The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717)

Summary The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100–550 mg/m² in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40–200 M. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t_1/2=49±9 min, t_1/2=739±209 min). 27%±2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6%±0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid.Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m² CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m²) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r=0.69, P=0.02)These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.This work was supported by grants from the Medical Research Council and Cancer Research Campaign, U. K.     

Changing aspects of radiation enteropathy

Fifty-two patients with radiation enteropathy secondary to radiation for abdominal or pelvic malignant neoplasms are described. This series (1977 to 1984) is compared with a series of 50 patients from the same institution over an earlier period (1961 to 1977). Intestinal obstruction was the principal complication in both series; 96% of the patients underwent either intestinal resection or anastomotic bypass of the affected segment. Changes that have occurred since the last report are as follows: changes in source of radiation energy (linear accelerator); less evidence of mucosal damage; increased serosal reaction ("serosal peel"); and increased use of elemental diets, parenteral nutrition, and long intestinal tubes in surgical management. Since postoperative radiation injury occurs most frequently in the pelvis, new developments for the exclusion of small bowel from the pelvis during radiation are reviewed. Changes in fractionation of radiation dosage should also be considered in patients with enteric symptoms during radiation therapy.     

Spoilage of hydrogel contact lenses by lipid deposits. Tear-film potassium depression, fat, protein, and alcohol consumption

"Jelly-bump" deposits, which are composed mainly of lipids, on high water content, extended-wear hydrogel lenses, are a clinically significant problem of unknown etiology. The authors explored the effect of nutrition on the frequency of deposition of these jelly bumps. Forty-three patients were included in this masked case-control study from five contact lens practices in North America. Thirty patients were lipid-depositor cases and 13 were controls. Tear specimens were drawn and analyzed for potassium by atomic-absorption spectrophotometry. Detailed dietary histories were conducted and diet nutrient composition was computed. Patients with diminished tear-potassium concentrations have an increased risk of jelly-bump deposition. Elevated intake of protein, alcohol, and cholesterol also appeared to be correlated significantly with increased jelly-bump deposition. The authors found that diabetics and the use of diuretics, anticholinergics, sympathomimetics, were associated with tear-film potassium depletion and lipid deposit formation.     

Northern infant syndrome: a deficiency state?

A syndrome is described that affected 16 Indian and Inuit infants roughly 3 months old, most of whom were born in settlements in the Canadian Arctic. The infants presented with a clinical picture that included hepatitis, hemolytic anemia, rickets and respiratory distress, a combination that resembled a syndrome first described in malnourished infants at the turn of the century by von Jaksch and Luzet. The clinical course was self-limited, and all the infants survived without sequelae. The cause of the syndrome was not determined; no infectious agents were discovered. However, low levels of vitamins A, C, D and E were found in a few infants in whom assays were done. The implications of these findings and their relation to the possible cause of this "northern infant syndrome" are discussed.     

Enhancing Behavior Change Skills in Health Extension Workers in Ethiopia: Evaluation of an Intervention to Improve Maternal and Infant Nutrition

Maternal and infant nutrition are problematic in areas of Ethiopia. Health extension workers (HEWs) work in Ethiopia’s primary health care system, increasing potential health service coverage, particularly for women and children, providing an opportunity for health improvement. Their roles include improving maternal and infant nutrition, disease prevention, and health education. Supporting HEWs’ practice with ‘non-clinical’ skills in behavior change and health communication can improve effectiveness. This intervention study adapted and delivered a UK-developed training intervention for Health Extension Workers (HEWs) working with the United Nations World Food Programme in Ethiopia. The intervention included communication and behavioral training adapted with local contextual information. Mixed methods evaluation focused on participants’ reaction to training, knowledge, behavior change, and skills use. Overall, 98 HEWs were trained. The intervention was positively received by HEWs. Pre-post evaluations of communication and behavior change skills found a positive impact on HEW skills, knowledge, and motivation to use skills (all p < 0.001) to change women’s nutritional behavior, also demonstrated in role-play scenarios. The study offered substantial learning about intervention delivery. Appropriate cultural adaptation and careful consideration of assessment of psychological constructs are crucial for future delivery.     

Prevalence of HIV and sexually transmitted and blood-borne infections,and related preventive and risk behaviours,among gay,bisexual and other men who have sex with men in Montreal,Toronto and Vancouver: results from the Engage Study

ObjectivesThe last Canadian biobehavioural surveillance study of HIV and other sexually transmitted and blood-borne infections (STBBI) among gay, bisexual and other men who have sex with men (GBM) was conducted in 2010. We designed a study to measure STBBI prevalence among GBM in metropolitan Montreal, Toronto and Vancouver and to document related preventive and risk behaviours.MethodsThe Engage Cohort Study used respondent-driven sampling (RDS) to recruit GBM who reported sex with another man in the past 6 months. At baseline, we examined recruitment characteristics of the samples, and the RDS-II-adjusted distributions of socio-demographics, laboratory-confirmed HIV and other STBBI prevalence, and related behaviours, with a focus on univariate differences among cities.ResultsA total of 2449 GBM were recruited from February 2017 to August 2019. HIV prevalence was lower in Montreal (14.2%) than in Toronto (22.2%) or Vancouver (20.4%). History of syphilis infection was similar across cities (14–16%). Vancouver had more HIV-negative/unknown participants who reported never being HIV tested (18.6%) than Toronto (12.9%) or Montreal (11.5%). Both Montreal (74.9%) and Vancouver (78.8%) had higher proportions of men who tested for another STBBI in the past 6 months than Toronto (67.4%). Vancouver had a higher proportion of men who used pre-exposure prophylaxis (PrEP) in the past 6 months (18.9%) than Toronto (11.1%) or Montreal (9.6%).ConclusionThe three largest cities of Canada differed in HIV prevalence, STBBI testing and PrEP use among GBM. Our findings also suggest the need for scale-up of both PrEP and STI testing among GBM in Canada.     

Suture patterns and corneal graft rotation in the cadaver eye

Torque and antitorque running sutures as described by Eisner are commonly used in penetrating keratoplasty. We tested the rotational effect of three different 16-bite running suture patterns on eight cadaver eyes, with the following results: (1) the torque pattern rotates the corneal graft counterclockwise by 0.7 +/- 0.1 mm at the wound or 11 degrees; (2) the antitorque pattern rotates the corneal graft clockwise by 0.7 +/- 0.1 mm at the wound or 11 degrees; (3) an intermediate "no torque" pattern, the bites of which form an isosceles triangle, produces no rotational effect. We recommend the use of a "no torque" pattern to minimize corneal graft rotation.     

The importance of risk assessment to the nation's health and economy

The global marketplace is changing rapidly. Never in history has the opportunity to capture new markets with new products and new generations of products been greater. However, never has the chance of losing established markets been higher. We are failing to develop new products despite the fact that Americans have paid for the science from which the world's new technologies were developed. There are many reasons for our failure to turn scientific leads into products. One of the most obvious is that we overestimate the risk of new technologies. Present policy uses a conservatively biased risk assessment process to estimate risk. This process uses many assumptions to bridge gaps in our scientific knowledge about risk. If we wish to be competitive, we must bring safe, inexpensive new products to the marketplace faster. We must seek ways of making our policies more effective while still protecting public health. Risk assessment sets the standards for product development, product approval, and environmental release. A slight miscalculation in "safety levels" can result in tens of billions of dollars in cost added to products. These added costs have a major and direct impact on the competitiveness of U.S. products in the global marketplace where differences in consumer acceptance can be calculated in a few percentage points difference in price.(ABSTRACT TRUNCATED AT 250 WORDS)