First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes.

OBJECTIVE: To evaluate the safety of IDN-6556, a novel anti-apoptotic pan-caspase inhibitor, administered in single and multiple ascending doses in normal volunteers and patients with hepatic dysfunction. MATERIALS AND METHODS: IDN-6556 was administered as a 30-minute intravenous infusion in rising doses to 3 groups: Group A, normal volunteers, given as a single infusion, Group B, normal volunteers, given q.i.d. for 7 days, Group C, patients with hepatic impairment (elevated transaminases, alanine transaminase, ALT and aspartate transaminase, AST), given q.i.d. for 7 days. RESULTS: The drug was well tolerated up to 10 mg/kg/infusion for a single dose, and 1.5 mg/kg/infusion q.i.d. for 7 days, with the dose-limiting adverse event of phlebitis or inflammation at the site of the infusion. This toxicity was predicted from animal studies. Clinically and statistically meaningful dose-related falls in transaminases were seen in all but 1 of the hepatic impaired patients. Two-way ANOVA analyses of the changes for all the IDN-6556 groups combined versus placebo were: ALT absolute change: p < 0.0001 and % change: p = 0.012, AST absolute and % changes: p < 0.0001. After discontinuation of the drug (after 7 days of dosing), the transaminases rapidly returned to the pre-treatment levels. CONCLUSIONS: Following intravenous administration of a novel anti-apoptotic caspase inhibitor, adverse events were mild-to-moderate in severity, resolved in a few days and did not result in any subject terminating treatment prematurely. The effects in hepatic impaired patients appear to be consistent with both the administration and subsequent abrupt withdrawal of an effective hepatoprotective drug that delays cell death in hepatocytes.

Detection of soft-tissue infections and osteomyelitis using a technetium-99m-labeled anti-granulocyte monoclonal antibody fragment.

UNLABELLED: Imaging of osteomyelitis and soft-tissue infections can be problematic with currently available agents; bone scans are often false-positive. Indium-111-oxine and 99mTc-HMPAO white blood cell (WBC) scans require ex vivo handling of blood with potential exposure to infectious agents, and 99mTc-antigranulocyte (IgG1) antibodies need 24 hr for final diagnosis. METHODS: We investigated the use of 99mTc-murine anti-granulocyte monoclonal Fab' fragment in 20 patients with suspected osteomyelitis of soft-tissue infections. All patients also had 99mTc bone scans and 111In-oxine or 99mTc-HMPAO white blood cell scans. The final diagnosis was confirmed by culture, biopsy, surgery, follow-up, x-rays, CT or MRI. In vitro studies performed on granulocytes demonstrated no effect on their function when the anti-granulocyte monoclonal antibody fragment was added. RESULTS: Sensitivity, specificity and diagnostic accuracy to detect infection was 88%, 75% and 80%, respectively. All lesions could be detected as early as 1 hr after injection of the antibody fragment. In comparison, WBC scanning had values of 86%, 78% and 81%, respectively. Some lesions could only be detected 24 hr following the injection of labeled WBCs. LeukoScan had three false-positives and WBC scanning had two false-positives. CONCLUSIONS: Immunoscintigraphy with 99mTc-NCA-90 Fab' fragments offers rapid localization of foci, rapid and simple use, a negligible HAMA response rate, no effect on granulocyte function and an accuracy comparable to WBC scanning.

Prevalence of Chlamydia trachomatis and the genital mycoplasmas in a nonmetropolitan population.

Results of cultures from patients with nonspecific urethritis (NSU) during a 4-year period were retrospectively analyzed. NSU cultures included chlamydiae and mycoplasmas. Seventy-five of 2,408 cultures run by the Missoula Community Hospital microbiology laboratory were positive for chlamydiae (3%). Seventy-five of 1,944 mycoplasma cultures were positive for Mycoplasma hominis (4%), 532 of 1,944 for Ureaplasma urealyticum (27%), and 305 of 1,944, for both (15%), for a total of 46% culture positive for any genital mycoplasma. Results of a prospective study of 40 NSU patients' cultures were tabulated separately. From these 40 patients, no chlamydiae were isolated, but the cultures were 15% positive for M. hominis, 42% positive for U. urealyticum, and 10% positive for both. These studies suggest that the prevalence of chlamydiae may vary with patient population and geographic area. In our population, the mycoplasmas appear to be over 15 times as common (3% vs. 46%).