Antimalarial activities of various 9-phenanthrenemethanols with special attention to WR-122,455 and WR-171,669.

Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, WR-33,063. WR-122,455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P.

Antimalarial activities of various 4-quinolonemethanols with special attention to WR-142,490 (mefloquine).

Pilot appraisals of the activities of a selected group of 4-quinolinemethanols against acute Plasmodium falciparum infections in owl monkeys indicated that compounds of this class are equally active against infections with chloroquine-resistant and chloroquine-susceptible strains and that this efficacy is not compromised by concomitant resistance to pyrimethamine, and in addition, identified three derivatives with outstanding activity (WR-226,253; WR-142,490; and WR-184,806). WR-142,490, the second 4-quinolinemethanol evaluated in the above model, was five times as active as chloroquine against infections with the chloroquine-susceptible, pyrimethamine-resistant strain and had a much larger therapeutic index. Expanded evaluations designed to support projected studies in human volunteers provided full confirmation of the pilot appraisals and in addition showed: (i) that the activity of WR-142,490 was a function of the total dose delivered, single doses being as effective as three or seven fractional doses administered over as many days; (ii) that intravenous administration of this agent was feasible and effective; and (iii) that the compound was at least as active against infections with P.

Mathematical basis of point-area deconvolution method for determining in vivo input functions.

The point-area method for deconvolution derives a "staircase" input function which, when convolved onto the characteristic function, gives an output function coincidental with the given output data points. The area--area method for deconvolution is shown to be erroneous.

Plasma free amino acid levels in human subjects after meals containing lactalbumin, heated lactalbumin, or no protein.

Plasma free amino acids were measured in six adult human subjects at four consecutive 1/2 hr intervals following meals containing either 50 g lactalbumin, 50 g heated lactalbumin, or no protein. After the lactalbumin meal, all essential and several nonessential amino acids increased in the plasma. After the heated lactalbumin meal, these increases were either much less or did not appear.

Quantitative aspects of pyrimethamine-sulfonamide synergism.

The experiments described in this report have dealt with the dimensions of therapeutic potentiation achieved when combinations of pyrimethamine and sulfadiazine were administered to rhesus monkeys infected with a drug-susceptible strain of Plasmodium cynomolgi or its pyrimethamine-resistant variant and to owl monkeys infected with strains of P. falciparum and P. vivax of varying degrees of resistance to this pyrimidine.

Activities of various 4-aminoquinolines against infections with chloroquine-resistant strains of Plasmodium falciparum.

The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine.

Age-related deterioration of pyramidal cell basal dendrites in rat auditory cortex.

The basal dendritic trees of layer V pyramidal cells in the rat auditory cortex were examined quantitatively in a group of 3-month-old and a group of 34- and 36-month-old rats. Two forms of analysis were used on the Golgi preparations: (1) the number of intersections between the basal dendrites and a series of concentric circles whose common center lies over the perikaryon center, and (2) the number of dendritic branches, by order, per neuron. The data indicate that in the old animals the density of the dendritic tree has decreased significantly within a radius of about 150mu of the perikaryon, yet the extent of the dendritic domain has not changed appreciably.

A model independent method for estimating the in vivo release rate constant of a drug from its oral formulations.

A simple equation by which the first-order release rate constant of a drug from its oral formulation can be calculated is derived. The derivation is independent of any hypothetical concepts of drug distribution or elimination.

Simple transformation method for predicting plasma drug profiles from dissolution rates.

A transformation factor is described which related in vitro drug dissolution from a preparation to the corresponding in vivo plasma drug concentrations. This factor, derived from the dissolution profile and the corresponding in vivo plasma concentration of a single formulation, was used to predict plasma concentration profiles of similar formulations simply from dissolution data.

The influence of smoking on the intersubject variation in pentazocine elimination.

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non-smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three-fold inter-subject variation in elimination was observed.

Membranous bodies in the cerebral cortex of aging rats: an electron microscope study.

Large complex membranous bodies are described in the cerebral cortex of adult rats. Although these bodies are not very prevalent, they appear with increasing frequency as the age of the animal increases from 12 to 28 months. The membranous bodies are composed of varying amounts of membranes, cytoplasm and empty vacuoles, and they occur within dendrites which must expand to accomodate them.

General derivation of the ideal intravenous drug input required to achieve and maintain a constant plasma drug concentration. Theoretical application to lignocaine therapy.

A constant plasma drug concentration can be achieved and maintained by the intravenous administration of an initial bolus loading dose in conjunction with a constant rate and an exponential intravenous drug infusion. The drug input required to achieve a constant plasma drug concentration is derived without making any assumptions about the nature of drug distribution within the body or elimination from the body.

General theory for rapidly establishing steady state drug concentrations using two consecutive constant rate intravenous infusions.

Steady state plasma drug concentrations can be achieved rapidly and safely by a drug input mode consisting of two consecutive constant rate intravenous infusions. A general method for calculating the relative rates of the two infusions is presented. The derivation is independent of the concepts of compartmental distribution and elimination of drugs within the body.

A general equation for the ratio of the areas below the blood or plasma concentration time-curves following intravenous and oral drug administration and its application to inter-subject variations in drug elimination.

1 When a drug is metabolized in the liver the total area under the plasma or blood concentration-time curve following oral drug administration is less than the area obtained after intravenous drug administration. This difference has been termed the 'first-pass effect'. 2 General equations for the areas below the blood or plasma concentration-time curve of a drug following intravenous and oral drug administration are derived.

General pharmacokinetic equations for linear mammillary models with drug absorption into peripheral compartments.

General equations are derived for the disposition functions of any compartment in a linear mammillary model, when the system input occurs into a peripheral compartment. Laplace transforms and matrix algebra are used to derive these equations. Equations describing the time-course of a drug in any compartment are readily obtainable using disposition and input functions.

Some effects of analogues of uracil on cell elongation and wall metabolism in excised pea root segments.

Excised root segments of Pisum sativum (L.) cut from the region 2-4 mm behind the root tip were cultured in a 2% sucrose medium containing analogues of uracil and proline. Of several uracil analogues tested only those containing a thiol group (2-thiouracil and 2-thio-6-azauracil) markedly stimulated the growth rate and prolonged the duration of growth of the segments, whereas other uracil analogues which enhanced growth affected only its duration.