Antimicrobial susceptibility of Shigella isolates in eight Asian countries, 2001-2004.

BACKGROUND AND PURPOSE: Shigellosis is a major health problem in developing countries, causing 91 million episodes and 414,000 deaths in Asia annually. Because of increasing trends towards drug resistance, this study was undertaken to monitor local resistance patterns of Shigella isolates from 8 Asian countries. METHODS: Ninety eight Shigella isolates collected from 8 centers in 8 Asian countries from July 2001 to July 2004 were analyzed in terms of serogroup distribution and antimicrobial susceptibility. RESULTS: The most common serogroup of Shigella isolates was Shigella flexneri (49/98, 50%), followed by Shigella sonnei (44/98, 45%). The highest resistance rate was found for trimethoprim-sulfamethoxazole (81%), followed by tetracycline (74%) and ampicillin (53%). Overall, 76 Shigella isolates (78%) were multidrug-resistant strains; S. flexneri had a higher multidrug resistance rate than S. sonnei (74% vs 23%). Increasing ciprofloxacin and ceftriaxone resistance was observed; approximately 10% and 5% of isolates were resistant to ciprofloxacin and ceftriaxone, respectively. Five ceftriaxone-non-susceptible strains (from Taiwan [3], Hong Kong [1] and The Philippines [1]) and 10 ciprofloxacin-non-susceptible strains (from Hong Kong [2], The Philippines [1], Korea [2], Vietnam [4] and Sri Lanka [1]) were isolated. CONCLUSIONS: High rates of multidrug resistance and steady increases in ceftriaxone and ciprofloxacin resistance of Shigella are serious pubic health concerns in Asian countries. Continuous monitoring of resistance patterns among Shigella isolates is necessary.     

Comparative metabolism of radiolabeled muraglitazar in animals and humans by quantitative and qualitative metabolite profiling.

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. This study describes the in vivo and in vitro comparative metabolism of [(14)C]muraglitazar in rats, dogs, monkeys, and humans by quantitative and qualitative metabolite profiling. Metabolite identification and quantification methods used in these studies included liquid chromatography/mass spectrometry (LC/MS), LC/tandem MS, LC/radiodetection, LC/UV, and a newly described mass defect filtering technique in conjunction with high resolution MS. After oral administration of [(14)C]muraglitazar, absorption was rapid in all species, reaching a concentration peak for parent and total radioactivity in plasma within 1 h. The most abundant component in plasma at all times in all species was the parent drug, and no metabolite was present in greater than 2.5% of the muraglitazar concentrations at 1 h postdose in rats, dogs, and humans. All metabolites observed in human plasma were also present in rats, dogs, or monkeys. Urinary excretion of radioactivity was low (<5% of the dose) in all intact species, and the primary route of elimination was via biliary excretion in rats, monkeys, and humans. Based on recovered doses in urine and bile, muraglitazar showed a very good absorption in rats, monkeys, and humans. The major drug-related components in bile of rats, monkeys, and humans were glucuronides of muraglitazar and its oxidative metabolites. The parent compound was a minor component in bile, suggesting extensive metabolism of the drug. In contrast, the parent drug and oxidative metabolites were the major components in feces, and no glucuronide conjugates were found, suggesting that glucuronide metabolites were excreted in bile and hydrolyzed in the gastrointestinal tract. The metabolites of muraglitazar resulted from both glucuronidation and oxidation. The metabolites in general had greatly reduced activity as PPARalpha/gamma activators relative to muraglitazar. In conclusion, muraglitazar was rapidly absorbed, extensively metabolized through glucuronidation and oxidation, and mainly eliminated in the feces via biliary excretion of glucuronide metabolites in all species studied. Disposition and metabolic pathways were qualitatively similar in rats, dogs, monkeys, and humans.     

Involvement of multiple cytochrome P450 and UDP-glucuronosyltransferase enzymes in the in vitro metabolism of muraglitazar.

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. The human major primary metabolic pathways of muraglitazar include acylglucuronidation, aliphatic/aryl hydroxylation, and O-demethylation. This study describes the identification of human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes involved in the in vitro metabolism of muraglitazar. [(14)C]Muraglitazar was metabolized by cDNA-expressed CYP2C8, 2C9, 2C19, 2D6, and 3A4, but to a very minimal extent by CYP1A2, 2A6, 2B6, 2C18, 2E1, and 3A5. Inhibition of the in vitro metabolism of muraglitazar in human liver microsomes, at a clinically efficacious concentration, by chemical inhibitors and monoclonal antibodies further supported involvement of CYP2C8, 2C9, 2C19, 2D6, and 3A4 in its oxidation. A combination of intrinsic clearance (V(max)/K(m)) and relative concentrations of each P450 enzyme in the human liver was used to predict the contribution of CYP2C8, 2C9, 2C19, 2D6, and 3A4 to the formation of each primary oxidative metabolite and to the overall oxidative metabolism of muraglitazar. Glucuronidation of [(14)C]muraglitazar was catalyzed by cDNA-expressed UGT1A1, 1A3, and 1A9, but not by UGT1A6, 1A8, 1A10, 2B4, 2B7, and 2B15. The K(m) values for muraglitazar glucuronidation by the three active UGT enzymes were similar (2-4 muM). In summary, muraglitazar was metabolized by multiple P450 and UGT enzymes to form multiple metabolites. This characteristic predicts a low potential for the alteration of the pharmacokinetic parameters of muraglitazar via polymorphic drug metabolism enzymes responsible for clearance of the compound or by coadministration of drugs that inhibit or induce relevant metabolic enzymes.     

