Acetaminophen overdose in the Military Health System.

PURPOSE: We report the annual trend, distribution, and determinants of acetaminophen overdose using data from the Military Health System. We also assess the proportion of individuals with an acetaminophen overdose who received a prescription for any acetaminophen-containing medication prior to their event. METHODS: Diagnostic International Classification of Diseases, 9th revision (ICD-9) codes from inpatient medical encounters were used to identify patients with acetaminophen overdose. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) for associations between selected socio-demographic characteristics and acetaminophen overdose. Pharmacy records for individuals with an acetaminophen overdose were obtained to evaluate the proportion who received a prescription for any acetaminophen-containing medication prior to their overdose. RESULTS: Annual age-adjusted and sex-adjusted prevalence of acetaminophen overdose increased by 38.5% from 2004 to 2008. Acetaminophen overdose was significantly more common in female subjects than in male subjects (aPR = 3.24, 95%CI = 2.97-3.55). Individuals aged 15-17 and 18-24 also were significantly more likely to have an overdose compared with those aged 45-64 (aPR = 6.06, 95%CI = 5.25-7.00 and aPR = 4.58, 95%CI = 4.01-5.23, respectively). Among active duty service members, acetaminophen overdose was six times more common in junior enlisted service members than in officers (aPR = 6.06, 95%CI = 3.90-9.40). The proportion of individuals with an inpatient overdose who had any prescription for an acetaminophen-containing medication in the 365, 30, and 7 days before the overdose was 53.3%, 23.7%, and 16.3%, respectively. CONCLUSIONS: Identification of at-risk populations will aid the military in ongoing efforts to decrease medication misuse. Findings suggest a potential need for improved labeling of over-the-counter medications and medication safety education efforts for unintentional acetaminophen overdose and continued efforts to identify individuals at risk for intentional overdose. Published 2012. This article is a US Government work and is in the public domain in the USA.

Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity.

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

Carbapenem-resistant Enterobacteriaceae and the correlation between carbapenem and fluoroquinolone usage and resistance in the US military health system.

Whether carbapenem or fluoroquinolone usage is correlated with carbapenem-resistant Enterobacteriaceae (CRE) has not been investigated at the level of an entire US nationwide managed health care system. We analyzed 75 million person-years of surveillance and 1,969,315 cultures from all 266 hospitals in the geographically dispersed US military health system. Incidences of CRE remained under 1 case per 100,000 person-years. Incidences of CRE increased relative to 2005 baseline levels in 3 of 7 subsequent years, then decreased in 2012 (P<0.05). Incident proportions of carbapenem resistance (CR) differed significantly among years, geographical regions, and bacterial species. Although use and resistance strongly correlated (R>0.80) for several "drug-bug" combinations, none were significant at the national or facility level. One exception was that inpatient consumption of fluoroquinolones was significantly correlated (P=0.0007) with CR in Escherichia coli when data from the major referral centers of the Southern and Northern regions were combined.

Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy.

In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8aand 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.

A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides.

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of beta-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents.

In only four chemical steps from naturally occurring artemisinin (1), trioxane dimers 6 and 7 were prepared on a multigram scale in overall 32-44% yields. In mice, both isonicotinate N-oxide dimer 6 and isobutyric acid dimer 7 were considerably more antimalarially efficacious than clinically used sodium artesunate (2) via both oral and intravenous administration. In the transgenic adenocarcinoma of mouse prostate model, some of the trioxane dimers had potent anticancer activity.

Orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents.

Short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. Almost exclusive formation of the trioxane 12alpha-stereoisomers simplifies product purification. Carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 degrees C for 24 h. When administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. Important for their practical in vivo administration, these new synthetic antimalarial trioxanes 3 and 5 are 14-20 times more soluble in water at pH 7.4 than is artelinic acid (1), a leading semisynthetic, herb-derived antimalarial trioxane drug candidate.

Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System.

