Early use of donepezil against psychosis and cognitive decline in Parkinson's disease: a randomised controlled trial for 2 years.

OBJECTIVES: Brain acetylcholine is decreased even in patients with cognitively preserved Parkinson's disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients. METHODS: A double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson's Psychosis Questionnaire (PPQ) B score ≥2 or C score ≥2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein ε4 genotyping. RESULTS: Kaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11-0.86) against psychosis in 48 weeks for apolipoprotein ε4 non-carriers. CONCLUSIONS: Although donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein ε4 may suppress the antipsychotic effect of donepezil. TRIAL REGISTRATION NUMBER: UMIN000005403.

Pharmacokinetics of caffeine self-administered in overdose in a Japanese patient admitted to hospital.

BACKGROUND: Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. CASE PRESENTATION: A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 µg/mL, 81 and 9.9 µg/mL, 63 and 12 µg/mL, and 21 and 14 µg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. CONCLUSIONS: The patient underwent infusion with bicarbonate Ringer's solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose.

Evaluation of the antiviral activity of chlorine dioxide and sodium hypochlorite against feline calicivirus, human influenza virus, measles virus, canine distemper virus, human herpesvirus, human adenovirus, canine adenovirus and canine parvovirus.

We evaluated the antiviral activity of a chlorine dioxide gas solution (CD) and sodium hypochlorite (SH) against feline calicivirus, human influenza virus, measles virus, canine distemper virus, human herpesvirus, human adenovirus, canine adenovirus and canine parvovirus. CD at concentrations ranging from 1 to 100 ppm produced potent antiviral activity, inactivating >or= 99.9% of the viruses with a 15 sec treatment for sensitization. The antiviral activity of CD was approximately 10 times higher than that of SH.

Inactivation of feline calicivirus, a norovirus surrogate, by chlorine dioxide gas.

The efficacy of gaseous chlorine dioxide (ClO2) against feline calicivirus (FCV), a norovirus surrogate, in the dry and the wet states on a hard surface was evaluated. We demonstrated that low-concentration ClO2 gas (mean 0.08 ppm, 0.22 microg/I) could inactivate FCV in the wet state with 0.5% fetal bovine serum (FBS) within 6 h in 45 to 55% relative humidity (RH) (> 3 log10 reductions) and FCV in the dry state with 2% FBS (percentage of FBS in the viral suspension) within 10 h in 75 to 85% RH (> 3 log10 reductions) at 20 degrees C, respectively. Furthermore, a < 0.3 ppm concentration of ClO2 gas (mean 0.26 ppm, 0.73 microg/l) could inactivate (below the detection limit) FCV in the dry state with 5% FBS within 24 h in 75 to 85% RH at 20 degrees C. In contrast, in 45 to 55% RH at 20 degrees C, ClO2 gas had little effect even when the FCV in the dry state was exposed to high-concentration ClO2 (mean 8 ppm, 22.4 microg/l) for 24 h. These results suggest that humidity plays an important role in the inactivation by ClO2 gas of FCV in the dry state. According to the International Chemical Safety Card, threshold limit values for ClO2 gas are 0.1 ppm as an 8-h time-weighted average and 0.3 ppm as a 15 min short-term exposure limit. From these data, we propose that the treatment of wet areas of human activity such as kitchens, toilets, etc., with low-concentration ClO2 gas would be useful for reducing the risk of infection by noroviruses (NV) without adverse effects. In addition, we believe that the application of a combination of a < 0.3 ppm concentration of ClO2 gas and a humidifier in places without human activity may make it possible to inactivate NV in the dry state on any surface within a contaminated room without serious adverse effects.

[Inhibition of hyphal growth of the fungus Alternaria alternata by chlorine dioxide gas at very low concentrations].

The efficacy of chlorine dioxide (ClO(2)) gas at very low concentrations for hyphal growth of Alternaria alternata related to fungal allergy was evaluated using a fungus detector. The fungus detector is a plastic sheet with a drop of spore-suspending medium, and it makes possible clear observations of hyphal growth with a light microscope. ClO(2) gas (average 0.075 ppm, 0.21 microg/l) inhibited hyphal growth of the fungus, but not germination of fungal spores. The hyphal length was more than 1780 mum under air conditions (control) and 49+/-17 microm under ClO(2) gas conditions for 72 h. According to the international chemical safety card, threshold limit values for ClO(2) gas are 0.1 ppm as an 8-h time-weight average and 0.3 ppm as a 15 min short-term exposure limit. From these data, we propose that treatment with ClO(2) gas at very low concentrations in space is a useful tool for the growth inhibition of fungi in the fields of food, medicine, etc. without adverse effects.

Chlorine Dioxide is a Better Disinfectant than Sodium Hypochlorite against Multi-Drug Resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii.

In this study, we evaluated and compared the antibacterial activity of chlorine dioxide (ClO2) and sodium hypochlorite (NaClO) on various multidrug-resistant strains in the presence of bovine serum albumin and sheep erythrocytes to mimic the blood contamination that frequently occurs in the clinical setting. The 3 most important species that cause nosocomial infections, i.e., methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa (MDRP), and multidrug-resistant Acinetobacter baumannii (MDRA), were evaluated, with three representative strains of each. At a 10-ppm concentration, ClO2 drastically reduced the number of bacteria of all MDRP and MDRA strains, and 2 out of 3 MRSA strains. However, 10 ppm of NaClO did not significantly kill any of the 9 strains tested in 60 seconds (s). In addition, 100 ppm of ClO2 completely killed all MRSA strains, whereas 100 ppm of NaClO failed to significantly lower the number of 2 MRSA strains and 1 MDRA strain. A time-course experiment demonstrated that, within 15 s, 100 ppm of ClO2, but not 100 ppm of NaClO, completely killed all tested strains. Taken together, these data suggest that ClO2 is more effective than NaClO against MRSA, MDRP, and MDRA, and 100 ppm is an effective concentration against these multidrug-resistant strains, which cause fatal nosocomial infections.

[Inactivation of feline calicivirus by chlorine dioxide gas-generating gel].

Noroviruses are one of the most important causes of acute gastroenteritis throughout the world. The aim of this study is to evaluate the efficacy of a chlorine dioxide gas-generating gel (ClO2 gel, 60 g) against feline calicivirus (FCV), a norovirus surrogate, in the wet state on glass dishes in a test sink (43 cm long, 75 cm wide, and 29 cm deep). The ClO2 gel permits sustained release of gaseous ClO2 (1.7 mg/h at 25°C), and was placed in one corner of the test sink. The glass dishes containing FCV suspension were placed at three positions in the test sink. We demonstrated that FCV was inactivated within 5h (>2 or >3 log10 reductions at three positions, n=20) in the test sink where the ClO2 gel was placed. These small quantities of ClO2 gel might be a useful tool for reducing the risk of infection by norovirus in wet environments such as kitchens and bathrooms under optimal condition.