Phase II clinical trial of carboplatin, ifosfamide, with oral mesna for metastatic breast carcinoma.

Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths.

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal.

The effect of probenecid on the pharmacokinetics of diflunisal and its glucuronide and sulphate conjugates was studied in 8 healthy volunteers. Diflunisal 250 mg b.d.

Mutations affecting the chemosensory neurons of Caenorhabditis elegans.

We have identified and characterized 95 mutations that reduce or abolish dye filling of amphid and phasmid neurons and that have little effect on viability, fertility or movement. Twenty-seven mutations occurred spontaneously in strains with a high frequency of transposon insertion. Sixty-eight were isolated after treatment with EMS.

Disposition of lorazepam in diabetes: differences between patients treated with beef/pork and human insulins.

The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls.

High-efficiency diffractionless beams of constant size and intensity.

Design considerations are presented for pairs of spherically aberrating elements that produce diffractionless beams of high efficiency and nearly constant size and intensity over specified ranges of axial position. An approximate design, assuming an aberration quadratic in radial ray positions, is followed by a final lens (mirror) specification that is verified through meridional ray tracing. This then provides an accurate determination of beam characteristics.

Disposition of lorazepam in Gilbert's syndrome: effects of fasting, feeding, and enterohepatic circulation.

The effects of fasting and feeding of a high-carbohydrate, low-fat diet on the glucuronidation and enterohepatic circulation (EHC) of lorazepam were examined in seven healthy men (age 18-30 years) and seven matched patients with Gilbert's syndrome. A simultaneous intravenous/oral dosing regimen was used, with half of each group receiving treatment with neomycin and cholestyramine (neo/chol) to block the EHC of the drug. Feeding increased the clearance of free lorazepam from 10.

The mec-8 gene of Caenorhabditis elegans affects muscle and sensory neuron function and interacts with three other genes: unc-52, smu-1 and smu-2.

Mutations in the Caenorhabditis elegans gene mec-8 were previously shown to cause defects in mechanosensation and in the structure and dye filling of certain chemosensory neurons. Using noncomplementation screens, we have identified eight new mec-8 alleles and a deficiency that uncovers the locus. Strong mec-8 mutants exhibit an incompletely penetrant cold-sensitive embryonic and larval arrest, which we have correlated with defects in the attachment of body muscle to the hypodermis and cuticle.

High glucose attenuates peptide agonist-evoked increases in cytosolic free [Ca2+] in rat aortic smooth muscle cells.

Incubation of cultured rat aortic smooth muscle cells (ASMCs) in a medium containing high glucose concentrations (25 mM) did not affect the basal cytosolic free calcium ([Ca2+]i) but led to significant reductions in peak [Ca2+]i response evoked by arginine vasopressin, angiotensin II, and endothelin-1 (ET-1). This was observed in both the presence and absence of extracellular Ca2+. Maintenance of rat ASMCs in a medium containing mannose (an osmotic control for high glucose) did not affect either the basal or peptide agonist-evoked increase in [Ca2+]i.

Analysis of polymorphic variation in drug metabolism: III. Glucuronidation and sulfation of diflunisal in man.

The urinary excretion of diflunisal (D) and its metabolites diflunisal sulfate (DS), diflunisal phenolic glucuronide (DPG), and diflunisal acyl glucuronide (DAG) were measured in 110 healthy, drug-free Caucasian volunteers given 50 mg of diflunisal by mouth. When expressed as fractional recoveries, DS, DPG, and DAG were strongly negatively correlated with one another. Metabolic ratios, on the other hand, correlated positively and tended to localize variability within a single enzyme pathway.

Analysis of polymorphic variation in drug metabolism: II. Effects of data transformation on the sensitivity and specificity of modal detection.

Simulations were conducted for a model of drug metabolism involving 2 parallel competing pathways of elimination, wherein the effects of variability in 1 enzyme pathway were examined with respect to variability in recovery of its metabolite and recovery of metabolite through the second, nonvaried, co-eliminating route. Expression of metabolite recoveries as fractions of the total recoverable drug yielded a statistic possessing variability similar to the pattern of variability induced in the enzyme itself. However, the transformation was subject to a "distributive" effect, in that the magnitude of variation in the downstream metabolite was reduced and transferred through reciprocal variations in availability of unmetabolized drug to other nonvaried pathways.

Analysis of polymorphic variation in drug metabolism: I. Kernal density estimation.

Kernel density estimation was examined as an objective, nonparametric approach to the detection of polymorphic variation in distributions containing multiple complex data sets. Power curves were constructed for the kernel density estimate based on its ability to detect worked bimodality in stimulated distributions as a function of the distribution size, the fraction contained within a particular subdistribution, and the location of the mean of that subdistribution with respect to the mean of the overall distribution. Comparisons were then made between kernel density estimation and the Kolmogorov-Smirnov test of maximal differences.

Seasonal and spatial population dynamics of the nitrogen-efficient guild in a desert bajada grassland.