AIM: To determine the rate ratio of neuropsychiatric hospitalizations in new users of varenicline compared to new users of nicotine replacement therapy (NRT) patch in the Military Health System (MHS). DESIGN, SETTING AND PARTICIPANTS: Varenicline (n = 19,933) and NRT patch (n = 15,867) users who initiated therapy from 1 August 2006 to 31 August 2007 within the MHS were included in this retrospective cohort study. After matching according to propensity scores, 10,814 users remained in each cohort. The study population included those with and without a history of neuropsychiatric disease. MEASUREMENTS: Patients were followed for neuropsychiatric hospitalizations defined by primary neuropsychiatric discharge diagnosis using ICD-9 codes from in-patient administrative claims. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated after propensity score matching on exposure for socio-demographic factors, health-care utilization, comorbidities, medication history and neuropsychiatric history. FINDINGS: There was no increase in the rate of neuropsychiatric hospitalizations in patients treated with varenicline compared to NRT patch when followed for 30 days (propensity-score matched HR = 1.14, 95% CI: 0.56-2.34). Results were similar after 60 days of follow-up. CONCLUSIONS: There does not appear to be an increase in neuropsychiatric hospitalizations with varenicline compared with nicotine replacement therapy patch over 30 or 60 days after drug initiation.

Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo.

The fumagillin family of natural products is known to inhibit angiogenesis through irreversible inhibition of human type 2 methionine aminopeptidase (MetAP2). Recently, fumagillin and TNP-470 were reported to possess antimalarial activity in vitro, and it was hypothesized that this inhibition was mediated by interaction with the putative malarial ortholog of human MetAP2. In this report, we have overexpressed and purified to near-homogeneity PfMetAP2 from bacteria, yeast, and insect cells. Although none of the recombinant forms of PfMetAP2 exhibited enzymatic activity in existing assays, PfMetAP2 proteins expressed in both yeast and insect cells were able to bind to fumagillin in a pull-down assay. The interaction between fumagillin and analogs with PfMetAP2 was further demonstrated using a newly established mammalian three-hybrid assay incorporating a conjugate between dexamethasone and fumagillin. Unlike human (Hs)MetAP2, it was found that PfMetAP2 is bound to fumagillin noncovalently. Importantly, a new analog of fumagillin, fumarranol, was demonstrated to interact with PfMetAP2 and inhibit the growth of both chloroquine-sensitive and drug-resistant Plasmodium falciparum strains in vitro. Antiparasite activity of fumagillin and fumarranol was also demonstrated in vivo using a mouse malaria model. These findings suggest that PfMetAP2 is a viable target, and fumarranol is a promising lead compound for the development of novel antimalarial agents.

An unusual type IB topoisomerase from African trypanosomes.

African trypanosomes are ancient eukaryotes that cause lethal disease in humans and cattle. Available drugs are inadequate and the need for new therapeutic targets is great. Trypanosoma brucei and related pathogens differ strikingly from higher eukaryotes in many aspects of nucleic acid structure and metabolism. We find yet another example of this in their unusual DNA topoisomerase IB. Type IB topoisomerases relieve the supercoils that accumulate during DNA and RNA synthesis, and are of considerable importance as the target for antitumor camptothecins. Dozens of type IB topoisomerases sequenced from eukaryotes, bacteria, and pox viruses are all encoded by a single gene that predictably contains a highly conserved DNA binding domain and C-terminal catalytic domain, linked by a nonconserved hydrophilic region. We find that topoisomerase IB in T. brucei is encoded by two genes: one for the DNA-binding domain and a second for the C-terminal catalytic domain. In keeping with this, highly purified fractions of native T. brucei topoisomerase IB catalytic activity contain two proteins, of 90 and 36 kDa. The native enzyme is conventional in its Mg2+-independence, ability to relax positive and negative supercoils, and inhibition by camptothecin. Camptothecin promotes the formation of a covalent complex between 32P-labeled substrate DNA and the small subunit. This unusual structural organization may provide a missing link in the evolution of type IB enzymes, which are thought to have arisen over time from the fusion of two independent domains. It also provides another basis for the design of selectively toxic drug candidates.

New chemical and biological aspects of artemisinin-derived trioxane dimers.

Joining two 10-deoxoartemisinin trioxane units via a p-diacetylbenzene linker produces new C-10 non-acetal dimers and. 1H NMR spectroscopy allows unambiguous assignment of the stereochemistry at C-10 in these dimers. Successful replacement of both carbonyl oxygen atoms in these diketone dimers by fluorine atoms produces new tetrafluorinated dimers and. Each dimer was evaluated in vitro for antimalarial, antiproliferative, and antitumor activities; ketone dimers and, more than fluorinated dimers and, are promising for chemotherapy of both malaria and cancer.