Eszopiclone and Zolpidem Do Not Affect the Prevalence of the Low Arousal Threshold Phenotype.

STUDY OBJECTIVES: We sought to determine whether non benzodiazepine sedative hypnotics (NBSH) reduce the occurrence of the low arousal threshold (LAT) phenotype. METHODS: Consecutive patients with suspected obstructive sleep apnea (OSA) referred for polysomnography (PSG) had demographic and PSG data abstracted. LAT was estimated using PSG criteria. After adjusting for pretest probability (PTP) for OSA, we calculated the effect that premedication with NBSHs has on LAT prevalence. RESULTS: Five hundred seventy-nine patients with a mean age and body mass index of 42.2 ± 10.1 y and 28.9 ± 4.5 kg/m2, respectively, had data available for analysis. Most patients (444, or 80.9%) had a LAT, and administering a NBSH (zolpidem or eszopiclone) on the same night as the PSG did not change LAT prevalence (NBSH: 339 (83.3%) versus no drug: 100 (80.6%); p = 0.50). Adjusting for PTP, neither administration of eszopiclone (odds ratio 0.80 (95% confidence interval: 0.33-2.0); 0.69) nor zolpidem (odds ratio 1.65 (95% confidence interval: 0.8-3.5); p = 0.19) reduced the odds that a patient had a LAT. NBSHs did not change the mean SpO2 nadir, percentage hypopneas, or apnea-hypopnea index. There was no association between zolpidem or eszopiclone dosing and SpO2 nadir (zolpidem: ß = -0.69, p = 0.80; eszopiclone: ß = -1.53, p = 0.68), percentage hypopneas (zolpidem: ß = 2.2, p = 0.43; eszopiclone ß = -6.2, p = 0.46), or apnea-hypopnea index (zolpidem: ß = 3.1, p = 0.22; eszopiclone: ß = 2.6, p = 0.39). CONCLUSIONS: The LAT is common in our population and NBSH premedication does not alter its occurrence. Further studies are needed to determine how the LAT can be optimally managed to improve OSA treatment.

Drug-induced liver injury from initial dose of infliximab.

Acute hepatotoxicity secondary to infliximab can occur with or without autoimmunity. A growing body of infliximab drug-induced liver injury cases without autoantibody formation is emerging. Nearly all other reported cases occur after at least three doses. This suggests infliximab may have a direct cytotoxic effect on the liver. We report a case of drug-induced liver injury resulting after an initial dose of infliximab.

Salivary uric acid as a noninvasive biomarker of metabolic syndrome.

BACKGROUND: Elevated serum uric acid is associated with obesity, hypertension and metabolic syndrome. Because a linear relationship exists between serum and salivary uric acid (SUA) concentration, saliva testing may be a useful noninvasive approach for monitoring cardiometabolic risk. The goal of this pilot study was to determine if SUA is increased in patients with metabolic syndrome and to investigate correlations between SUA and individual cardiometabolic risk factors. FINDINGS: Volunteers between the ages of 18 and 65 without conditions known to affect serum uric acid levels were recruited. Height, weight, blood pressure and waist circumference were measured and a full lipid panel along with fasting blood glucose was obtained. Saliva samples were collected and uric acid levels were determined. 78 volunteers, 35% of whom had metabolic syndrome, completed the study. SUA was significantly elevated in patients with metabolic syndrome (p=.002). The incidence of metabolic syndrome in the 4th quartile for SUA was 67% compared to 25% in quartiles1-3 combined. Significant correlations were seen between SUA and systolic blood pressure (r=.440, p=.000), diastolic blood pressure ( r=.304, p=.007), waist circumference (r=.332, p=.003), BMI ( r=.269, p=.018), fasting blood glucose ( r=.341, p=.002), triglycerides (r=.410, p=.000), HDL ( r=.237, p=.036) and the number of cardiometabolic risk factors present (r=0.257, p=.023). CONCLUSIONS: These results suggest that SUA may be a useful biomarker for noninvasive monitoring of cardiometabolic risk. Larger studies are needed to validate this approach.

Detection of homocysteine and C-reactive protein in the saliva of healthy adults: comparison with blood levels.

Inflammation and cardiovascular disease are associated with elevated serum levels of C-Reactive Protein (CRP) and homocysteine. The presence of both molecules in saliva provides an opportunity for development of non-invasive assessments of disease risk. However, salivary CRP and homocysteine reference ranges and their correlation with serum levels are unknown. This study investigated if CRP and homocysteine could be routinely detected in the saliva of healthy adults and the relationship between salivary and blood levels. CRP and homocysteine concentrations were determined using ELISA and enzymatic assays respectively. Homocysteine was detected in only two saliva samples (n = 55). CRP was measurable in all saliva samples (range: 0.05 to 64.3 mug/L; median = 1.2 mug/L) and plasma samples (range: 0.14 to 31.1 mg/L; median = 2.0 mg/L). Regression analysis demonstrated no relationship between CRP concentration in saliva and plasma (R(2) = 0.001). Generalized linear models including variables such as saliva flow rate and time since eating or drinking also did not pass lack of fit testing. Therefore, a relationship between CRP concentration in saliva and blood could not be established in this group of subjects. More sensitive detection methods are needed to determine if a correlation between salivary and serum homocysteine levels exists.

Nonclinical safety profile of telbivudine, a novel potent antiviral agent for treatment of hepatitis B.

Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.

2'-C-Methyl branched pyrimidine ribonucleoside analogues: potent inhibitors of RNA virus replication.

RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.

Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2'-C-methylcytidine.

In our search for new therapeutic agents against chronic hepatitis C, a ribonucleoside analogue, 2'-C-methylcytidine, was discovered to be a potent and selective inhibitor in cell culture of a number of RNA viruses, including the pestivirus bovine viral diarrhea virus, a surrogate model for hepatitis C virus (HCV), and three flaviviruses, namely, yellow fever virus, West Nile virus, and dengue-2 virus. However, pharmacokinetic studies revealed that 2'-C-methylcytidine suffers from a low oral bioavailability. To overcome this limitation, we have synthesized the 3'-O-l-valinyl ester derivative (dihydrochloride form, valopicitabine, NM283) of 2'-C-methylcytidine. We detail herein for the first time the chemical synthesis and physicochemical characteristics of this anti-HCV prodrug candidate, as well as a comparative study of its pharmacokinetic parameters with those of its parent nucleoside analogue, 2'-C-methylcytidine.

Synthesis, physicochemical and pharmacokinetic studies of potential prodrugs of beta-L-2'-deoxycytidine, a selective and specific anti-HBV agent.

beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, beta-L-dC.