A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.     

Effect of water of hydration on the measurement of the protein efficiency ratio of casein and soybean protein with rats

The hydration of soybean protein or casein prior to mixing of the diet improves the apparent protein efficiency ratio (PER). The PER of soybean protein was improved more than that of casein, so that an increase in adjusted PER of soybean protein was observed also. The improvement did not appear to be associated with digestibility. It is theorized that some diets with dry protein isolates may be less acceptable to the rat due to the dusty nature of the isolate. Consequently, diets with such isolates may have a lower PER. The effect can be overcome by hydrating the protein isolates prior to mixing the diet.     

Cancer mortality in relation to asbestos in municipal water supplies

The mortality experience of twenty-two municipalities in Quebec grouped by evidence of exposure to asbestos fibers in water supplies (known high, possible high, and probable low exposures) was evaluated. Excess mortality due to cancer of the stomach (males), pancreas (females), and lung (males) was observed in the two municipalities with known high exposures. The excesses among males have been due to occupational exposure to asbestos. The absence of excess mortality due to pancreatic cancer among males suggested that the excess among females was not due to waterborne asbestos. The study therefore did not reveal evidence of excess cancer mortality that could be attributed to exposure to asbestos in drinking water.     

Induction of the cortical reaction in hamster eggs by membrane-active agents

Fusion of capacitated spermatozoa with the vitelline membrane, but not actual penetration, appears to initiate the cortical reaction in hamster eggs. The reaction can be artificially induced by the application of positively charged particles to the vitelline surface, a situation which may normally be prevented by the zona pellucida. Exposure of hamster eggs to neuraminidase, to lectins (concanavalin A and phytohaemagglutinin-P), to a monovalent ionophore (boromycin) and to 1,3-bis(4-chlorocinnamylideneamino)guanidine elicits a cortical granule discharge resulting in a block to fertilization. These agents all appear to act by inducing depolarization of the vitelline membrane.     

Laparoscopic resection of esophageal epiphrenic diverticulum

Fifty-four episodes of Xanthomonas maltophilia infection were observed in 52 HIV-infected patients out of 2062 assessed (2.52%) over a 6-year period: sepsis/bacteraemia in 44 cases, lower airways infection in 5 cases, urinary tract infection and pharyngitis in 2 cases each, and lymph node involvement in one patient. X. maltophilia represented the fourth most common non-mycobacterial bacterial pathogen responsible for bacteraemia in HIV-infected patients: 44 cases out of 721 diagnosed (6.1%). When compared with non-typhoid Salmonella spp. bacteraemia, an increased risk to develop X. maltophilia disseminated infection was seen according to the progression of HIV-related immunodeficiency, the occurrence of leukopenia-neutropenia, central venous catheterization, previous antibiotic and/or corticosteroid treatment, and hospitalization. In 3 patients suffering from concurrent AIDS-related disorders, X. maltophilia infection contributed to death, while a recurrence occurred in 2 cases only. Due to the poor antimicrobial susceptibility of this pathogen (also confirmed in our series), X. maltophilia bacteraemia associated with advanced HIV infection and concurrent risk factors, may represent a potentially severe disease.     

Carbon dioxide laser serial microtrapdoor flap excision of subglottic stenosis

The recent development of microspot micromanipulators for the carbon dioxide laser with 250-microns spot sizes has greatly facilitated the extension of endolaryngeal procedures to children and neonates. It is possible to accurately develop microtrapdoor flaps within the limited exposures in the pediatric subglottis. We have used serial microtrapdoor flaps in the excision of subglottic scar tissue in eight children. In five children, the stenosis was improved with relief of stridor. In three children, the flaps were used as an adjunct to laryngotracheoplasty. The surgical techniques of this procedure are detailed in this report.     

Adenoviral-mediated delivery of the herpes simplex virus thymidine kinase gene selectively sensitizes human ovarian carcinoma cells to ganciclovir

One strategy used for gene therapy of cancer is molecular chemotherapy. This approach is based on selective expression of an encoded toxin in cancer cells to achieve their eradication. One potential advantage of this strategy derives from a phenomenon, termed the bystander effect, whereby only a fraction of cells needs to be transduced to eradicate a tumor population. Despite the theoretical advantages of this phenomenon, it has only been described in a few cellular targets. Therefore, we undertook strategies to develop a molecular chemotherapy approach for ovarian carcinoma utilizing the herpes simplex virus thymidine kinase (HSV-TK) gene. Initially, we established that human ovarian carcinoma cell lines could be transduced at high efficiency with adenoviral vectors encoding reporter genes. We next determined that the human ovarian cell line SKOV3 could exhibit bystander killing by stably transducing it to express HSV-TK and performing cell mixing experiments with varying percentages of HSV-TK-expressing and HSV-TK-nonexpressing cells. Based on these findings, we constructed a recombinant adenovirus encoding HSV-TK and utilized it to induce human ovarian carcinoma cell lines to the sensitizing effects of ganciclovir. In addition, primary cultures of ovarian carcinoma cells were found to be highly transducible with recombinant adenoviral vectors and could be induced to the sensitizing effects of ganciclovir after induction of HSV-TK expression by the adenoviral vector. These studies indicate that molecular chemotherapy using a recombinant adenoviral vector expressing HSV-TK may provide a rational strategy for human ovarian carcinoma.