One-Year Efficacy and Safety Assessment of Ripasudil, a Rho Kinase Inhibitor, in an Addition to or Replacing Existing Treatment Regimens: A Retrospective Study.

Purpose: To evaluate efficacy and safety of ripasudil for 1 year in addition to or replacing existing treatment regimens. Methods: We retrospectively reviewed the medical records for 128 eyes of 128 glaucoma patients who were prescribed ripasudil as an addition to or a switch from their preexisting antiglaucoma instillations. We investigated the rate and factors for discontinuation and intraocular pressure (IOP) reduction. Results: Almost half of the patients (60 eyes) discontinued ripasudil treatment before the 1 year mark, while remaining patients completed the treatment. The lack of efficacy and development of adverse effects were significantly correlated with discontinuation (P < 0.001) in the Cox proportional hazards model. In the Kaplan-Meier curve, adverse effects occurred in earlier phase and almost 60% dropped out within 3 months after ripasudil administration. However, adverse effects also occurred randomly throughout the study period. In patients who continued ripasudil, the mean IOPs (mmHg) at baseline, 6 and 12 months after treatment were 17.7 ± 5.1, 14.6 ± 5.0, and 14.8 ± 3.8 in the Addition group, and 17.8 ± 4.1, 15.4 ± 3.2, and 15.4 ± 5.0 in the Switch group, respectively (all P values <0.05). Conclusions: Almost half of the patients discontinued ripasudil owing to the lack of efficacy and the generation of adverse effects within the 1 year. In the remaining half, the addition and switching of ripasudil to the existing glaucoma treatment effectively reduced IOP for 1 year.

Assessment of PKA and PKC inhibitors on force and kinetics of non-failing and failing human myocardium.

AIMS: Heart failure (HF) is a prevalent disease that is considered the foremost reason for hospitalization in the United States. Most protein kinases (PK) are activated in heart disease and their inhibition has been shown to improve cardiac function in both animal and human studies. However, little is known about the direct impact of PKA and PKC inhibitors on human cardiac contractile function. MATERIAL AND METHODS: We investigated the ex vivo effect of such inhibitors on force as well as on kinetics of left ventricular (LV) trabeculae dissected from non-failing and failing human hearts. In these experiments, we applied 0.5 µM of H-89 and GF109203X, which are PKA and PKC inhibitors, respectively, in comparison to their vehicle DMSO (0.05%). KEY FINDINGS AND CONCLUSION: Statistical analyses revealed no significant effect for H-89 and GF109203X on either contractile force or kinetics parameters of both non-failing and failing muscles even though they were used at a concentration higher than the reported IC50s and Kis. Therefore, several factors such as selectivity, concentration, and treatment time, which are related to these PK inhibitors according to previous studies require further exploration.

Cost-Effectiveness of Elbasvir/Grazoprevir Versus Daclatasvir Plus Asunaprevir in Patients with Chronic Hepatitis C Virus Genotype 1b Infection in China.

BACKGROUND AND OBJECTIVE: New direct-acting antivirals (DAAs) have high efficacy and tolerability in the treatment of hepatitis C virus (HCV) infection. The objective of this study was to assess the cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) versus daclatasvir plus asunaprevir (DCV + ASV) in Chinese patients with chronic HCV genotype (GT) 1b infection stratified by cirrhosis status and treatment history. METHODS: A cohort state-transition model was constructed to simulate the course of chronic HCV infection in patients stratified by cirrhosis status and treatment history. The model projected lifetime outcomes and costs in terms of HCV treatment, laboratory tests, clinical procedures, and hospitalizations. Mean age of the study cohort at baseline was 45 years, based on published sources. Sustained virologic response (SVR) rates were derived from clinical trials. Healthcare resource utilization and health utilities were extracted or estimated from published studies in Chinese populations. The stability of the base-case analysis was validated by deterministic and probabilistic sensitivity analyses. RESULTS: In each subpopulation of Chinese patients, treatment with EBR/GZR dominated treatment with DCV + ASV, with lower costs and higher quality-adjusted life-years (QALYs). Sensitivity analysis demonstrated that EBR/GZR was the cost-effective option compared to DCV + ASV in 77.4-97.4% or 94.1-100% of model simulations in Chinese treatment-naïve or treatment-experienced patients, respectively, as the cost-effectiveness threshold changed from zero to US$24,150/QALY (three times GDP per capita in China). CONCLUSIONS: Treatment with EBR/GZR was the cost-effective option for patients with chronic HCV GT1b infection in China, regardless of cirrhosis status or treatment history.

