Evaluation of the cost-effectiveness of dexrazoxane for the prevention of anthracycline-related cardiotoxicity in children with sarcoma and haematologic malignancies: a European perspective.

BACKGROUND: Anthracycline-treated childhood cancer survivors are at higher risk of cardiotoxicity, especially with cumulative doses received above 250 mg/m2. Dexrazoxane is the only option recommended for cardiotoxicity prevention in high-risk patients supported by randomised trials but its cost-effectiveness in paediatric cancer patients has not been established. METHODS: A cost-effectiveness model applicable to different national healthcare system perspectives, which simulates 10,000 patients with either sarcoma or haematologic malignancies, based upon baseline characteristics including gender, age at diagnosis, cumulative anthracycline dose and exposure to chest irradiation. Risk equations for developing congestive heart failure and death from recurrence of the original cancer, secondary malignant neoplasms, cardiac death, pulmonary death, and death from other causes were derived from published literature. These are applied to the individual simulated patients and time until development of these events was determined. The treatment effect of dexrazoxane on the risk of CHF or death was based upon a meta-analysis of randomised and non-randomised dexrazoxane studies in each tumour type. The model includes country specific data for drug and administration costs, all aspects of heart failure diagnosis and management, and death due to different causes for each of the five countries considered; France, Germany, the UK, Italy, and Spain. RESULTS: Dexrazoxane treatment resulted in a mean QALY benefit across the five countries ranging from 0.530 to 0.683 per dexrazoxane-treated patient. Dexrazoxane was cost-effective for paediatric patients receiving anthracycline treatment for sarcoma and for haematologic malignancies, irrespective of the cumulative anthracycline dose received. The Incremental Cost Effectiveness Ratio (ICER) was favourable in all countries irrespective of anthracycline dose for both sarcoma and haematological malignancies (range: dominant to €2196). Individual ICER varied considerably according to country with dominance demonstrated for dexrazoxane in Spain and Italy and ratios approximately double the European average in the UK and Germany. CONCLUSIONS: Dexrazoxane is a highly cost-effective therapy for the prevention of anthracycline cardiotoxicity in paediatric patients with sarcoma or haematological malignancies in Europe, irrespective of the healthcare system in which they receive treatment. These benefits persist when patients who receive doses of anthracycline > 250 mg/m2 are included in the model.

Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution.

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

How to avoid having to run - hide - fight".

"Zero incidents" is the goal every security planner should work to achieve. The tools to build a "zero incidents" environment involve: * Acknowledging that violence is preventable. * Providing optimum customer service to every visitor, patient, family member. They are all VIP'S. * A strong emphasis on documentation. * Honoring and responding to staff intuition. *A proactive threat response program-policy. * Teaching all staff the verbal/non-verbal warning signs of violence. * Proactively contacting individuals of concern, making direct contact. * Having a strong domestic violence response and support plan. Active Shooter and Code Silver planning should also involve the crucial component of violence prevention and "zero incidents" philosophy. By merging these two, security planners will achieve the best of all possible outcomes. They will teach staff how to run, hide and fight and at the same time build a culture and workforce that provides both maximum customer support and staff awareness.

Suicide prevention in healthcare.

Healthcare facilities as growing venues for suicide by patients, family members, and others is a challenge which cannot be ignored by security and safety professionals working together with clinicians and social workers, according to the author who presents a checklist of winning strategies to achieve a "zero incidents" suicide prevention program.

Lucilia sericata chymotrypsin disrupts protein adhesin-mediated staphylococcal biofilm formation.

Staphylococcus aureus and Staphylococcus epidermidis biofilms cause chronic infections due to their ability to form biofilms. The excretions/secretions of Lucilia sericata larvae (maggots) have effective activity for debridement and disruption of bacterial biofilms. In this paper, we demonstrate how chymotrypsin derived from maggot excretions/secretions disrupts protein-dependent bacterial biofilm formation mechanisms.

Hospitals and terrorism: the realities; the future; mitigating risks.

Terrorist acts near hospitals and actual attacks on hospitals have become frequent in other countries and should not be ignored by security planners in this country, the author warns. In this article he sets forth steps which can be taken now to deal with and prevent such occurrences here.

Synthetic approaches to a chiral 4-amino-3-hydroxy piperidine with pharmaceutical relevance.

Four synthetic strategies were evaluated towards the preparation of (-)-(3R,4R)-1-benzyl-4-(benzylamino)piperidin-3-ol (1), which was constructed with control over the relative and absolute stereochemistry of the 4,3-amino alcohol moiety. The first strategy employed a novel Rh(I) catalyzed asymmetric hydrogenation, while two other strategies exploited the existing stereochemistry in 2-deoxy-D-ribose, and the fourth explored both biocatalytic and classical resolution techniques as a means to impart enantioenrichment to racemic intermediates en route to targeted structure (-)-1.

