No abstract

Simultaneous immunological titration of DOPA and 5-hydroxytryptophan decarboxylase activities, from a number of tissues of various species, showed that the two activities were not distinguishable with a monospecific antiserum to hog kidney decarboxylase. Together with previous findings, these data firmly establish thb concept that in mammalian tissues the two enzyme activities are associated with a single protein, namely aromatic L-amino acid decarboxylase.The enzymatic synthesis of the biogenic amines serotonin, dopamine, and norepinephrine involves decarboxylation of the corresponding amino acids, 5-hydroxytryptophan and 3.4-dihydroxyphenylalanine (DOPA). DOPA decarboxylase (EC 4.1.1.26) was the first enzyme of the catecholamine biosynthetic pathway to be discovered (1). After the isolation and identification of serotonin (2, 3), Clark, Weissbach, and Udenfriend (4) found significant DOPA decarboxylase activity in their most highly purified preparations of 5-hydroxytryptophan decarboxylase (EC 4.1.1.28) from guinea pig kidney. For a number of reasons, they considered that the two activities represented distinct enzymes. However, as analytical procedures improved; reports from many laboratories made it appear more likely that a single enzyme acts on both substrates (5-16). In view of their evidence that a partially purified enzyme from guinea pig kidney decarboxylated a large number of aromatic -amino acids, including DOPA and 5-hydroxytryptophan, Lovenberg, Weissbach, and Udenfriend (i4) proposed that the enzyme be named "aromatic i-amino acid decarboxylase".Because the amiies resulting from decarboxylation are localized differently and are thought to have distinct physiological functions, many investigators have found it difficult to accept the hypothesis that the same enzyme is involved in both pathways. The recent demonstration that a single, homogeneous enzyme from hog kidney decarboxylates all the naturally occurring aromatic amino acids (17) is a necessary, but not a sufficient, condition for the "single enzyme" hypothesis. The possibility remains that a second enzyme may also exist, at least in some tissues. Recently, Sims and Bloom (18) have reported that, after intracisternal administration of 6-hydroxydopamine to rats, DOPA decarboxylase activities were substantially decreased in certain areas of the brain, while the 5-hydroxytryptophan decarboxylase activities were no different from controls.In the present report, evidence is presented in support of the "single enzyme" hypothesis. It is shown that DOPA decarboxylase and 5-hydroxytryptophan decarboxylase activities are not immunologically distinguishable. DOPA decarboxylase activity was assayed as described (17). The availability of carboxyl-labeled 5-hydroxytryptophan made it possible to assay 5-hydroxytryptophan decarboxylase by a basically similar method. All conditions were the same as those for the DOPA decarboxylase assay, with the following exceptions: the buffer was Tris * HCl (pH 8.

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

Ceftriaxone (Ro 13-9904) was compared with other newer f3-lactam antibiotics for activity in experimental infections of mice with Enterobacteriaceae, Haemophilu influenzae, Pseudomonas aeruginosa, and gram-positive bacteria. Overall, ceftriaxone was equal or superior to cefotaxime and cefoperazone against systemic infections. All three drugs were highly potent against most organisms but were considerably less active against P. aeruginosa. However, ceftriaxone tended to be more active ihan the other two agents against 8 of the 10 P. aeruginosa strains tested. Ceftriaxone, cefmenoxime (SCE 1365), and moxalactam were all highly active against systemic infections with 16 strains of Enterobacteriaceae, whereas ceftriaxone was more active against infections with two strains of streptococci. When the drugs were administered at various time intervals before infection, ceftriaxone was superior to cefotaxime, cefmenoxime, and moxalactam. This suggested that ceftriaxone might be eliminated from mice more slowly than the other drugs. In the case of cefotaxime, this was directly confirmed by microbiological assays of plasma samples. In a murine meningitis model induced by Klebsiella penumoniae or Streptococcus pneumoniae, ceftriaxone was more active than ampicillin or cefotaxime. Ceftriaxone was more active than ampicillin, cefotaxime, piperacillin, cefamandole, or carbenicillin in a pneumococcal pneumonia model in mice. These studies indicate that ceftriaxone is a potent, broadspectrum cephalosporin with unusual pharmacokinetic properties.Ceftriaxone (Ro 13-9904), a 2-aminothiazolyl methoxyimino cephalosporin derivative, has exhibited high orders of activity, both in vitro (1,2,5,7,11,13,14,17, 18)

The role of platelet-activating factor (PAF) in ischemic acute renal failure was evaluated by administering an oral PAF antagonist (Ro-24-4736) to rats prior to or after interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF antagonist prior to ischemia, renal function was less impaired and histological abnormalities was less pronounced when compared with postischemic kidneys from vehicle-treated animals. Serum creatinine (mg/ dl) 24 h following renal ischemia was 1.58 +/- 0.17 in the PAF antagonist-treated rats compared with 2.19 +/- 0.15 in rats given placebo (P < 0.01). There was less necrosis in the outer medulla of kidneys of PAF antagonist-treated animals (P < 0.01). Tissue myeloperoxidase activity at 48 and 72 h postischemia was lower in kidneys of PAF antagonist-treated rats (P < 0.05). The PAF antagonist was also protective when administered 30 min but not 2 h following the ischemic insult. The coincident use of anti-intercellular adhesion molecule-1 monoclonal antibody did not confer additional protection over that observed with the oral PAF antagonist alone. These data suggest that PAF contributes to the pathophysiology of renal ischemic injury, perhaps by its effects on leukocyte-endothelial interactions. An orally active PAF antagonist can protect against the development of ischemic acute renal failure.