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195.

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

Daclatasvir combined with asunaprevir is a cost-effective and cost-saving treatment for hepatitis C infection in China.

Aim: To evaluate the cost-effectiveness of the novel all-oral direct-acting antiviral regimen daclatasvir + asunaprevir (DUAL), versus interferon-based regimens for the treatment of chronic hepatitis C virus genotype 1b infection. Methods: Inputs for a lifetime Markov model were sourced from clinical trials and published literature. Outputs include disease management costs, life expectancy, quality-adjusted life-years and cost-effectiveness. Sensitivity analyses assessed the drivers of cost-effectiveness and sustained virologic response thresholds at which DUAL is cost-saving. Results: DUAL was associated with discounted incremental quality-adjusted life-years of 1.29-3.85 and incremental life-years of 0.85-2.59 per patient, with discounted lifetime cost savings of USD$1415-8525. Associated sustained virologic response rates could fall to 45.1-84.8%, while remaining dominant. Conclusion: Treatment with DUAL provides significant clinical benefit, while accruing lower lifetime costs.

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China.

BACKGROUND: Hepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China. OBJECTIVES: This study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China. METHODS: A cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted. RESULTS: For HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective. CONCLUSION: DCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

Cost Effectiveness of Daclatasvir Plus Asunaprevir Therapy for Chinese Patients with Chronic Hepatitis C Virus Genotype 1b.

BACKGROUND AND OBJECTIVES: Daclatasvir plus asunaprevir has shown superior efficacy and safety for treating hepatitis C virus genotype 1b infection in comparison with pegylated interferon and ribavirin. The objective of this analysis is to investigate the cost effectiveness of daclatasvir plus asunaprevir compared with interferon-α-based therapies from the perspective of the Chinese healthcare system. METHODS: A Markov model was established to measure economic and health outcomes of daclatasvir plus asunaprevir compared with general interferon-α plus ribavirin and pegylated interferon plus ribavirin for hepatitis C virus genotype 1b infection. We also considered the two following scenarios: 24 weeks of daclatasvir plus asunaprevir used as a second-line treatment for ineligible/intolerant and non-responding patients with HCV during 48 weeks of first-line interferon-α plus ribavirin (interferon-α plus ribavirin and daclatasvir plus asunaprevir) or pegylated interferon plus ribavirin (pegylated interferon plus ribavirin and daclatasvir plus asunaprevir) treatment. Clinical costs and utility inputs were derived from the published literature. The incremental cost-effectiveness ratio was shown as costs in US dollars per quality-adjusted life-years gained. Uncertainty was examined by one-way and probabilistic sensitivity analyses. RESULTS: Compared with interferon-α plus ribavirin, pegylated interferon and ribavirin, interferon-α plus ribavirin plus daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin plus daclatasvir plus asunaprevir strategies, daclatasvir plus asunaprevir gained an additional 0.62, 0.32, 0.20, and 0.15 quality-adjusted life-year with increasing costs of US$11,950, US$671, US$8366, and -$3783, respectively. The incremental cost-effectiveness ratios of pegylated interferon and ribavirin, daclatasvir plus asunaprevir, interferon-α plus ribavirin and daclatasvir plus asunaprevir, and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir against the baseline interferon-α plus ribavirin strategy were US$37,930, US$19,233, US$8495, and US$33,031 per quality-adjusted life-year gained. Daclatasvir plus asunaprevir and interferon-α plus ribavirin plus daclatasvir plus asunaprevir were presented as the cost-effective alternatives, and pegylated interferon plus ribavirin and pegylated interferon plus ribavirin and daclatasvir plus asunaprevir strategies dominated. The model outputs were sensitive to a patient's age, discount rate, and the risk ratio between pegylated interferon plus ribavirin and interferon-α plus ribavirin. CONCLUSIONS: Daclatasvir plus asunaprevir in the Chinese setting is likely to be cost effective for treating hepatitis C virus genotype 1b infection.