Computationally designed and experimentally confirmed diastereoselective rhodium-catalyzed Pauson-Khand reaction at room temperature.

The computational analysis of the rhodium-catalyzed Pauson-Khand reaction indicates that the key transition state is highly charge-polarized, wherein different diastereoisomers have distinctively different charge polarization patterns. Experimental studies demonstrate that chloro-enynes provide the optimal σ-electron-withdrawing group to promote polarization and thereby reduce the activation barrier to provide a highly diastereoselective reaction at room temperature.

Critical issues on gun violence in the hospital workplace.

The authors stress the need for keeping guns out of hospitals and their belief that healthcare security directors should take the lead in the battle for "gun control." They also present the responses, pro and con, to a blog advocating this belief from hospital security professionals.

Preventing hospital gun violence: best practices for security professionals to review and adopt.

Maintaining a safe, violence-free and therapeutic work place will become the greatest challenge for hospital security professionals, the author predicts, thanks to the surge in gun sales and the increase in gun violence. By recognizing this fact and adhering to best practices, we can greatly reduce the likelihood of gun violence in hospitals, he says. In this article, he presents 18 best practices that should be reviewed for offsetting and preventing such violence.

Multiple-dose pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in patients with HIV-1 infection.

BACKGROUND AND OBJECTIVE: This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection. METHODS: This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days' oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8. RESULTS: Overall, 63 patients (mean age 33.9 +/- 8.7 years; mean weight 71.6 +/- 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5-2.5 hours. Pharmacokinetics were linear over the range 200-800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200-800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [C(max)] = 5.55 +/- 1.94 pmol/million cells for 800-mg twice-daily administration). Apri-citabine was well tolerated. CONCLUSION: Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.

Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection.

Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65-80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6-7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10 HIV RNA copies/ml, respectively, after 10 days of treatment (P<0.0001 versus placebo). ATC showed a low propensity to select for resistance mutants in vitro and during clinical monotherapy. ATC was well tolerated in volunteers and in HIV-infected patients. This promising profile suggests that ATC may be useful in treating patients who have failed previous lamivudine- or emtricitabine-containing regimens. Further studies to evaluate the long-term efficacy and tolerability of ATC are underway.

Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients.

OBJECTIVE: Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development for patients with HIV disease. This study evaluated the antiretroviral efficacy, tolerability and safety of apricitabine monotherapy, administered for 10 days in antiretroviral-naive, HIV-1 infected adults. METHODS: Adult patients (> or = 18 years) with HIV infection (CD4 count > or = 250 cells/microl; plasma HIV-1 RNA level 5000-100 000 copies/ml) were randomized to 10 days' double-blind oral therapy with placebo or apricitabine 400 mg/day, 800 mg/day, 1200 mg/day, or 1600 mg/day. RESULTS: At 7 days, all apricitabine doses produced statistically significant log10 reductions in plasma HIV RNA levels from baseline relative to placebo (n = 13; P < 0.0001), as follows: -1.16 (400 mg; n = 11), -1.28 (800 mg; n = 12), -1.44 (1200 mg; n = 14), -1.30 (1600 mg; n = 13). After 10 days, the log10 viral load reductions with apricitabine 1200 mg (-1.65; P = 0.01) and 1600 mg/day (-1.58; P = 0.04) were significantly greater than that with the 400-mg dose (-1.18). No clinically relevant changes were observed in CD4 or CD8 cell indices. Apricitabine was well tolerated and showed no tendency to select any particular resistance mutation. CONCLUSION: Apricitabine monotherapy showed promising antiretroviral efficacy, good tolerability and a low propensity for resistance selection in antiretroviral-naive HIV-infected patients treated for 10 days. These results warrant further evaluation of the long-term clinical efficacy and tolerability of apricitabine.

Pharmacokinetics of single oral doses of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in healthy volunteers.

