Antimicrobial susceptibilities and plasmid contents of Neisseria gonorrhoeae isolates from commercial sex workers in Dhaka, Bangladesh: emergence of high-level resistance to ciprofloxacin

Commercial sex workers (CSWs) serve as the most important reservoir of sexually transmitted diseases (STD), including gonorrhea. Periodic monitoring of the antimicrobial susceptibility profile of Neisseria gonorrhoeae in a high-risk population provides essential clues regarding the rapidly changing pattern of antimicrobial susceptibilities. A study concerning the prevalence of gonococcal infection among CSWs was conducted in Bangladesh. The isolates were examined with regards to their antimicrobial susceptibility to, and the MICs of, penicillin, tetracycline, ciprofloxacin, cefuroxime, ceftriaxone, and spectinomycin by disk diffusion and agar dilution methods. The total plasmid profile of the isolates was also analyzed. Of the 224 CSWs, 94 (42%) were culture positive for N. gonorrhoeae. There was a good correlation between the results of the disk diffusion and agar dilution methods. Some 66% of the isolates were resistant to penicillin, and 34% were moderately susceptible to penicillin. Among the resistant isolates, 23.4% were penicillinase-producing N. gonorrhoeae (PPNG). 60.6% of the isolates were resistant and 38.3% were moderately susceptible to tetracycline, 17.5% were tetracycline-resistant N. gonorrhoeae, 11.7% were resistant and 26.6% had reduced susceptibility to ciprofloxacin, 2.1% were resistant and 11.7% had reduced susceptibility to cefuroxime, and 1% were resistant to ceftriaxone. All PPNG isolates contained a 3.2-MDa African type of plasmid, and a 24.2-MDa conjugative plasmid was present in 34.1% of the isolates. Since quinolones such as ciprofloxacin are recommended as the first line of therapy for gonorrhea, the emergence of significant resistance to ciprofloxacin will limit the usefulness of this drug for treatment of gonorrhea in Bangladesh.     

Assessment of analgesia in human chronic pain. Randomized double-blind crossover study of once daily Repro-Dose morphine versus MST Continus

Objective: This study evaluated Repro-Dose morphine (RDM; Reliadol from Nycomed Pharma), a new once daily controlled-release morphine formulation, against twice daily MST Continus (MST) at steady state in patients with chronic opioid responsive pain. Methods: A randomized double-blind two-way crossover design was used to evaluate the efficacy and adverse effects of RDM once daily or MST twice daily, at the same total daily doses, in patients with chronic stable pain (dose range 20–120 mg per day). During the RDM limb of the study active drug was administered in the evening and placebo in the morning. Dextromoramide was provided as escape analgesia throughout the study. Following a 5-day screening period, during which stability of oral opioid dose was verified, patients underwent two 5-day treatment periods, (one MST, one RDM) in random sequence. Pain scores, escape analgesia requirements and side-effects were compared using data from days 3, 4 and 5 of each treatment period. Any events or medication changes occurring during the study period thought liable to influence analgesia were regarded as protocol violations. Overall assessment and period preference was assessed by direct questioning. RDM treatment was regarded as successful if the amount of escape medication required during the RDM period was equal to or less than that required during the MST period. Results: Forty-seven patients were included in the study, of whom 40 completed both periods [the intention to treat (ITT) population], 31 in strict accordance with the protocol [the per protocol (PP) population]. Results were similar for both populations. There was no significant difference in pain scores or incidence of adverse events occurring during the MST and RDM periods. For the ITT population, requirements for escape medication during the RDM period were less than, equal to or greater than those recorded during the MST period for 14, 15, and 11 patients, respectively. Twenty-nine of 40 patients (72.5%) were therefore RDM treatment successes (95% confidence interval 56.1–85.4%). The percentage of patients preferring RDM (45%) combined with those with no preference (32.5%) was significantly higher than those preferring MST (22.5%; P = 0.0003). Conclusions: Oral morphine administered as RDM once daily is at least as effective and well tolerated as MST twice daily, with over 70% of patients in this double-blind crossover study reporting that RDM was equal or superior to MST. Received: 6 April 1998 / Accepted in revised form: 23 January 1999     

Quasi-reversible two-electron reduction of oxygen at iodine submonolayer-coated gold electrode in alkaline media

Oxygen reduction reaction (ORR) was investigated using polycrystalline gold (Au (poly)) electrode modified with chemisorbed iodine (I_(ads)) submonolayer (sub I_(ads)) in O₂-saturated 0.1 M KOH solution. The sub I_(ads) was tailored by potential-dependent partial reductive desorption of I_(ads) from its full monolayer. The Au (1 1 1) facet of the Au (poly) electrode was considered to remain bared at the sub I_(ads)/Au (poly) electrode. The interesting finding of the present study is that (unlike the bare Au (poly) electrode) the sub I_(ads)/Au (poly) electrode exhibited a quasi-reversible two-electron reduction of O₂ in alkaline media. The probable origin of the observed quasi-reversible behavior of the ORR is discussed. Experimental investigations were performed using cyclic and steady-state voltammetric, amperometric and coulometric techniques.     