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study.

CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.

Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan.

BACKGROUND: The advent of highly efficacious, well-tolerated, all-oral direct-acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money. OBJECTIVES: To evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan. METHODS: A previously published Markov model was used to estimate the cost-effectiveness of daclatasvir + asunaprevir compared with sofosbuvir/ledipasvir on the basis of a matching-adjusted indirect comparison of pivotal trials and modeling inputs specific to the Japanese setting. A de novo budget impact model was developed and used to predict the cost implications of differing treatment sequences. RESULTS: Cost-effectiveness results demonstrated minimal difference in terms of benefit (0.037 fewer QALYs and 0.014 fewer life-years with daclatasvir + asunaprevir); nevertheless, a significant difference in cost was predicted (estimated ¥2,299,700 [US $21,695] reduction with daclatasvir + asunaprevir). The budget impact analysis estimated that treatment with daclatasvir + asunaprevir is expected to be less expensive than treatment with sofosbuvir/ledipasvir (as the proportion of patients initially treated with sofosbuvir/ledipasvir increased from 0% to 100%, total costs increased from ¥206 to ¥403 billion [US $1.94 billion to US $3.80 billion]). CONCLUSIONS: On the basis of results from an established cost-effectiveness model and a conventional budget impact analysis, treatment with daclatasvir + asunaprevir is expected to be cost-saving compared with treatment with sofosbuvir/ledipasvir in Japan with similar health outcomes, regardless of treatment sequence.

Vascular Toxicity Risk Assessment of MC18 and MC70, Novel Potential Diagnostic Tools for In Vivo PET Studies.

The P-glicoprotein (P-gp) inhibitor MC18 has been recently proposed as a valuable PET tracer to measure P-gp expression in vivo. The aim of this study was to evaluate the toxic hazard towards the vasculature of MC18 along with the structurally related and more potent P-gp inhibitor MC70. Their effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of fresh and cultured rat aorta rings as well as on Cav 1.2 channel current (ICa1.2 ) of A7r5 cells were studied. At concentrations >10 µM, MC18 and MC70 decreased cell viability causing evident morphological changes. In fresh rat aorta rings, both compounds (0.1-100 µM) antagonized phenylephrine-induced contraction in a concentration-dependent manner, with IC50 values in the range of 1.67-14.49 µM, whereas only MC18 caused a concentration-dependent decrease of the 60 mM K+ (K60)-induced responses. In rings cultured for 7 days with both compounds (1-10 µM), 10 µM MC70 significantly reduced, while 10 µM MC18 completely prevented the contractile response to both phenylephrine and K60. MC18 and MC70 (0.1-100 µM) inhibited ICa1.2 in a concentration-dependent manner with IC50 values of 16.81 and 32.13 µM, respectively. These findings demonstrate that MC18-induced vascular effects took place at concentrations that are at least three orders of magnitude higher than those (≤10 nM) allowing in vivo measurement of P-gp expression. Thus, MC18, and possibly MC70, can be considered promising PET tools for in vivo P-gp quantification.

Economic evaluation of 5-HT3 receptor antagonists in combination with dexamethasone for the prevention of 'overall' nausea and vomiting following highly emetogenic chemotherapy in Chinese adult patients.

