Cartilage protective agent (CPA) Ro 32-3555, a new matrix metalloproteinase inhibitor for the treatment of rheumatoid arthritis.

CPA was well tolerated at all dose levels (10-150 mg) following single oral dose administration to healthy male volunteers. There was no relationship between the intensity, duration and number of adverse events reported and the dose of CPA. There was a dose-related increase in exposure as measured by AUC0-infinity and Cmax. Administration of 10 mg CPA following food resulted in a delayed tmax, and a significant decrease in Cmax but not AUC0-infinity.

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics.

AIMS: The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple-dose regimens. METHODS: Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. RESULTS: Endogenous concentrations of levodopa and 3-OMD increased dose-dependently (from 8 up to 52 microg l(-1) and from 0.02 up to 0.50 mg l(-1) , respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration-time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l(-1) h at benserazide doses of 100-200 mg three times daily. Benserazide caused a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106 mg l(-1) h at doses of 200 mg. Formation of DOPAC was dose-dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. CONCLUSIONS: The benserazide-dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

Piscirickettsia salmonis gen. nov., sp. nov., the causative agent of an epizootic disease in salmonid fishes.

A novel intracellular pathogen morphologically similar to the ehrlichiae has been isolated in cell culture and identified as the cause of an epizootic disease of salmonid fish. Like the ehrlichiae, the salmonid pathogen, designated strain LF-89, replicates within membrane-bound cytoplasmic vacuoles in host cells. This agent is the first with characteristics of this type to be isolated from a fish. Analysis of the LF-89 16S rRNA indicated that, unlike the ehrlichiae, LF-89 is a gamma proteobacterium distantly related to Coxiella burnetii and perhaps Wolbachia persica. A new genus and species (Piscirickettsia salmonis gen. nov., sp. nov.) are proposed for this organism, with ATCC(R) VR 1361 as the type strain.

Measurement of cerebral monoamine oxidase B activity using L-[11C]deprenyl and dynamic positron emission tomography.

A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19-6327). From the results, it followed that the rate constant for irreversible binding (k3) appeared to be a better index of MAO-B activity than the net influx constant Ki. Furthermore, regional analysis demonstrated that Ki, but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.

Transconjugation between Bacteria in the Digestive Tract of the Cutworm Peridroma saucia.

Transconjugants arising from transfer of plasmid R388::Tn1721 between donor and recipient strains of Enterobacter cloacae were detected in samples from the digestive tracts and fecal pellets of variegated cutworms (Peridroma saucia).

The influence of levodopa on gastric emptying in man.

1. Simultaneous radioisotopic (99Tc-DTPA) gastric emptying measurements and paracetamol pharmacokinetic studies were performed in eight healthy male volunteers with and without levodopa (125 mg orally). 2. In the absence of levodopa gamma camera imaging showed rapid mono or biexponential emptying in all subjects and the plasma concentration-time curves for paracetamol displayed a single major peak. 3. In the presence of levodopa the time to 90% emptying was prolonged from 32 +/- 24 min to 81 +/- 20 min (P less than 0.01). Gastric emptying was interrupted by a plateau phase in six subjects and this pattern of emptying was associated with double peaks in the plasma concentration-time curves of both levodopa and paracetamol. The time to the end of the plateau phase of emptying correlated with the time to the trough plasma concentrations of paracetamol and levodopa. 4. There was excellent agreement between the plasma concentration-time curves of levodopa and paracetamol, i.e. time to initial peak, r = 0.946, P less than 0.001; time to trough concentration r = 0.943, P less than 0.01; time to second peak r = 0.974, P less than 0.001. 5. The results indicate that levodopa inhibits gastric emptying and thus influences its own absorption. Temporary inhibition of gastric emptying by levodopa (or a metabolite) is the cause of the multiple plasma peaks commonly observed following oral levodopa.

The cutworm Peridroma saucia (Lepidoptera: Noctuidae) supports growth and transport of pBR322-bearing bacteria.

Variegated cutworms were exposed to bean plants in microcosms sprayed with pBR322-carrying strains of Enterobacter cloacae, Klebsiella planticola, and Erwinia herbicola. The three bacterial species exhibited differential survival on leaves, in soil, and in guts and fecal pellets (frass) of the insects. High numbers of Enterobacter cloacae(pBR322) were detected in all samples, while the other species were unable to establish residence in the insect. To assess the impact of this colonization on site-to-site transport of microorganisms, larvae were fed plants that had been sprayed with the bacteria and then were transferred to uninoculated plants. Cutworms were efficient carriers of Enterobacter cloacae(pBR322), as indicated by its rapid appearance on uninoculated leaves and continued persistence in the insects for 3 days after transfer. Few Erwinia herbicola(pBR322) and K. planticola(pBR322) were obtained from larvae after transfer, although up to 10(3) CFU/g were detected in soil and on plants. Differences in bacterial survival and growth were confirmed by incubating frass overnight and observing the change in population numbers. The proportion of total samples showing at least a 25-fold increase during incubation was 68% for Enterobacter cloacae(pBR322), 39% for K. planticola(pBR322), and 0% for Erwinia herbicola(pBR322). Our results emphasize the role that cutworms and possibly other insects have in persistence and growth of microorganisms in the environment.

The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.

1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/- 2.8 (s.d.) ml min-1 kg-1 in the elderly compared with 23.4 +/- 4.1 ml min-1 kg-1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration-time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/- 0.29 l kg-1) than in the young (1.65 +/- 0.39 l kg-1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/- 588 ng ml-1h in the elderly compared with 1056 +/- 282 ng ml-1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/- 0.12 compared with 0.41 +/- 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/- 0.9 ml min-1 kg-1 compared with 9.3 +/- 1.0 ml min-1 kg-1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)