A quantitative assessment of depression and thyroid dysfunction secondary to interferon-alpha therapy in patients with hepatitis C.

The most effective treatment for hepatitis C virus (HCV) is interferon-alpha (IFN) therapy in combination with ribavirin. Although symptoms of depression are among the most common side effects of IFN therapy in treating patients with HCV, the mechanisms by which IFN produces these neuropsychiatric side effects remain unclear. In the brain, IFNs are involved in a number of regulatory functions, including but not limited to regulation of the endocrine system via the hypothalamic-pituitary-adrenal and -thyroid axes. The purpose of this study was to assess the effect of IFN therapy on thyroid function and to characterize the relationship between thyroid dysfunction and major depressive disorder during IFN therapy in patients with hepatitis C. Thirty-three patients with HCV were administered the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Axis I Disorders (SCID) and completed the Beck Depression Inventory (BDI). Patients were on IFN for an average of 6 to 12 months depending on their viral genotype. Serum samples were collected at baseline, during and after IFN therapy, and measured for free thryoxine (FT4) and TSH levels. Patients who developed IFN-induced depression were treated with selective serotonin reuptake inhibitor antidepressants. Only one patient developed transient IFN-induced overt hypothyroidism, but he did not develop depression. Analysis of variance showed that there were no significant differences in either FT4 or TSH serum levels between patients who developed major depressive disorder (MDD) (no.= 10) during IFN therapy and those who did not (no.=23). These results illustrate the frequency and severity of depressive symptoms associated with IFN therapy and the apparent absence of a relationship between IFN-induced MDD and changes in thyroid function.

Assessment of accuracy and analysis time of a novel device to monitor sleep and breathing in the home.

Obstructive sleep apnea is increasingly recognized as a common and debilitating disorder. As a result, a variety of diagnostic technologies have evolved to potentially decrease cost and improve access and ease of assessment. In this study we compared the Healthdyne NightWatch (NW) System (a home sleep diagnostic methodology) to standard polysomnography (PSG) in two sleep centers. Two separate studies were completed. NW was compared to a simultaneously obtained PSG in 30 patients (IN-LAB study). Seventy additional patients were studied in both the home with NW and in the laboratory with PSG (HOME-LAB study). The NW system records eye movement, leg movement, SaO2, nasal-oral airflow, chest and abdominal wall motion, body position and heart rate on a solid state recorder, which permits sleep staging based on body and eye movement and standard respiratory assessment. For the PSG, standard paper recording techniques were used. The IN-LAB study revealed a correlation between NW and PSG for total sleep time of r = 0.72, with NW tending to score some awake time as nonrapid eye movement sleep. The correlation for apnea-hypopnea index (AHI) was r = 0.94 between systems, with a sensitivity of 100% and specificity of 63.6% at an AHI threshold of 10. The HOME-LAB study demonstrated understandably poor correlations between NW and PSG for most measures of sleep, which is likely a product of night-to-night variability in sleep, home versus laboratory effects and the differences in sleep staging methodology. However, the correlation for AHI was r = 0.92, with a sensitivity of 90.7% and a specificity of 70.4% at an AHI threshold of 10. Using a new methodology to assess agreement between diagnostic systems, we observed 78.6% diagnostic agreement between NW and PSG in the HOME-LAB study, with NW underestimating AHI 4.3% of the time and overestimating it in 17.1% of cases. This may relate to night-to-night variability in AHI or greater NW computer sensitivity to subtle hypopneas. We conclude that NW provides an accurate determination of AHI in both the home and laboratory, using limited instrumentation. The analysis time for NW is also reduced compared to PSG, and patients generally prefer the NW evaluation.

Pharmacokinetics and metabolism of inhaled methyl chloride in the rat and dog.

Methyl chloride (MeCl) metabolism and pharmacokinetics were studied in male Fischer 344 rats and male beagle dogs. Apparent steady-state blood MeCl concentrations were proportionate to exposure concentration in rats and dogs exposed to 50 and 1000 ppm. Furthermore, blood MeCl concentrations were similar in both species when they were exposed to the same concentration. A linear two-compartment open model described the blood MeCl data: alpha and beta phase elimination half-times corresponded to approximately 4 and 15 min, respectively, in rats, and 8 and 40 min in dogs. Rats exposed for 6 hr to 0, 50, 225, 600, or 1000 [14C]MeCl were evaluated for tissue nonprotein sulfhydryl (NPSH), total 14C activity, nonextractable tissue 14C activity, and urinary metabolites. MeCl-induced NPSH depletion was dose-related and was greatest in liver. Total 14C in liver and kidney was approximately proportionate to exposure concentrations. Relative concentrations of nonextractable 14C decreased at 600 to 1000 ppm MeCl suggesting a dose-dependent metabolic pathway for MeCl in the rat. Metabolites in urine included N-acetyl-S-methylcysteine, methylthioacetic acid sulfoxide, and N-(methylthioacetyl)glycine. These metabolites are likely to be products of a reaction between MeCl and glutathione. A nonradiometric analysis of a putative MeCl metabolite (S-methylcysteine) was performed in dogs exposed to MeCl; this method was not a sensitive indicator of MeCl exposure.

Ethyl chloride: a two-week inhalation toxicity study and effects on liver non-protein sulfhydryl concentrations.

Male and female Fischer 344 rats (6/sex/exposure concentration) and male beagle dogs (2/exposure concentration) exposed to 0, 1600, 4000 or 10 000 ppm ethyl chloride (EtCl) for 6 hr/da, 5 da/wk for 2 weeks showed no toxicologically significant treatment-related effects on body weights; clinical chemistry, hematology, or urinalysis parameters; neurology (dogs only were examined); gross pathology or histopathology. The only treatment-related differences in organ or relative organ weights (in rats or dogs) were slight, but statistically significant increases in liver to body weight ratios of male rats exposed to 4000 or 10,000 ppm EtCl (4.9 and 7.5% respectively). Liver non-protein sulfhydryl (NPSH) concentration was measured in male Fischer rats and male B6C3F1 mice that were exposed for 6 hours to 0, 1600, 4000 or 10,000 ppm EtCl (mice were exposed to 0 or 4000 ppm EtCl only). Liver NPSH, measured 1/2 hr post exposure, was less than control values in 4000 ppm exposed rats (88% of control value), 4000 ppm exposed mice (64%), and 10,000 ppm exposed rats (89%). The slight decreases in rat liver NPSH seem consistent with the increased liver to body weight ratios. The toxicity data indicate that 2-week repeated exposures to EtCl concentrations that were up to 10 times the current A.C.G.I.H. T.L.V. (1000 ppm) caused minimal treatment-related effects in dogs and rats.