Ethnic variation in cholecystectomy rates and outcomes, Manitoba, Canada, 1972-84.

We used population-based data from the Province of Manitoba's universal health insurance plan to compare the cholecystectomy experience of Native Americans and non-Natives from 1972 to 1984. The age-adjusted cholecystectomy rates for Native females were higher than for non-Native females with the peak rate occurring at age 30-39 for Native Americans and at age 60-69 for non-Natives. The rates for males were three times lower than for females and did not differ between Natives and non-Natives. Native Americans were more likely readmitted to hospital for surgical complications than non-Natives and this held true after controlling for age, sex, rural versus urban residence, teaching versus non-teaching hospital, multiple discharge diagnoses or complex versus simple cholecystectomy (relative odds 1.46, 95 per cent confidence interval 1.17, 1.18). The explanation for the relatively high rates of cholecystectomy among Native American females may be related to high rates of known risk factors for gallstone disease (such as obesity and high parity). However, the higher rates of surgical complications require further study.     

Clinical and immunological results of corneal allograft rejection

Of 111 episodes of graft rejection in 66 patients, 62 responded to therapy with graft clearing (responders); 49 did not (non-responders). Both groups were of similar age, sex, and etiology; both had a similar rate of glaucoma and a similar rate of previous grafting. In responders the graft reaction was shorter in duration (2.2 vs. 5.6 wks. p less than 0.005), and it was necessary to increase the number of glaucoma medications more often in non-responders compared to responders (41% vs. 19%, p less than 0.02). The interval from surgery to reaction was similar in responders and non-responders (18.2 vs. 13.3 mos., p greater than 0.1). An epithelial rejection line was present in 11% of responders, but was not present in non-responders (p less than 0.05). Lymphocytotoxic antibody development correlated with rejection in 16 of 64 episodes. Patients who responded to treatment were more frequently asymptomatic (p less than 0.05) or were treated earlier following the onset of symptoms compared to non-responders (p less than 0.0001).     

Flavonoids from the leaves ofRhododendron brachycarpum

The flavonoids isolated from the leaves ofRhododendron brachycarpum, were identified as quercetin, avicularin, quercitrin and hyperin.     

Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.     

Case-control study of proximal and distal colon cancer and diet in Wisconsin

The relationship between diet and subsite-specific colon cancer was investigated using dietary histories obtained from a statewide, population-based sample of 152 proximal colon cancer patients, 201 distal colon cancer patients and 618 general population controls. The results do not support hypotheses that (1) dietary fat and cholesterol are more strongly related to proximal colon cancer and (2) vegetables and other dietary sources of fiber are more strongly associated with distal colon cancer. Vegetable consumption over lifetime was consistently protective for both proximal and distal colon cancer. Odds ratios and 95% confidence intervals for the most significant dietary factors (based on high vs. low consumption) for proximal colon cancer were: salad, 0.29 (0.17, 0.48); miscellaneous vegetables, 0.58 (0.35, 0.97); cruciferous vegetables, 0.59 (0.35, 0.97); processed lunchmeat, 2.04 (1.31, 3.17); pan-fried foods, 1.79 (1.15, 2.80); eggs, 1.75 (1.02, 2.99) and for distal colon cancer they were: salad, 0.43 (0.28, 0.67); cruciferous vegetables, 0.44 (0.28, 0.71); cheese, 0.62 (0.40, 0.96); processed lunchmeat, 1.79 (1.17, 2.73); pan-fried foods, 1.55 (1.03, 1.27). The results support recommendations that the "prudent diet" (low-fat, high-vegetable) may reduce colon cancer risk.     

The role of the FDA in the effort against AIDS.

The Food and Drug Administration has instituted several pro-active measures to expedite the review of treatments, diagnostics, and vaccines for AIDS and related conditions. In particular, the agency has established a special designation--1-AA--for a potential AIDS product which gives top priority to its review. This special expedited review process for AIDS products has provided for greater cooperation between their sponsors and FDA''s reviewers. AIDS products also receive prompt consideration for orphan product status--a status providing financial incentives to the developers of treatments for certain rare and complex diseases. FDA''s special procedures for AIDS drugs have resulted in several major advances in available AIDS treatments. Foremost among these was the FDA''s review and approval of zidovudine (commonly known as AZT) as the first effective palliative for AIDS within 107 days--an agency record. Similarly, the agency quickly evaluated and approved ELISA and Western blot diagnostic kits for detecting the presence of HIV antibody. These test kits have made an important contribution to safeguarding the nation''s blood supply. The agency has also instituted new "treatment" investigational new drug regulations to allow earlier pre-approval distribution of promising experimental treatments to patients with immediately life-threatening conditions, including persons with AIDS. Under this system and its earlier prototype, eligible AIDS patients were able to receive pre-approval treatment with zidovudine and trimetrexate (an experimental drug for the treatment of AIDS patients with Pneumocystis carinii pneumonia who have experienced severe adverse reactions using standard approved therapies). The agency has made institutional reforms to effectively streamline the review of candidate AIDS treatments and vaccines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy

Chlordecone (CD) pretreatment is known to markedly potentiate CCl₄ hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl₄. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl₄ combination treatment might be involved in this interaction. To test this hypothesis, CCl₄ hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl₄ combination treatment. CCl₄ (100 l/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl₄ 1 or 7 days after the surgical manipulations. CCl₄-induced increases in LW/BW were observed in CD + PH rats receiving CCl₄ 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl₄-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl₄ lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl₄ 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl₄ administration is involved in the marked amplification of CCl₄ toxicity by CD.Abbreviations CD chlordecone - GSH reduced glutathione - GSSG oxidized glutathione - PH partial hepatectomy - SH shamhepatectomy - CTRL control, not surgically manipulated - N normal diet - LW/BW liver weight-to-body weight ratio - SGPT serum glutamic; pyruvic transaminase - SGOT serum glutamic oxaloacetic transaminase - ICD isocitrate dehydrogenase These studies were made possible by a grant from the US Environmental Protection Agency R-811072A preliminary report of these findings was presented at the 70th Annual Meetings of the Federation of American Societies for Experimental Biology at St. Louis, MO (Fed Proc 45: 1051, 1986)A. N. Bell is a Predoctoral Toxicology Trainee and Robert A. Young is a Postdoctoral Trainee supported by Toxicology Training grant from National Institute of Environmental Health Science ES-07045     

Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia.

Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), all groups have described clinical relapses despite continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15;17) translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to significantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10(-6) mol/L). No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and "resistance" to continuous treatment with all-trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.