Pharmacokinetics of clomethiazole in healthy adults.

The systemic availability of clomethiazole was assessed by comparing blood levels after intravenous and oral administration. Clomethiazole was rapidly absorbed after oral administration to volunteers, particularly when administered as syrup. The fraction of the given dose that reached the systemic circulation after 1 capsule of clomethiazole (192 mg clomethiazole) was 0.25 +/- 0.18, after 2 capsules (384 mg clomethiazole) 0.38 +/- 0.18, and after 15 ml syrup (480 mg clomethiazole) 0.42 +/- 0.20. The time-blood concentration profiles were consistent with a two-compartment open model and the mean elimination half-lives of 3.6--5.0 hrs. were found for the different formulations and administration routes. Elimination half-lives showed little variation and a mean systemic clearance of 49 ml/min./kg was found for clomethiazole after intravenous administration. Clomethiazole is bound to human plasma proteins (63.4 +/- 1.6%, 37 degrees), a binding which is not affected by Vacutainer sample tubes. The blood/plasma distribution of clomethiazole was 0.76 +/- 0.02 at 37 degrees. A sensitive mass fragmentographic assay for the determination of clomethiazole in blood/plasma down to levels of 1 ng/ml (6.2 nmol/l) is described.

Essential amino acids in the treatment of advanced uremia: twenty-two months' experience in a 5-year-old girl.

The value of conservative treatment in a case of chronic advanced renal failure was investigated in a 5-year-old girl with congenital hypoplastic kidneys. Before treatment the patient was severely anorexic and her plasma urea nitrogen was 180 mg/100 ml. Protein restriction alone was fruitless. After a transitional period on total parenteral therapy the patient was put on a maintenance oral diet, where an energy-rich diet was supplemented with essential amino acids including histidine. Plasma urea nitrogen dropped and stayed at about 50 mg/100 ml during the whole treatment in spite of a rising plasma creatinine from 10 to 24 mg/100 ml. The general condition of the patient normalized as she went into an anabolic state with weight gain and growth in height. The nitrogen balance studied in two different periods was positive. An acute attack of pancreatitis, secondary to hyperparathyroidism, ended the patient's life after 22 months of treatment.

Topological and functional organization of the mitochondrion.

The morphological and biochemical properties of isolated mitochondrial inner and outer membranes are summarized and discussed in relation to the functional organization of the intact mitochondrion. The enzymatic composition of the mitochondrial inner compartment is compared to over-all mitochondrial function. The role of the mitochondrial outer compartment is discussed with reference to both the inner membrane-matrix fraction and the intact mitochondrion.

An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study.

Preparations of rat-liver mitochondria catalyze the oxidation of exogenous NADH by added cytochrome c or ferricyanide by a reaction that is insensitive to the respiratory chain inhibitors, antimycin A, amytal, and rotenone, and is not coupled to phosphorylation. Experiments with tritiated NADH are described which demonstrate that this "external" pathway of NADH oxidation resembles stereochemically the NADH-cytochrome c reductase system of liver microsomes, and differs from the respiratory chain-linked NADH dehydrogenase. Enzyme distributation data are presented which substantiate the conclusion that microsomal contamination cannot account for the rotenone-insensitive NADH-cytochrome c reductase activity observed with the mitochondria. A procedure is developed, based on swelling and shrinking of the mitochondria followed by sonication and density gradient centrifugation, which permits the separation of two particulate subfractions, one containing the bulk of the respiratory chain components, and the other the bulk of the rotenone-insensitive NADH-cytochrome c reductase system. Morphological evidence supports the conclusion that the former subfraction consists of mitochondria devoid of outer membrane, and that the latter represents derivatives of the outer membrane. The data indicate that the electron-transport system associated with the mitochondrial outer membrane involves catalytic components similar to, or identical with, the microsomal NADH-cytochrome b(5) reductase and cytochrome b(5).