Comparative effects of different doses of ribavirin plus interferon-alpha2b for therapy of chronic hepatitis C: results of a controlled, randomized trial.

Compared to either drug alone, therapy with the combination of ribavirin and interferon-alpha leads to improved rates of response in patients with chronic hepatitis C. Side effects often mandate downward dose adjustment or cessation of therapy, and the optimal dose of ribavirin has not been established. The aim of this study was to learn whether 600 mg ribavirin per day would prove as efficacious as 1,000-1,200 mg/day when combined with interferon (3 million units thrice weekly) for therapy of patients previously treated with standard interferon who had failed to respond or who had relapsed. We enrolled 69 patients with chronic hepatitis C and compensated liver disease: 45 were men, 65 were Caucasian, 48 were infected with genotype 1 hepatitis C virus. By random assignment, 35 received 600 mg ribavirin/day (group A), whereas the other 34 received 1,000 mg (< or = 75 kg body wt) or 1,200 mg/day (>75 kg body wt) (group B). At baseline, the two groups were well matched for demographic and laboratory features. In both groups, mean serum levels of alanine aminotransferase (ALT) and hepatitis C viral (HCV) RNA levels fell promptly and remained significantly lower than baseline throughout 24 weeks of therapy. There was no significant difference in mean levels of ALT or HCV RNA during therapy or at the end of follow-up (24 weeks after cessation of therapy). At the end of 24 weeks of posttherapy follow-up, 12 patients in each group had undetectable HCV RNA in serum, whereas 11 (31%) in group A and 9 (26.5%) in group B had normal serum ALT levels. The lower doses of ribavirin (group A) were tolerated better. In conclusion, in previous nonresponders or relapsers to interferon done, combination therapy with interferon-alpha2b (3 MU thrice weekly) + 600 mg ribavirin/day is tolerated better and is as effective as interferon plus higher (standard) doses of ribavirin (1,000-1,200 mg/day).

Secretory villous adenomas that cause depletion syndrome.

Secretory villous adenomas of the colon have been known to cause a depleting syndrome characterized by dehydration, prerenal azotemia, hyponatremia, hypokalemia, metabolic acidosis, obtundation, and, in severe cases, death. We describe 1 case of classic depleting syndrome and review the literature on possible mechanisms. Both cyclic adenosine monophosphate and prostaglandin E2 have been implicated as possible secretagogue compounds in the pathogenesis of this syndrome unique to the secretory variant form of villous adenomas. Indomethacin as a prostaglandin inhibitor has been used with apparent benefit in controlling the volume of rectal effluent in patients with secretory villous adenomas.

A calcium antagonist drug binding site in skeletal muscle sarcoplasmic reticulum: evidence for a calcium channel.

The sarcoplasmic reticulum (S.R.) of rabbit skeletal muscle has been found to contain a single, high affinity binding site for the Ca antagonist drug [3H]-nitrendipine. Two subfractions of the reticulum were studied, the heavy (HSR) and light (LSR) preparations, which exhibited similar nitrendipine equilibrium dissociation constants (KD) of 1nM. Crude cardiac and brain membranes assayed under the same conditions exhibited KD values of 0.2-0.3nM. The concentration of binding sites per mg. protein (Bmax) in HSR was found to be very high, namely 6.7 picomoles/mg, some four times greater than that of LSR. [3H]-nitrendipine binding to HSR was reversible and inhibited by the Ca antagonists flunarizine and verapamil, and by the intracellular Ca release antagonist TMB-8 (8-diethylamino-octyl 3,4,5-trimethylbenzoate hydrochloride). However, unlabelled nitrendipine at 2 X 10(-5)M had no effect on contraction of isolated electrically stimulated rabbit lumbrical or rat diaphragm muscles, nor did it affect the neuromuscular junction as studied in rat phrenic nerve-diaphragm preparations. Also, little effect of 2 X 10(-5)M nitrendipine was seen on net 45Ca uptake by HSR. These results suggest that [3H]-nitrendipine binding to skeletal muscle S.R. resembles that of brain membranes, which also contain a high affinity binding site for [3H]-nitrendipine and which similarly are pharmacologically insensitive to this dihydropyridine type of Ca channel blocking agent. Since HSR is also enriched in calsequestrin and terminal cysternae from which Ca is released in vivo, it seems likely that the [3H]-nitrendipine binding sites in S.R. are associated with Ca channels in the S.R.