This study examined the temporal and spatial variation in the populations of bacteria from a Chihuahuan desert bajada grassland that could grow on nearly nitrogen-free medium, a nitrogen-efficient guild (NEG). A Curtis similarity index of 0.876 and nearly identical diversity and equability indexes (H' = 1.

Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not confined to a congeneric series.

Many attempts have been made to describe quantitative structure-pharmacokinetic relationships within a congeneric series of drug molecules. The goal is to develop a predictive relationship that could predict in vivo results for other drugs within that series. These studies typically evaluate pharmacokinetic parameters that are reflective of both distribution and elimination processes.

Pharmacokinetics of morphine sulfate in patients with burns.

Morphine sulfate (MS) pharmacokinetics was evaluated in seven patients with a mean body surface area burn of 21.5% to ascertain a rational basis for the management of pain in patients with burns. Treatments included a MS constant rate infusion followed by an oral MS solution (MS-OS) (5 to 15 mg administered every 3 hours) and then a 30 mg MS-controlled release tablet (MS-CR) every 8 hours.

[Radiologic methods of evaluating colonic transit time in functional disorders of the large intestine].

Based upon literature and personal experience the authors review radiological techniques of evaluating colonic transit time in functional disorders of the large intestine. The distribution of given per os markers in the whole colon indicates prolonged transit time, which takes place in constipation of colonic inertia type. In the case of markers accumulation in the distal segment of the large intestine we encounter functional constipation of outlet obstruction type.

A herpes simplex virus type 1 ICP22 deletion mutant is altered for virulence and latency in vivo.

The in vivo function of the herpes simplex virus type 1 immediate early gene ICP22 has been investigated in mice and guinea pigs using a deletion mutant (del22Z) of HSV-1(F) that lacks all but 18 nucleotides of the ICP22 coding sequence. This mutant carries the bacterial lacZ gene at the site of the deletion and makes functional beta-galactosidase, but is unable to synthesize any detectable ICP22 messenger RNA or protein in vitro. Del22Z was impaired in its ability to cause death in mice following intracerebral, intraperitoneal, or intravaginal inoculation.

Tailoring home care services to meet physician and patient needs: a market-based approach.

The services offered by the home care division of a medical center should correspond to the needs of both physicians and patients who are to be served. This study addresses the physician segment, the primary referral source for home care. It measures both the absolute and the relative importance of a range of offerings which a home care services division provides in a mid-sized, full service, medical center.

Multiple-dose lorazepam kinetics: shuttling of lorazepam glucuronide between the circulation and the gut during day- and night-time dosing intervals in response to feeding.

Lorazepam kinetics were examined in seven healthy males age 18 to 30 years after single- and multiple-dose lorazepam administration and in the presence and absence of neomycin and cholestyramine to block the enterohepatic circulation of the drug. Methods used a simultaneous i.v.

Behavioral characterization of the excitatory and desensitizing effects of intravesical capsaicin and resiniferatoxin in the rat.

This study characterized the excitatory (nociceptive) and desensitizing (antinociceptive) properties of the natural pungent substances, capsaicin (CAP) and resiniferatoxin (RTX) instilled in the bladder (intravesical, i.ves.) via an indwelling cannula in awake, freely moving rats.

Effect of water and nitrogen additions on free-living nitrogen fixer populations in desert grass root zones.

In this study we measured changes in population levels of free-living N2-fixing bacteria in the root zones of potted Bouteloua eriopoda and Sporobolus flexuosus plants as well as the photosynthetic indices of the plants in response to added nitrogen, added water, and added water plus nitrogen treatments. In addition, N2 fixer population changes in response to added carbon source and nitrogen were measured in plant-free soil columns. There were significant increases in the numbers of N2 fixers associated with both plant species in the water and the water plus nitrogen treatments.

Reliability of sexual risk behavior interviews with psychiatric patients.

Test-retest interviews examining recent sexual activity were administered to 27 severely ill psychiatric patients after stabilization. Three reports were judged to be questionable. For the 16 sexually active patients among the remaining 24, high test-retest reliability was found for number of sexual partners, frequency of episodes, and proportions of episodes involving vaginal intercourse and use of condoms.

In vitro characterization of a herpes simplex virus type 1 ICP22 deletion mutant.

We report the construction of a deletion mutant (del22Z) that is unable to synthesize any detectable messenger RNA or protein products from the herpes simplex virus type 1 (HSV-1) immediate early ICP22 gene upon infection. The del22Z deletion mutant lacks all but 18 nucleotides of the ICP22 coding sequence and carries the bacterial lacZ gene at the site of the deletion. No other known open reading frames or flanking sequences were disrupted.

Molecular and genetic analysis of unc-7, a Caenorhabditis elegans gene required for coordinated locomotion.

Mutations in the Caenorhabditis elegans gene unc-7 confer an uncoordinated phenotype. Wild-type animals trace smooth, sinuous waves as they move; unc-7 mutants make irregular bends or kinks along their bodies, particularly when they move forward. The unc-7 locus has also been implicated in the nematode's response to volatile anesthetics.