Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma.

BACKGROUND: Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914). METHODS: This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 106 cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate. RESULTS: Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5-98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients-most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019). CONCLUSION: The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options. TRIAL REGISTRATION: JapicCTI-183914.

Target-Site Investigation for the Plasma Prolactin Response: Mechanism-Based Pharmacokinetic-Pharmacodynamic Analysis of Risperidone and Paliperidone in the Rat.

To understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semiphysiologically based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). We performed a microdialysis study in rats to obtain detailed plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-glycoprotein (P-gp) functioning on brain distribution, we performed experiments in the absence or presence of the P-gp inhibitor tariquidar (TQD). PK and PKPD modeling was performed by nonlinear mixed-effect modeling. Plasma, brain ECF, and CSF PK values of RIS and PAL were well described by a 12-compartmental semi-PBPK model, including metabolic conversion of RIS to PAL. P-gp efflux functionality was identified on brain ECF for RIS and PAL and on CSF only for PAL. In the PKPD analysis, the plasma drug concentrations were more relevant than brain ECF or CSF concentrations to explain the prolactin response; the estimated EC50 was in accordance with reports in the literature for both RIS and PAL. We conclude that for RIS and PAL, the plasma concentrations better explain the prolactin response than do brain ECF or CSF concentrations. This research shows that PKPD modeling is of high value to delineate the target site of drugs.

Population Pharmacokinetics of Patritumab Deruxtecan in Patients With Solid Tumors.

Patritumab deruxtecan is an antibody-drug conjugate consisting of a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. As part of the pharmacometric analysis informing dose selection for later-stage development, population pharmacokinetics (PK) analysis of patritumab deruxtecan was conducted with pooled serum PK data from patients with HER3-expressing solid tumors (from 3 phase 1/2 studies in breast, lung, and colorectal cancer; N = 425) treated over the dose range of 1.6 to 8.0 mg/kg intravenously every 3 weeks. Population PK modeling for deruxtecan (DXd)-conjugated antibody (representing patritumab deruxtecan) and unconjugated MAAA-1181a (DXd, payload) was carried out sequentially. DXd-conjugated antibody PK was described using a 2-compartment model with parallel linear and nonlinear clearance. Unconjugated DXd PK was described using a 1-compartment model with linear clearance and release of DXd as a first-order, time-dependent function of the level of DXd-conjugated antibody in the central compartment. Preliminary covariate evaluation was conducted for prespecified covariates of pharmacological plausibility and clinical interest. The final model retained weight (on linear clearance and central volume) and albumin level, sex, and tumor type (on linear clearance) for DXd-conjugated antibody, and weight (on release rate constant) and hepatic function (on clearance) for unconjugated DXd. Effects of these covariates on the exposure metrics were generally mild and did not require dose adjustment for subpopulations in subsequent development. Further PK characterization for patritumab deruxtecan will evolve with emerging data.

DS-5670a, a novel mRNA-encapsulated lipid nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2: Results from a phase 2 clinical study.

BACKGROUND: DS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2. METHODS: The study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part. A total of 80 Japanese participants were assigned to receive intramuscular DS-5670a, containing either 30 or 60 µg of mRNA, as two injections administered 4 weeks apart. Safety was assessed by characterization of treatment-emergent adverse events (TEAEs). Immunogenicity was assessed by neutralization titers against SARS-CoV-2, anti-RBD immunoglobulin (Ig)G levels, and SARS-CoV-2 spike-specific T cell responses. Plasma pharmacokinetic parameters of DS-5670a were also evaluated. RESULTS: Most solicited TEAEs were mild or moderate with both the 30 and 60 µg mRNA doses. Four participants (10 %) in the 60 µg mRNA group developed severe redness at the injection site, but all cases resolved without treatment. There were no serious TEAEs and no TEAEs leading to discontinuation. Humoral immune responses in both dose groups were greater than those observed in human convalescent serum; the 60 µg mRNA dose produced better responses. Neutralization titers were found to be correlated with anti-RBD IgG levels (specifically IgG1). DS-5670a elicited antigen-specific T helper 1-polarized cellular immune responses. CONCLUSIONS: The novel mRNA-based vaccine candidate DS-5670a provided favorable immune responses against SARS-CoV-2 with a clinically acceptable safety profile. Confirmatory trials are currently ongoing to evaluate the safety and immunogenicity of DS-5670a as the primary vaccine and to assess the immunogenicity when administered as a heterologous or homologous booster. TRIAL REGISTRY: https://jrct.niph.go.jp/latest-detail/jRCT2071210086.

