Elimination of antibiotic-resistant plasmids by quinolone antibiotics

Of 7 plasmids we tested, the plasmid pORF2 was eliminated in vitro with the most efficiency by treatment with subinhibitory concentrations of novobiocin, coumermycin and 10 quinolones. It showed a cure rate of 43% by enoxacin; 12% by novobiocin, pefloxacin, ciprofloxacin and CI-934; 7% by coumermycin and ofloxacin; 9% by amifloxacin; and 4% by AM-833. On the other hand, pSC194, pBR322 and pMH612 were poorly cured in vitro by quinolones, except pSC194 which was cured 33% by enoxacin. R1, pP1603, and pUB110 were unaffected by the treatment. Mice were challenged intraperitoneally with a 2XLD50 of Escherichia coli carrying the ORF2 plasmid and were treated per os with 1 X or 1/2 X ED50 of either enoxacin or CI-934. The frequency of loss of ampicillin resistance determined 3 h after treatment shows curing effects of 92% for CI-934, 89% for enoxacin and 20% for untreated control.     

The combination of prazosin and verapamil in the treatment of essential hypertension

An exaggerated fall in blood pressure has been reported with the combination of an alpha 1-blocker and a calcium antagonist. This study investigated, in a placebo-controlled, randomized crossover trial, the clinical usefulness of the combination of prazosin (2 mg b.i.d.) and verapamil (160 mg b.i.d.). Therapeutic efficacy was monitored at regular outpatient visits: average supine and erect blood pressures were, respectively, 175/99 and 176/103 mm Hg with placebo, 160/91 and 164/96 mm Hg with single drug treatment, and 152/84 and 152/89 mm Hg with combination therapy. This significant and clinically useful reduction in blood pressure had an overall magnitude of approximately 28/18 mm Hg (supine) and 29/19 mm Hg (erect). Further measurements were made during a series of intensive study days, and the most important additional finding was a pharmacokinetic interaction that resulted in increased peak concentrations and bioavailability of prazosin. In conclusion, the combination of prazosin and verapamil proved effective in the treatment of 12 patients with essential hypertension who had been poorly responsive to conventional treatment with a beta-blocker and thiazide diuretic.     

An analysis for blood manganese used to assess environmental exposure

In this graphite-furnace atomic-absorption spectrometric method for measuring manganese in whole blood, we use a pyrolytic platform to minimize interference by sample matrix. For optimal sample ashing we denature the sample within the furnace with nitric acid and use oxygen as the purge gas at low temperatures. The mean manganese concentration found in blood from 15 unexposed city dwellers was 215 (2 SD 135) nmol/L. By comparison, the range of manganese concentrations in blood sampled from a group of Australian aborigines living near a surface manganese ore deposit on Groote Eylandt, Northern Territory, was much higher (median 405 nmol/L, range 175 to 990 nmol/L).     

A Comparison Between Recipients Receiving Matched Kidney and Those Receiving Mismatched Kidney from the Same Cadaver Donor

The optimal allocation of cadaveric kidneys for transplantation with reference to human leukocyte antigen (HLA) match and sharing these organs to a distant center remains controversial. The current analysis was performed using the United Network for Organ Sharing (UNOS) database for cadaveric kidney transplants (Tx) between 1988 and 1997. The graft survivals of zero-mismatch (matched) kidneys with the mate (mismatched) kidneys were compared. There were 2385 donors and 4770 Tx. Significant differences in recipient demographics between matched and mismatched Tx were: fewer African-American race (AA) in the matched group (9.0% vs. 21.9%), higher number of previous Tx (25.5% vs. 14.8%) and elevated mean cold ischemia time (24.0 vs. 22.2 h). Post-Tx dialysis requirements were similar (22.8% vs. 24.1%, p = 0.62) and matched kidneys had to travel more distance (920 vs. 232 miles). Using a Cox model, the matched group had a decreased relative hazard of graft failure of 23.0% (p = 0.0002) or 35% (p < 0.0001) with and without censoring for death. There was significantly better graft survival in the matched recipients in all pairs except AA (matched) and non-AA (mismatched). For older donors (> or = 50 years, n = 1508), the matched grafts survival was marginally significant (p =0.05). Matched kidneys have improved survival compared with the mismatched kidneys despite the longer distance traveled. The benefit of mismatched transplants was predominantly seen in non-AA.     

Poly(methyl methacrylate) synthetic grit formulations sustain the delivery of nicarbazin, a contraceptive agent, in pest waterfowl.

Sixty-three mallards were fed one of ten poly(methyl methacrylate) based synthetic grit formulations containing varying concentrations of a proposed wildlife contraceptive (nicarbazin), plasticizer (acetyl tributylcitrate) and/or cross-linking agent (1,4-butanediol diacrylate). Release characteristics of the contraceptive agent were monitored for the purpose of developing a contraceptive formulation for control of pest waterfowl in urban settings. The addition of plasticizer increased the erosion rate (t(1/2)=0.97-2.85 days), cross-linking the polymer matrix slightly decreased the erosion rate (t(1/2)=4.45-5.05 days) and increasing the concentration of the contraceptive agent increased the erosion rate (t(1/2)=3.3 and 9.9 days at 60% and 7.5% active ingredient, respectively). The larger and smaller grit pieces had longer half lives at 11.0 and 11.6 days, respectively while the mid sized grit had a half life of 4.95 days. Control grit had a half life of 12.7 days based on weight loss. Analysis of blood and feces for monitoring release from the grit and approximate indirect plasma levels of the active ingredient proved feasible.     

Penetration and distribution of three lipophilic probes in vitro in human skin focusing on the hair follicle.

Fluorescent model substances of increasing lipophilicity (Oregon Green) 488, Bodipy, FL C5 and Bodipy 564/570 C5) were selected to enable the visualization in the skin using confocal laser scanning microscopy. After measuring the penetration for 18 h, the nonfixed human scalp skin was imaged from the bottom parallel to the stratum corneum and in a cross-section view perpendicular to the skin surface. The images were evaluated by calculating relative accumulation values for different penetrants. The studies indicate that the penetrated amount is highest for Bodipy FL C5 (medium lipophilicity) and lowest for Bodipy 564/570 C5 (high lipophilicity) whereas Bodipy 564/570 C5 (high lipophilicity) reveals the highest relative accumulation in parts of the hair follicle compared to Oregon Green 488 (low lipophilicity). The addition of 30% (v/v) ethanol to the donor phase of substance with a low lipophilicity increases the follicular delivery. From our results we conclude that delivery to the hair follicle can be improved by increasing the drugs lipophilicity and optimizing the composition of the donor phase. However, no conclusion can be drawn about the actual route of transport to the hair follicle.