Community-acquired methicillin-resistant Staphylococcus aureus infection in Singapore is usually "healthcare associated".

OBJECTIVE: To assess the frequency of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections. SETTING: A teaching hospital in Singapore. METHODS: Prospectively collected surveillance data were reviewed during a 1-year period to determine the extent and origin of community-acquired MRSA infections. RESULTS: Whereas 32% of 383 MRSA infections were detected less than 48 hours after hospital admission and would, by convention, be classified as "community acquired," all but one of these were among patients who had been exposed to outpatient centers including dialysis or chemotherapy clinics, visiting nurses, community hospitals, or all three. CONCLUSIONS: With health care increasingly being delivered in an outpatient setting, community-acquired MRSA infections are often acquired in hospital-related sites and most may be more accurately described as "healthcare acquired." Infection control measures need to move beyond the traditional paradigm of acute care hospitals to effectively control the spread of resistant pathogens.     

Influence of pesticide regulation on acute poisoning deaths in Sri Lanka

OBJECTIVES: To assess in a developing Asian country the impact of pesticide regulation on the number of deaths from poisoning. These regulations, which were implemented in Sri Lanka from the 1970s, aimed to reduce the number of deaths - the majority from self-poisoning - by limiting the availability and use of highly toxic pesticides. METHODS: Information on legislative changes was obtained from the Ministry of Agriculture, national and district hospital admission data were obtained from the Sri Lanka Health Statistics Unit, and individual details of deaths by pesticide poisoning were obtained from a manual review of patients' notes and intensive care unit records in Anuradhapura. FINDINGS: Between 1986 and 2000, the total national number of admissions due to poisoning doubled, and admissions due to pesticide poisoning increased by more than 50%. At the same time, the case fatality proportion (CFP) fell for total poisonings and for poisonings due to pesticides. In 1991_92, 72% of pesticide-induced deaths in Anuradhapura were caused by organophosphorus (OP) and carbamate pesticides - in particular, the WHO class I OPs monocrotophos and methamidophos. From 1991, the import of these pesticides was reduced gradually until they were banned for routine use in January 1995, with a corresponding fall in deaths. Unfortunately, their place in agricultural practice was taken by the WHO class II organochlorine endosulfan, which led to a rise in deaths from status epilepticus - from one in 1994 to 50 in 1998. Endosulfan was banned in 1998, and over the following three years the number of endosulfan deaths fell to three. However, at the end of the decade, the number of deaths from pesticides was at a similar level to that of 1991, with WHO class II OPs causing the most deaths. Although these drugs are less toxic than class I OPs, the management of class II OPs remains difficult because they are, nevertheless, still highly toxic, and their toxicity is exacerbated by the paucity of available facilities. CONCLUSION: The fall in CFP amidst a rising incidence of self-poisoning suggests that Sri Lanka's programmes of pesticide regulation were beneficial. However, a closer inspection of pesticide-induced deaths in one hospital revealed switching to other highly toxic pesticides, as one was banned and replaced in agricultural practice by another. Future regulation must predict this switching and bear in mind the ease of treatment of replacement pesticides. Furthermore, such regulations must be implemented alongside other strategies, such as integrated pest management, to reduce the overall pesticide availability for self-harm.     

3-arylimino-2-indolones are potent and selective galanin GAL3 receptor antagonists

A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).     

Hemangiopericytoma of the uterus: Report of a case with a comprehensive review of the literature

A case of locally recurrent and metastatic uterine hemangiopericytoma successfully treated with surgery, radiotherapy and chemotherapy is presented. The patient is alive without evidence of detectable tumor, 13 years after the initial diagnosis. Review of the literature revealed 64 reported cases of uterine hemangiopericytoma. The clinical features are not sufficiently characteristic to enable the diagnosis to be made preoperatively. However, with the help of histological and ultrastructural studies a definite diagnosis of hemangiopericy toma can be made. The primary treatment is radical surgery which usually involves total hysterectomy and bilateral salpingo-oophorectomy. The prognosis of uterine hemangiopericy toma is better than that of other sites. However, long follow-up of these patients is necessary because of the tendency to local and distant recurrence many years after the initial treatment. The recurrent tumor should be treated aggressively with surgery, radiotherapy, and chemotherapy as long-term survival is not unusual.     

Divalent cation interactions with a carboxylated derivative of scleroglucan

Divalent cation binding was investigated on a semisynthetic carboxylate derivative obtained from the fungal polysaccharide scleroglucan. Polarography, circular dichroism and isothermal microcalorimetry were used to study both the binding ability of Cu(II), Pb(II), and Zn(II) ions and the macromolecular properties of the systems under investigation. A theoretical model, proposed by Schwarz for the cooperative binding, was used to evaluate binding constants and the parameter σ related to the degree of cooperativity. All findings are discussed in terms of the differences in the binding ability of the different cations investigated. Pb(II) ions exhibit the higher affinity for oxidised scleroglucan and, in addition to this, its binding process is characterised by a cooperative behavior due to the onset of a disorder-to-order conformational transition of the polysaccharidic backbone. On the other hand, Cu(II) ions are less effective in the binding and unable to induce the conformational transition.