A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis.

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T­cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open­label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model.

We investigated hepatotoxicity induced by ticlopidine (TIC) in glutathione (GSH)-depleted rats by pre-treatment of a well-known GSH synthesis inhibitor, L-buthionine-S,R-sulfoxinine (BSO). Although sole administration of either TIC or BSO showed no signs of hepatotoxicity, combined administration of TIC with BSO induced hepatotoxicity, which was characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Administration of radio-labeled TIC in combination with BSO resulted in significantly higher covalent binding to rat liver proteins than that observed after sole dosing of radio-labeled TIC. Pre-treatment of 1-aminobenzotriazole, a non-specific inhibitor of P450s, completely suppressed both hepatotoxicity and the increased hepatic covalent binding caused by TIC co-treatment with BSO. The results obtained in this animal model suggest that GSH depletion and covalent binding may be involved in hepatotoxicity induced by TIC. These observations may help to understand the risk factors and the mechanism of hepatotoxicity of TIC in humans.

Metabolism of ticlopidine in rats: identification of the main biliary metabolite as a glutathione conjugate of ticlopidine S-oxide.

We have identified several novel metabolites of ticlopidine, a well known antiplatelet agent and have revealed its metabolic route in rats. The main biliary metabolite of ticlopidine was characterized as a glutathione (GSH) conjugate of ticlopidine S-oxide, in which conjugation had occurred at carbon 7a in the thienopyridine moiety. Quantitative analysis revealed that 29% of the dose was subjected to the formation of reactive intermediates followed by conjugation with GSH after oral administration of ticlopidine (22 mg/kg) to rats. In vitro incubation of ticlopidine with rat liver 9000 g supernatant fraction (S9) fractions led to the formation of multiple metabolites, including 2-oxo-ticlopidine, the precursor for the pharmacologically active ticlopidine metabolite, [1-(2-chlorobenzyl)-4-mercaptopiperidin-(3Z)-ylidene] acetic acid. A novel thiophene ring-opened metabolite with a thioketone group and a carboxylic acid moiety has also been detected after incubation of 2-oxo-ticlopidine with rat liver microsomes or upon incubation of ticlopidine with rat liver S9 fractions.

Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice.

We investigated the hepatotoxicity induced by AQ using a glutathione (GSH)-depleted mice model. Although sole administration of either AQ or L-buthionine-S,R-sulfoxinine (BSO), a well-known GSH synthesis inhibitor, produced no significant hepatotoxicity, combined administration of AQ with BSO induced hepatotoxicity characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Pretreatment of aminobenzotriazole, a nonspecific inhibitor for P450s, completely suppressed the above hepatotoxicity caused by AQ co-treatment with BSO. Administration of radiolabeled AQ in combination with BSO exhibited significantly higher covalent binding to mice liver proteins than that observed after sole dosing of radiolabeled AQ. The results obtained in this GSH-depleted animal model suggest that the reactive metabolite of AQ formed by hepatic P450 binds to liver proteins, and then finally leads to hepatotoxicity. These observations may help to understand the risk factors and the mechanism for idiosyncratic hepatotoxicity of AQ in humans.

Are 1994 alcohol production and the sales deregulation policy in Japan associated with increased road traffic fatalities among adult and teenage males and females in Japan?

INTRODUCTION: International studies have shown a significant association between alcohol availability and traffic crashes that involve alcohol-impaired drivers. A key limitation to previous alcohol availability and motor vehicle crash (MVC) evaluation research is the assumption of population homogeneity in responding to the policies. The present analysis focuses on the evaluation of the impact of alcohol availability on different segments of the Japanese population by comparing MVC fatality rates from before and after implementation of the alcohol deregulation policy in 1994. SUBJECTS AND METHOD: Poisson regression with robust standard error was used to model the before-to-after change in incidence rate ratios (IRR) in adult males, adult females, teenage males and teenage females. To control potential confounders, unemployment rate, vehicle miles of travel (VMT), vehicle registration, and number of drivers licensed in Japan were added to the model. The exponents of the fitted coefficients are equivalent to incidence rate ratios. RESULTS: Implementation of the policy deregulating alcohol sales and production did not appear to increase traffic fatalities among adult or teenage males or females in Japan. We found that male adult fatalities demonstrated a statistically significant decline following enactment of the deregulation policy in 1994. DISCUSSION: Contrary to previous research, the findings of this study demonstrated lower rates of fatalities and higher compliance with alcohol-related driving legislation in Japanese society following implementation of the deregulation policy in 1994. Further well designed, nonaligned studies on alcohol availability and traffic fatalities in other countries are urgently needed.

