Celecoxib as adjunctive therapy for treatment of colorectal cancer.

OBJECTIVE: To describe the role of celecoxib as adjunctive therapy in the treatment of familial adenomatous polyposis (FAP), an inherited autosomal dominant predisposition syndrome for colorectal cancer. DATA SOURCES: Literature was evaluated through MEDLINE search (1995-March 2000) and through secondary sources, using the search terms celecoxib, cyclooxygenase-2 inhibitors, and familial adenomatous polyps. DATA SYNTHESIS: Observational studies have found a decreased rate of colorectal cancer in people who regularly took aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). The Food and Drug Administration granted accelerated approval in December 1999 for the NSAID celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, for adjunctive therapy in patients with FAP, based on a six-month, randomized, controlled clinical trial. CONCLUSIONS: Aspirin and other NSAIDs reduce the incidence of colorectal cancer in the general population. Limited clinical studies in patients with FAP using nonaspirin NSAIDs have shown a reduction in polyp burden. A current clinical trial using celecoxib has also shown a reduction in polyp burden in patients with FAP. The long-term clinical impact of using a selective COX-2 inhibitor is not known, since celecoxib has not been studied beyond six months in patients with FAP. By reducing the polyp burden in FAP patients, celecoxib may be useful as adjunctive chemotherapy, in addition to routine endoscopic surveillance and surgery.

Evolution of a neonatal gentamicin dosing protocol in a small community hospital.

The effects of conventional dosage of gentamicin of 2.5 mg/kg given every 12 hours was retrospectively investigated in a small community hospital. Consistent with previous results in large hospitals, the conventional dosage of gentamicin commonly resulted in serum concentrations associated with toxicosis. Results were compared with those obtained prospectively according to a gentamicin dosing protocol that used a formula based on gestational age. The gestational age regimen provided similar peak and significantly lower trough serum concentrations; statistical analysis indicated no demographic differences in the compared groups. Very few neonates who received gentamicin according the gestational age formula were exposed to gentamicin serum concentrations associated with an increased risk of toxicosis. An absence of any significant differences in mean peak and trough serum concentrations in subgroups of neonates treated according to the gestational age formula suggested that use of the gentamicin dosing protocol was appropriate for all neonates. The dose of 3.5 mg/kg used in the gestational age formula was predicted to have resulted in initial gentamicin peak serum concentrations > 5 micrograms/ml in nearly 90% of neonates. The experience obtained with the gestational age formula allowed revision of the gentamicin dosing protocol to provide for more cost-responsible serum concentration monitoring.

Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome.

Feline immunodeficiency virus (FIV), formerly called feline T-lymphotropic lentivirus, causes an immune deficiency in cats that is very similar to the acquired immune deficiency syndrome in humans (N. C. Pedersen, E. M. Ho, M. L. Brown, and J. K. Yamamoto, Science 235:790-793, 1987). We have examined the reverse transcriptase of this virus to determine whether it is similar enough to the reverse transcriptase of the human immunodeficiency virus type 1 (HIV-1) to enable its use as a model for chemotherapy for acquired immune deficiency syndrome. The FIV reverse transcriptase is similar to that of HIV-1 in sensitivity to the noncompetitive inhibitor phosphonoformate (Ki, 0.3 microM) and relative insensitivity to phosphonoacetate. This enzyme was also sensitive to two competitive inhibitors, the 5'-triphosphates of 2', 3'-dideoxythymidine (Ki, 3.4 nM) and 3'-azido-3'-deoxythymidine (AZT; Ki, 6.2 nM). The ratios of Ki/Km for these two competitive inhibitors are similar to the ratios calculated from previously reported data for the HIV-1 enzyme assayed under identical conditions. In contrast, the FIV enzyme is different from the reverse transcriptase of avian myeloblastosis virus in sensitivity to those inhibitors. The replication of FIV in Crandell feline kidney cells was inhibited by AZT; virus production was inhibited more than 95% by 1.0 microM AZT.