BACKGROUND: Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is undergoing clinical development for the treatment of HIV-1 infection. This study was performed to investigate the pharmacokinetics of single oral doses of apricitabine in healthy volunteers. METHODS: A total of 26 healthy volunteers (14 males, 12 females) took part in this study. Participants received single oral doses of apricitabine 400 mg, 800 mg and 1600 mg in ascending order at intervals of at least 1 week. Concentrations of apricitabine in plasma and urine were monitored over 24 hours after dosing. RESULTS: Apricitabine was rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) being attained approximately 1.5-2 hours after dosing. Plasma concentrations declined in a log-linear manner over at least 12 hours, with an elimination half-life of approximately 3 hours. The majority of the dose (65-80%) was excreted in the urine as unchanged drug within 24 hours. The pharmacokinetics of apricitabine were largely linear with respect to dose. In the overall study population, the area under the concentration-time curve (AUC) decreased by 4% with a dose of 800 mg and by 14% with the 1600 mg dose compared with the value predicted from the 400 mg dose. In females, however, there was a slightly greater departure from linearity: AUC decreased by 8% with a dose of 800 mg, and by 21% with a dose of 1600 mg. When pharmacokinetic parameters were normalised for bodyweight, there were no significant differences between values in males and females. There was no evidence of enantiomeric interconversion of apricitabine. All doses of apricitabine were well tolerated. CONCLUSION: Apricitabine is rapidly absorbed and shows predictable pharmacokinetics after oral administration. Clearance is predominantly by renal excretion of the unchanged drug, which suggests a low potential for interactions with drugs that are subject to hepatic metabolism.

Challenges for the clinical development of new nucleoside reverse transcriptase inhibitors for HIV infection.

There is a need for new antiretroviral drugs with activity against HIV isolates resistant to currently available agents and improved short and long-term tolerability profiles. Clinical trial designs for nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs) are restricted by the characteristics of these agents (for example, their cross-resistance, resistance threshold and interaction profiles), the ethical need to ensure that patients are not maintained on suboptimal regimens, and regulatory requirements (for example, with regards to trial designs and patient populations). For example, consideration of cross-resistance profiles must influence the way in which an NRTI in development is sequenced to minimize any impact on future treatment options. The resistance threshold is determined by the number of mutations required to diminish sensitivity to a given drug. Pharmacokinetic or pharmacodynamic interactions restrict how NRTIs may be combined during clinical development. Doses may be selected on the basis of results from short-term monotherapy studies in treatment-naive patients, but such studies cannot establish the long-term efficacy or tolerability of new agents used in combination regimens. Confirmatory studies in treatment-naive populations do not meet the medical and regulatory needs for clinical data in treatment-experienced populations, while studies in treatment-experienced populations are subject to numerous clinical and logistical difficulties. Intensification, switch and hybrid study designs all offer suitable approaches to the evaluation of NRTIs with novel resistance profiles. Switch studies are particularly useful for agents with resistance profiles that suggest a specific sequencing approach in treatment and for those with the potential, based on pharmacokinetic data, for interactions with other agents. The successful development of new NRTIs will depend upon a thorough appreciation of these many and complex issues, not only among those involved in the design of clinical studies, but also those contributing to their review and conduct.

Intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes.

The crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner.

Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers.

The Migraine Disability Assessment (MIDAS) questionnaire is a brief, self-administered questionnaire designed to quantify headache-related disability over a 3 month period. The MIDAS score has been shown to have moderately high test-retest reliability in headache sufferers and is correlated with clinical judgment regarding the need for medical care. The aim of the study was to examine the validity of the MIDAS score, and the five items comprising the score, compared to data from a 90 day daily diary used, in part, to record acute disability from headache. In a population-based sample, 144 clinically diagnosed migraine headache sufferers were enrolled in a 90 day diary study and completed the MIDAS questionnaire at the end of the study. The daily diary was used to record detailed information on headache features as well as activity limitations in work, household chores, and non-work activities (social, family and leisure activities). The MIDAS score was the sum of missed work or school days, missed household chores days, missed non-work activity days, and days at work or school plus days of household chores where productivity was reduced by half or more in the last 3 months. Validity was assessed by comparing MIDAS items and the MIDAS score with equivalent measures derived from the diary. The MIDAS items for missed days of work or school (mean 0.96, median 0) and for missed days of household work (mean 3.64, median 2.0) were similar to the corresponding diary-based estimates of missed work or school (mean 1.23, median 0) and of missed household work (mean 3.93, median 2.01). Values for missed days of non-work activities (MIDAS mean 2.6 and median 1 versus diary mean 2.22 and median 0.95) were also similar. Responses to MIDAS questions about number of days where productivity was reduced by half or more in work (mean 3.77, median 2.00) and in household work (mean 3.92, median 2.00) significantly overestimated the corresponding diary-based measures for work (mean 2.94, median 1.06) and household work (mean 2.22, median 0.98). Nonetheless, the overall MIDAS score (mean 14.53, median 9.0) was not significantly different form the reference diary-based measure (mean 13.5, median 8.4). The correlation between the MIDAS summary score and an equivalent diary score was 0.63. The group estimate of the MIDAS score was found to be a valid estimate of a rigorous diary-based measure of disability. The mean and median values for the MIDAS score in a population-based sample of migraine cases were similar to equivalent diary measures. The correlation between the two measures was in the low moderate range, but expected given that two very different methods of data collection were compared.