts in specimens of the tumor. Good correlation was found between the results obtained with these three methods. The relationship between accumulation of Ga-67 in the tumor and the histologic type of tumor was also studied. Undifferentiated carcinomas, and tumor cells in squamous-cell carcinomas showed significantly more Ga-67 than tumor cells in adenocarcinomas. No correlation was found between the presence of inflammatory infiltrates in or around the tumor and the grade of the scintigraphic images. In the autoradiograms, lymphocytes, plasma cells, granulocytes, and macrophages showed less radioactivity than the tumor cells--or none at all. Collagen fibers appeared to have bound some Ga-67, but necrotic areas showed no uptake.

Treatment of theophylline intoxication: a model study utilizing peritoneal dialysis.

This study shows that peritoneal dialysis of theophylline-intoxicated rats results in withdrawal of approximately 27% of the administered dose of theophylline in 4 hr. Clinical consequences of this experience are considered.

The extraction of antiepileptic drugs. Model study on partition coefficients.

To compare the extraction behaviour of hexane, toluene, chloroform, 1,2-dichloroethane, diethylether, ethyl acetate and acetone towards phenobarbital, phenytoin, primidone and carbamazepine, partition coefficients of these drugs between the above solvents and water (saturated with ammonium sulphate when working with acetone) were measured at different pH-conditions. Acetone rendered the highest partition coefficients for all drugs. Ethyl acetate was second in the range, except for carbamazepine, which showed a specific affinity for the chlorinated hydrocarbons.

Autoradiographic model experiments with 67Ga and 99mTc.

In order to evaluate the feasibility to localize correctly 67Ga citrate and 99mTc pertechnetate in tissues, the resolution of these radioactive compounds were measured in a model system using four different autoradiographic techniques, wet as well as dry. Wet autoradiographic techniques gave an almost complete loss of 67Ga. In deparaffinized sections of fixed and paraffin-embedded tissue the remaining 67Ga, which was probably bound to proteins, gave a resolution of 2.6 mu. 99mTc was either completely lost in wet techniques or the procedure could not be performed at all because of the very short half life of 99mTc. The resolution of 67Ga in a dry autoradiographic technique (according to Stumpf) was 6.9 mu and the resolution of 99mTc 22.6 mu. The technique in which frozen sections are thawed on dry film and consequently dryed, gave slightly better resolutions than the dry technique (according to Stumpf) with 67Ga as well as 99mTc. It is concluded that for the histological localization of 67Ga and 99mTc a dry technique is required. However, the use of a wet technique can be considered, provided a loss of the radioisotope is acceptable and the procedure is controlled by a dry technique.