Background Two pivotal Phase III trials compared the efficacy of palonosetron, ondansetron and granisetron, combined with dexamethasone, for the prevention of nausea and vomiting following highly emetogenic chemotherapy. However, an economic evaluation of these three regimens in the real-world setting of Chinese adult patients has not been determined. Objectives To estimate, from the perspective of the Chinese healthcare system, which of these frequently used strategies consisting of 0.25 mg palonosetron (0.25P), 16 mg ondansetron (Onda), and 3 mg granisetron (Gran), is the most cost-effective option in patients following highly emetogenic chemotherapy. Methods A Markov decision-analytic model was developed. The health and economic outcomes of the three strategies; 0.25P, Onda, and Gran were investigated. The clinical and utility data were taken from published studies. The cost data were calculated according to current local Chinese practices. Sensitivity analyses were performed to determine the impact of uncertainty regarding the results. Results The base-case analysis showed that the 0.25P strategy yielded maximum health benefits compared with the other two strategies. However, the probabilistic sensitivity analysis demonstrated that the Gran strategy was the most cost-effective approach when the willingness-to-pay threshold was not more than US$22,515/quality-adjusted life year. Moreover, palonosetron is not cost-effective in preventing 'overall' nausea and vomiting following highly emetogenic chemotherapy in Chinese patients. Conclusions Our analysis suggests that, compared with palonosetron and ondansetron, 3 mg granisetron may be a cost-effective treatment option in the current Chinese healthcare setting.

Characterization and assessment of nanoencapsulated sanguinarine chloride as a potential treatment for melanoma.

Sanguinarine has a history of use in both folk medicine and early dermatology for the treatment of cutaneous neoplasms. Applied indiscriminately, bloodroot is an escharotic agent with potential to cause extensive tissue necrosis. However, when used in a controlled fashion, sanguinarine imparts selective cytotoxic/anti-proliferative activity through multiple mechanisms against human/ murine melanoma. To exploit sanguinarine's observed activity against melanoma, a targeted delivery system is required. We present a sol-gel based nanoparticulate platform for encapsulating sanguinarine chloride(sang-np)-a targeted therapeutic capable of steady, reliable delivery of predictable quantities of drug over a sustained time period with minimal undesirable effects. Size and release kinetics of sang-np were characterized using dynamic light scattering and ultraviolet-visible spectroscopy respectively. In vitro efficacy of sang-np was assessed. At both 2 and 24 hours, free sanguinarine killed > 90% of B16 melanoma cells, assessed via MTT assay. At 2 hours, sang-np killed a portion of melanoma cells, increasing to percentages comparable to free sanguinarine by 24 hours. Control(empty) nanoparticles exerted minimal toxicity to melanoma cells at both time points. TUNEL assay revealed that treatment with both sanguinarine and sang-np induces apoptosis in B16 melanoma cells, suggesting that both treatments act via the same mechanism of action. These data confirm controlled release of sanguinarine from sang-np, as well as comparable efficacy and mechanism of action to sanguinarine alone. This suggests that nanoparticle delivery of sanguinarine may be a unique approach to capitalize on this potent agent's inherent anti-tumor activity and overcome many of the limitations with its current formulation.

Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users.

BACKGROUND: Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. METHODS: In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. RESULTS: Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. CONCLUSION: This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

[Evaluation of muscle relaxant requirement for hospital anesthesia].

The rationale for cost-effectiveness of modern muscle relaxants (MR) administration in general anesthesia was evaluated. New MRs are more expensive than traditionally used pipecuronium and succinylcholine. However, the old MRs are often required as a block reversion with anticholinesterase medicines at the end of surgery, the longer artificial lung ventilation and observation in patients during recovery in intensive care unit. It was found that the district military hospital had done an annual average of about 900 general anesthesia assisted with artificial ventilation and muscle relaxation. About 2% of all anesthesias accrue to short-term anesthesia, the 27% to medium-term and 71% to long-term. 81% of the medium-term anesthesia accrue small hospitals. According to cost/effectiveness the most optimal muscle relaxants administration scheme for short-term (up to 30 min) anesthesia was mivacurium, for the operation of medium duration (30-120 min)--rocuronium, for long-term (120 min)--pipecuronium. An electronic form of annual report, which allows to obtain the necessary data for calculation of annual muscle relaxants demand and costs both in hospital and in the whole of the armed forces quickly, was developed.

