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The pharmacology and chemotherapy of a new penicillin, 6[D(-)-a-aminophenylacetamido] penicillanic acid, are described. It is non-toxic, is absorbed orally and is distributed throughout the body in a manner similar to other penicillins. It is eliminated unchanged from the body in high concentrations in the bile and urine. Almost all of the antibiotic can be accounted for in the urine and intestinal contents 2 hr after intramuscular administration but not after oral administration. It is concluded that the antibiotic is not metabolized within the body. Studies with infected animals show that it is as effective as the existing oral penicillins against Staphylococcus pyogenes Smith (penicillin sensitive), Streptococcus pyogenes Group A and Diplococcus pneumoniae. It is ineffective against penicillin-resistant Staphylococci. When tested in mice infected with the gram-negative organisms, Salmonella typhimurium and Klebsiella pneumoniae, it was considerably more active than tetracycline and chloramphenicol.There is a need for a penicillin which is effective orally and having activity against both gram-negative and gram-positive organisms. Benzylpenicillin, although lacking in toxicity, is unfortunately not absorbed after oral administration and its activity against gram-negative organisms is limited. Doyle, Nayler & Smith (1961) have synthesized a new penicillin, ampicillin (6[D( -)-a-aminophenylacetamido] penicillanic acid), which largely overcomes these disadvantages. The preliminary pharmacology and chemotherapy has been reported by . Full details of the pharmacological and chemotherapeutic evaluation are now presented. METHODSIn all experiments benzylpenicillin was administered as its sodium salt. Ampicillin, which was 84% pure, was also administered as its sodium salt, all doses being given in terms of the pure compound. The antibiotics were assayed by the cup-plate technique using Sarcina lutea as the test organism. The zone diameters obtained for the control dilutions of the antibiotics were plotted against the log of the concentration, and from the regression line obtained the concentrations of the antibiotics in the specimens were estimated by interpolation. The appropriate dilutions of the controls and samples were made in phosphate buffer pH 7.0

Summary The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.There have recently been two important advances relating to the improvement of anti-emetic treatment given to patients undergoing anti-cancer therapies. Firstly, it was found that, unlike conventional doses of metoclopramide (Maxolon; Beecham Pharmaceuticals) which antagonise dopamine receptors and stimulate gastric motility, high doses of the drug greatly reduced cis-platin-evoked emesis (Gralla et al., 1981). In contrast, even high doses of the dopamine antagonists, domperidone (Motilium; Janssen Pharmaceuticals) or alizapride, have little or no ability to prevent cis-platininduced emesis (Tonato et al., 1985;Saller & Hellenbrecht, 1985). Mechanisms other than dopamine receptor antagonism have therefore been implicated in this antiemetic action of metoclopramide (McRitchie et al., 1984).Secondly, metoclopramide is an antagonist of 5-hydroxytryptamine (5-HT) acting on 5-HT3 receptors (previously known as 5-HT M-receptors; see Bradley et al., 1986 for definition of this receptor) located in the peripheral nervous system (Fozard, 1984a); the effective concentrations of metoclopramide are higher than those required to antagonise dopamine receptors or to stimulate gut motility (Sanger, 1984). We subsequently suggested that such high doses of metoclopramide may prevent cis-platin-induced emesis by means of antagonising 5-HT3 receptors .The involvement of 5-HT3 receptors in the mechanisms of emesis have now been further investigated using chemo-and radio-emetic stimuli in the ferret. The ferret has previously been shown to be suitable for studying emesis evoked by cisplatin (Florczyk et al., 1982;), a combination of doxorubicin and cyclophosphamide (Schurig et al., 1984) or by whole-body irradiation (Andrews et al., 1986;Gylys & Gidda, 1986