Inhibition of ocular angiogenesis by diced small interfering RNAs (siRNAs) specific to vascular endothelial growth factor (VEGF).

The effects of diced small interfering RNAs (siRNAs) designed for vascular endothelial growth factor (VEGF) on the expression of VEGF in human retinal pigment epithelial cell line ARPE-19 cells in vitro and on corneal angiogenesis in vivo were examined. The exposure to diced siRNAs significantly reduced the VEGF mRNA expression in ARPE-19 cells with minimal toxicity. In suture-induced corneal angiogenesis models, diced siRNAs minimized the severity of angiogenesis. Histological analysis displayed no particular tissue damage in the conjunctiva where siRNA was injected. The approach using diced siRNAs can be a new tool for various neovascular ocular diseases.

Impact of lowering the legal BAC limit to .03 on teenage drinking and driving related crashes in Japan.

In June of 2002, a revision to part of the Road Traffic Act drastically increased the penalties for drinking and driving offences. Most notably, the legal BAC limit for driving lowered from 0.05 mg/ml to 0.03 mg/ml. The rationale for the new lower BAC limit in Japan was predicated on the assumption that drinking drivers will comply with the new lower limit by reducing the amount of alcohol they consume prior to driving, thereby lowering their risk of crash involvement. This, in turn, would lead to fewer alcohol-related crashes, deaths and injuries. The chief objective of this research is to quantify the extent to which lowering the legal limit of BAC has reduced teenager involved motor vehicle injuries and fatalities in Japan since 2002. Most notably, the introduction of reduced BAC limit legislation resulted in a statistically significant decrease in the number of alcohol impaired young drivers on the road in Japan, indicating responsiveness to the legal change among this group. Since the introduction of the 0.03 BAC law, statistically significant decreases were observed in alcohol-related crashes, alcohol related injuries and single vehicle night time crashes among 16-19 year old drivers, as we hypothesized. In comparison, the rates of total crashes, injuries and pedestrian fatalities showed no statistically significant decline or increase in the period following the introduction of the BAC law.

SNF2H interacts with XRCC1 and is involved in repair of H2O2-induced DNA damage.

The protein XRCC1 has no inherent enzymatic activity, and is believed to function in base excision repair as a dedicated scaffold component that coordinates other DNA repair factors. Repair foci clearly represent the recruitment and accumulation of DNA repair factors at sites of damage; however, uncertainties remain regarding their organization in the context of nuclear architecture and their biological significance. Here we identified the chromatin remodeling factor SNF2H/SMARCA5 as a novel binding partner of XRCC1, with their interaction dependent on the casein kinase 2-mediated constitutive phosphorylation of XRCC1. The proficiency of repairing H2O2-induced damage was strongly impaired by SNF2H knock-down, and similar impairment was observed with knock-down of both XRCC1 and SNF2H simultaneously, suggesting their role in a common repair pathway. Most SNF2H exists in the nuclear matrix fraction, forming salt extraction-resistant foci-like structures in unchallenged nuclei. Remarkably, damage-induced formation of both PAR and XRCC1 foci depended on SNF2H, and the PAR and XRCC1 foci co-localized with the SNF2H foci. We propose a model in which a base excision repair complex containing damaged chromatin is recruited to specific locations in the nuclear matrix for repair, with this recruitment mediated by XRCC1-SNF2H interaction.

Crystal structure of family GH-8 chitosanase with subclass II specificity from Bacillus sp. K17.