The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphomas: summary of the scientific assessment of the committee for medicinal products for human use.

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m(2) administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician's best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

[Quantitative assessment of neuromuscular block of the orbicularis oculi muscle]. / Quantitative Erfassung der neuromuskulären Blockade des Musculus orbicularis oculi.

In a prospective clinical study neuromuscular block at the orbicular ocular muscle was examined qualitatively and quantitatively by an AMG approach. The signals were recorded, visualized and evaluated simultaneously under PC-support after TOF-stimulation in 20 s intervals. Fifty ASA I and II patients were included into the study. After oral premedication with midazolam 10-15 mg, anaesthesia was induced with propofol 2 mg/kg and alfentanil 0.02 mg/kg and maintained by means of propofol 6-8 mg/kg/h and alfentanil 0.02 mg/kg/h. After intubation and signal stabilization, mivacurium 0.75 mg/kg was administered and neuromuscular blockade was recorded online. The measured acceleration at the orbicular ocular muscle amounted 0.9 g on average. Maximal neuromuscular block was registered at 78.5% and the TOF-ratio of 0.8 was achieved after 14.1 min. The low values of the AMG-signals of the orbicular ocular muscle requiring very high technical demands on the measuring instrument. Additional problems arise through the considerable temporal expenditure for discovering the optimal location of stimulation. During the AMG monitoring the position dependence of the measured values of the sensors must be taken into consideration. These technical problems restrict the suitability of the AMG at the orbicular ocular muscle as a quantitative neuromuscular monitoring tool.

Equi-lasting doses of rocuronium, compared to mivacurium, result in improved neuromuscular blockade in patients undergoing gynecological laparoscopy : [Des doses de durée équivalente de rocuronium, comparé au mivacurium, améliorent la curarisation chez des patientes qui subissent une laparoscopie gynécologique].

PURPOSE: To compare equi-lasting doses of a short-acting (mivacurium) to an intermediate-acting (rocuronium) neuromuscular relaxant, with regard to intubating conditions, efficacy, number of maintenance doses, hemodynamic alterations, adverse events and costs, in patients undergoing laparoscopic gynecological surgery. METHODS: Sixty patients were randomly allocated to receive either 0.2 mg*kg(-1) (3 x ED(95)) mivacurium or 0.5 mg*kg(-1) (1.7 x ED(95)) rocuronium, under propofol/fentanyl anesthesia. T1, first twitch of the train-of-four (TOF) and TOF ratio (T4:T1) were used to evaluate neuromuscular block using the Relaxometer(R) mechanomyograph. The trachea was intubated when T1 was maximally suppressed. Neuromuscular block was maintained at 25% T1 with equi-lasting doses of 0.075 mg*kg(-1) mivacurium or 0.15 mg*kg(-1) rocuronium. RESULTS: Mean (min) +/- SD mivacurium onset time (1.9 +/- 0.4) was longer than that of rocuronium (1.3 +/- 0.3). This did not yield a statistical difference in intubating conditions between the two groups. Interval 25-75% T1 recovery and time to 0.8 TOF recovery were prolonged following rocuronium (11.9 +/- 3.9, 52.6 +/- 15.5 respectively) compared to mivacurium (6.7 +/- 2.3, 39.2 +/- 8.1 respectively). More patients, 22/30, required mivacurium maintenance doses compared to 14/30 patients in the rocuronium group. Arterial blood pressure declined and 13/30 patients manifested erythema following mivacurium administration. The acquisition costs of rocuronium (6.93 Euro/patient) were 23% lower compared to mivacurium (8.96 Euro/patient). CONCLUSION: Equi-lasting doses of rocuronium resulted in favourable intubating conditions more rapidly, improved hemodynamic stability, required less frequent administration of maintenance doses and were not associated with erythema, compared to mivacurium.

