An intramolecular Heck reaction (90 f 91) serves as the key step in the total synthesis of the titled compounds. The synthetic route is based on utilizing the Wieland-Miescher ketone (5) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to an A ring precursor (6). Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
In a study of the effectiveness of high intravenous doses of metoclopramide as an antiemetic, 41 patients with advanced cancer who were being treated with cisplatin were entered into two double-blind trials. In the first trial patients were randomly assigned to receive either metoclopramide or placebo, and in the second trial they received either metoclopramide or prochlorperazine. Patients given metoclopramide had significantly fewer episodes of emesis than patients given placebo (medians, 1.0 vs. 10.5; P = 0.001) or prochlorperazine (medians, 1.5 vs. 12.0; P = 0.005). Metoclopramide was superior to placebo and to prochlorperazine in reducing the volume of emesis (P = 0.001 and P = 0.022, respectively) and was more effective than placebo in shortening the duration of nausea (P = 0.042) and vomiting (P = 0.028). Side effects from metoclopramide were minor, with mild sedation frequently observed; one patient had a brief extrapyramidal reaction. We conclude that metoclopramide in high intravenous doses has greater antiemetic activity than placebo or prochlorperazine in patients receiving cisplatin chemotherapy.
Hydroxyurea, hydroxyurethane, and dihydroxyurea inhibit incorporation of thymidine into the DNA of monolayers of HeLa cells. They do not affect incorporation of uridine into RNA or of leucine into protein. In contrast, hydroxylamine inhibits cellular incorporation of all three precursors: thymidine, uridine, and leucine. Hydroxyurea does not affect thymidine kinase, thymidylate kinase, or DNA polymerase reactions, but it does inhibit incorporation of cytidylic and guanylic acids into DNA in cell-free supernatants.
One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a "metabolic therapy" program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.
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