Crystal structures of chitosanase from Bacillus sp. K17 (ChoK) have been determined at 1.5 A resolution in the active form and at 2.0 A resolution in the inactive form. This enzyme belongs to the family GH-8, out of 93 glycoside hydrolase families, and exhibits the substrate specificity of subclass II chitosanase. The catalytic site is constructed on the scaffold of a double-alpha(6)/alpha(6)-barrel, which is formed by six repeating helix-loop-helix motifs. This structure is quite different from those of the GH-46 chitosanases and of GH-5. Structural comparison with CelA (a cellulase belonging to the same family GH-8) suggests that the proton donor Glu122 is conserved, but the proton acceptor is the inserted Glu309 residue, and that the corresponding Asp278 residue in CelA is inactivated in ChoK. The four acidic residues, Asp179, Glu309, Asp183 and Glu107, can be involved in substrate recognition through interactions with the amino groups of the glucosamine residues bound in the -3, -2, -1 and +1 sites, respectively. The hydrophobic Trp235, Trp166, Phe413 and Tyr318 residues are highly conserved for binding of the hexose rings at the -3, -2, +1 and +2 sites, respectively. These structural features indicate that enzymes in GH-8 can be further divided into three subfamilies. Different types of chitosanases are discussed in terms of convergent evolution from different structural ancestors.

[Social networks in drinking behaviors among Japanese: support network, drinking network, and intervening network].

PURPOSE: The national representative sample was analyzed to examine the relationship between respondents' drinking practice and the social network which was constructed of three different types of network: support network, drinking network, and intervening network. METHOD: Non-parametric statistical analysis was conducted with chi square method and ANOVA analysis, due to the risk of small samples in some basic tabulation cells. RESULTS: The main results are as follows: (1) In the support network of workplace associates, moderate drinkers enjoyed much more sociable support care than both nondrinkers and hard drinkers, which might suggest a similar effect as the French paradox. Meanwhile in the familial and kinship network, the more intervening care support was provided, the harder respondents' drinking practice. (2) The drinking network among Japanese people for both sexes is likely to be convergent upon certain types of network categories and not decentralized in various categories. This might reflect of the drinking culture of Japan, which permits people to drink everyday as a practice, especially male drinkers. Subsequently, solitary drinking is not optional for female drinkers. (3) Intervening network analysis showed that the harder the respondents' drinking practices, the more frequently their drinking behaviors were checked in almost all the categories of network. A rather complicated gender double-standard was found in the network of hard drinkers with their friends, particularly for female drinkers. Medical professionals played a similar intervening role for men as family and kinship networks but to a less degree than friends for females. CONCLUSION: The social network is considerably associated with respondents' drinking, providing both sociability for moderate drinkers and intervention for hard drinkers, depending on network categories. To minimize the risk of hard drinking and advance self-healthy drinking there should be more research development on drinking practice and the social network.

[Drinking and domestic violence: findings from clinical survey of alcoholics].

The purpose of this paper is to analyze the domestic violence in the families of alcoholics. We examined the actual state of domestic violence in alcoholics' families and compared this whith a national representative sample. The results are as follows: (1) Domestic violence in families of alcoholics is serious. (2) In such families, 63.5% of wives had been injured as a result of physical violence by the husband. (3) In 86.6% of such incidents, the husband or the woman herself had been drinking. (4) Physical, social and economical violence leads to the breakdown of marital relationships. (5) After alcoholics give up drinking, their levels of domestic violence are reduced.

Political economy of tobacco control policy on public health in Japan.

Tobacco use, particularly smoking, remains the number one cause of preventable disease and mortality in Japan. This review of the tobacco control policy and public health is the first to offer a composite review of the subject within Japan. This review attempts to evaluate the most important aspects of the current political economy of the tobacco control policy, and concludes that more effective control policies must be employed to minimize the impact of smoking on the public's health in Japan. Further the article attempts to place the approaches in the larger context of tobacco control, providing a vision for the future of tobacco prevention and control based on current knowledge. Tobacco use will remain the leading cause of preventable illness and death in Japan, until tobacco prevention and control efforts are commensurate with the harm caused by tobacco. Taken together, the results of various studies have clearly shown that control measures can influence tobacco smoking patterns, and in turn, the rate of tobacco-related problems. Government tobacco taxes have not kept pace with inflation for years. Availability of tobacco is virtually unlimited with easy access and the prices being very low due to the strong currency of Japan. Thus Japan must be one of the most tobacco accessible countries. It is important to ensure that people are not conditioned to smoke tobacco by an unduly favourable economic and commercial environment. For that reason, prevention advocates have called for substantial regulation of tobacco products and appeal for both tobacco tax increases and tobacco taxes to be indexed to inflation. In this review, present tobacco related public health policies in Japan are discussed with implication for prevention of tobacco related problems. Continued research in this area will be necessary to determine the most effective policies of reducing tobacco related problems in Japan.