The impact of choice of muscle relaxant on postoperative recovery time: a retrospective study.

UNLABELLED: To test the hypothesis that the use of long-acting muscle relaxants is associated with prolonged postoperative recovery when compared with the use of shorter-acting relaxants, we undertook a retrospective study of 270 patients with induced paralysis recovering from general anesthesia. We calculated the mean recovery time associated with each muscle relaxant used. Regression analyses were performed to control for potential confounding of the results by length and type of surgery, as well as age and sex. Taking these into account, the adjusted difference in mean recovery time between patients receiving short- and intermediate-acting relaxants (mivacurium, atracurium, and vecuronium) versus those receiving long-acting relaxants (d-tubocurarine, pancuronium, and pancuronium and d-tubocurarine combination) was 30 min (95% confidence interval [CI] 8-53). The adjusted difference in mean recovery time between patients receiving vecuronium and those receiving pancuronium (i.e., the single most frequently used drug in each category) was 33 min (95% CI 1-66). Shortened recovery time accounted for an estimated average $37.95 decrease in recovery room charge per patient when vecuronium was used instead of pancuronium, versus a $22.84 increase in drug cost. Our data and analyses support the hypothesis that the use of long-acting muscle relaxants is associated with prolonged recovery after surgery and provide preliminary evidence that restricting the use of the more expensive, shorter-acting muscle relaxants may represent a false economy. IMPLICATIONS: In this retrospective study, the use of old-fashioned, inexpensive, long-acting paralyzing drugs was found to be associated with prolonged postoperative recovery. This has implications when deciding whether, as an economic measure, to restrict the use of the more expensive, shorter-acting paralyzing drugs, because prolonged recovery also has a price.

Dose response, recovery, and cost of doxacurium as a continuous infusion in neurosurgical intensive care unit patients.

OBJECTIVES: To determine the optimal dosing of doxacurium as a continuous infusion in neurosurgical patients with traumatic brain injury; to determine the effects of bolus administration of doxacurium on heart rate (HR), blood pressure (BP), and intracranial pressure (ICP); to monitor neuromuscular recovery after discontinuation of prolonged doxacurium infusion; and to compare the cost of doxacurium with other current neuromuscular blocking drugs. DESIGN: Prospective, open-label study. SETTING: Neurosurgical intensive care unit (ICU) of a university-affiliated teaching hospital. PATIENTS: Eight critically ill, mechanically ventilated patients with traumatic head injury and normal renal and hepatic function. Patients had ICP monitoring. INTERVENTIONS: A bolus injection of doxacurium (0.05 mg/kg) followed by a continuous infusion (0.015 mg/kg/hr), adjusted to maintain one twitch during Train-of-Four nerve stimulation of the adductor pollicis muscle. MEASUREMENTS AND MAIN RESULTS: Bolus injections of doxacurium did not alter the HR, BP, or ICP. Patients were paralyzed 66 +/- 12 (SEM) hrs, with recovery of the fourth twitch occurring 118 +/- 19 mins after infusion of the doxacurium was discontined. There were no incidences of prolonged weakness, myopathy, or other adverse events. CONCLUSIONS: Continuous infusion of doxacurium provides stable neuromuscular blockade for neurosurgical patients with traumatic brain injury. Doxacurium is devoid of clinically important interactions with HR, BP, or ICP and is less costly than other neuromuscular blockers used in the ICU.

Nelfinavir (Viracept) approved: fourth protease inhibitor available.

AIDS: The Food and Drug Administration (FDA) approved nelfinavir (Viracept) for both adult and pediatric use for treatment of HIV infection when antiretroviral therapy is warranted. The drug is the fourth protease inhibitor to gain FDA approval. The recommended dose for adults is 750 mg three times daily, taken with food. The package insert warns of several potential drug interactions, and cautions that the most usual side effect is diarrhea. Developer Agouron Pharmaceuticals has established patient assistance programs to help patients pay for the medication, and are making the drug available through government discount programs.^ieng