Effects of Hepatic Ischemia-Reperfusion Injury on the P-Glycoprotein Activity at the Liver Canalicular Membrane and Blood–Brain Barrier Determined by In Vivo Administration of Rhodamine 123 in Rats

Purpose

To investigate the effects of normothermic hepatic ischemia-reperfusion (IR) injury on the activity of P-glycoprotein (P-gp) in the liver and at the blood–brain barrier (BBB) of rats using rhodamine 123 (RH-123) as an in vivo marker.

Methods

Rats were subjected to 90 min of partial ischemia or sham surgery, followed by 12 or 24 h of reperfusion. Following intravenous injection, the concentrations of RH-123 in blood, bile, brain, and liver were used for pharmacokinetic calculations. The protein levels of P-gp and some other transporters in the liver and brain were also determined by Western blot analysis.

Results

P-gp protein levels at the liver canalicular membrane were increased by twofold after 24 h of reperfusion. However, the biliary excretion of RH-123 was reduced in these rats by 26%, presumably due to IR-induced reductions in the liver uptake of the marker and hepatic ATP concentrations. At the BBB, a 24% overexpression of P-gp in the 24-h IR animals was associated with a 30% decrease in the apparent brain uptake clearance of RH-123. The pharmacokinetics or brain distribution of RH-123 was not affected by the 12-h IR injury.

Conclusions

Hepatic IR injury may alter the peripheral pharmacokinetics and brain distribution of drugs that are transported by P-gp and possibly other transporters.     

Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells

Aggregation of high-affinity IgE receptor FcepsilonRI induces sequential activation of nonreceptor-type protein-tyrosine kinases and subsequent tyrosine phosphorylation of cellular proteins, leading to degranulation in mast cells. A hematopoietic cell-specific adaptor protein, 3BP2, that was originally identified as an Abl SH3-binding protein was rapidly tyrosine phosphorylated by the aggregation of FcepsilonRI on rat basophilic leukemia RBL-2H3 cells. Tyrosine phosphorylation of 3BP2 did not depend on calcium influx from external sources. To examine the role of 3BP2 in mast cells, we overexpressed the SH2 domain of 3BP2 in the RBL-2H3 cells. Overexpression of 3BP2-SH2 domain resulted in a suppression of antigen-induced degranulation as assessed by beta-hexosaminidase release. Even though overall tyrosine phosphorylation of cellular protein was not altered, antigen-mediated tyrosine phosphorylation of phospholipase C-gamma (PLC-gamma) and calcium mobilization were significantly suppressed in the cells overexpressing the 3BP2-SH2 domain. Furthermore, antigen stimulation induced the association of 3BP2-SH2 domain with LAT and other signaling molecule complexes in the RBL-2H3 cells. FcepsilonRI-mediated phosphorylation of JNK and ERK was not affected by the overexpression of 3BP2-SH2 domain. These data indicate that 3BP2 functions to positively regulate the FcepsilonRI-mediated tyrosine phosphorylation of PLC-gamma and thereby the signals leading to degranulation.     

Response to docetaxel/carboplatin in patients with hormone-refractory prostate cancer not responding to taxane-based chemotherapy

Few treatment options are available for patients with metastatic hormone-refractory prostate cancer (HRPC) that is not responsive to or continues to progress after taxane-based chemotherapy. Although single-agent carboplatin has modest activity in HRPC, carboplatin chemotherapy could induce a synergistic effect when combined with taxanes in patients with disease resistant to taxane-based chemotherapy. We report a case series of 4 consecutive patients treated with docetaxel (60-70 mg/m2) plus carboplatin (area under the curve of 4/5) following progression after taxane-based chemotherapy. Prostate-specific antigen levels decreased by > 50% in all 4 patients and were associated with improvement in symptoms in 3 of 4 patients. Treatment was well tolerated, with fatigue as the most common reported side effect. Patients received 4-11 cycles of treatment and, after initiation of docetaxel/carboplatin chemotherapy, survival ranged from 4.5 months to 12 months. In this small series, there is a suggestion of a greater than expected response with carboplatin and docetaxel for patients who exhibit disease progression despite taxane-based chemotherapy or do not respond to therapy. A clinical trial to evaluate this effect has been initiated.