[Drinking practice and alcohol-related problems: the national representative sample survey for Healthy Japan 21].

This article is the first survey report in Japan concerning the adult drinking behaviors and its overall alcohol-related problems based on a national representative sample. It deals with a wide range of alcohol topics such as frequency, volume, cultural aspects, social influence and its effect on individuals, both positive and negative as well as various other alcohol related problems. The report identified, for further implementation of Japan's national health program, "Healthy Japan 21", the following areas of focus; 1) 5% of males and 0.5% of females who are considered "Hard Drinker", the most prioritized target. Seemingly small portion of females, 0.5%, is far beyond the planned goal level. 2) The cultural and regional competency is highly expected for policy discussion and evaluation in order to decrease the hard drinker population by 20% off. 3) Clarify the definition of a "Hard drinker" and disseminate the information publicly for functional health monitoring activity by local governments.

[Adolescents alcohol related traffic accidents and mortality in 1999-2000--problem and solutions].

There are a number of factors that give traffic accidents and injuries a prominent position among public health agenda. Injuries, major public health challenge throughout the world and which account for 10% of global mortality, are often ignored as a major cause of death and may require innovative strategies to reduce their toll. Traffic accidents prevention traditionally have been as the domain of law enforcement, societal responses have primarily been a repressive or containment nature. The role of the health sector has tended to be limited to one of treatment and disability prevention, or in other words, damage control. Global Status Report on alcohol use 2001 revealed that drinking has risen steadily among young people in Japan and children between the ages of 13 and 17 have drunk to intoxication or unconsciousness. It also appears that young people in Japan are beginning to drink at earlier ages, while research has found earlier initiation of alcohol use to be associated alcohol dependence and alcohol related injury in later in life. Motor vehicle traffic accidents are a leading cause of death among children, adolescents and young adults between 16 and 20 years of age even though high school students were prohibited from having drivers licenses by internal school rules, this age group was the primary responsible party for 30% of accidents and fatal accidents in 2000. This underlies the fact that how significant role they play as a contributors to the overall traffic problem in Japan. Unlike major causes of deaths such as cancer and heart diseases and despite the critical problem in public health, there are few epidemiological studies on youth involvement in traffic accidents, morbidity and mortality in Japan.

International policies on alcohol impaired driving: are legal blood alcohol concentration (BAC) limits in motorized countries compatible with the scientific evidence?

Borkenstein et al. (1974) study indicated that drivers with BACs of 0.05 to 0.09 per cent were twice as likely to crash as drivers with a zero BAC. Drivers with BACs from 0.10 to 0.14 per cent were ten times as likely to have a fatal crash in 1964. There have been numerous efforts during the history of motorized countries to control the consumption of alcohol and the problems associated with it through legislative mandate, it was not until the 1970s that acceptance of legal BAC (Blood Alcohol Concentration) limits laws became widespread. In particular, as more and more people drive automobiles, the number of traffic accidents involving drunken drivers has soared, and many of these are known to be related to the consumption of alcohol. Thus, legislators find themselves under increasing pressure to find a reasonable and fair solution to the question of alcohol impaired driving, as the scientific evidence about alcohol consumption level and psycho motor functions impairment came to clear. A landmark event in the development of policies regarding impaired driving was the establishment of the fact that consumption of alcohol does, in fact, increase the probability of traffic crashes. Legal limit laws specify a maximum permissible BAC limit for drivers. Currently, a BAC laws range from zero tolerance and 0.02 to 0.10% constitutes prima facie evidence in most countries for 'Driving under Influence of Alcohol.' This latter standard is too permissive, as driving skills deteriorate and crash involvement risk increases beginning at 0.02%. There are consequences attached to setting a BAC limit so high that a 72 kg man can drink five bottles of beer and still be under legal limit. In this sense high legal BAC limit may influence people to make bad estimates of their relative risk of injury or death while driving. Provided there is adequate political will, millions of lives could be saved in the coming years. This review is an attempt to examine in detail the available information about legal BAC limit laws, and issue of considerable interest to both policy makers and the public.

Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.

Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain.