Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.     

To be or not to be: Future lives in economic evaluation

Sometimes healthcare will affect the health of people living in the future, or their chance of coming into existence. Should such outcomes be valued in health-economic evaluation? Guidelines implicitly recommend their inclusion but this rule has counterintuitive implications and is not consistently applied in practice. We suggest making a distinction between “necessary” and “potential” future lives in Health Technology Assessment. Necessary lives will exist independent of our healthcare choices and should be included. Potential lives are choice-dependent and should be excluded. This rule offers intuitive solutions within the HTA framework, and it changes the cost-effectiveness of several interventions where necessary future lives are affected.     

Autologous chondrocyte implantation versus microfracture for knee cartilage injury: a prospective randomized trial, with 2-year follow-up

The objective was to evaluate the functional performance over a 2-year period following autologous chondrocyte implantation (ACI) in an open knee procedure compared to microfracture. Objective functional outcome was studied as secondary analysis in a subgroup of patients, in a randomized clinical trial, with concealed allocation and independent evaluators. Sixty-seven patients with local cartilage defect, with a mean size of 2.4 cm2 (SD 1.5) of the femoral condyle of the knee were included. Thirty-three patients underwent the microfracture and 34 the ACI procedure. An identical rehabilitation protocol was implemented for both groups. Active knee flexion and extension range, anterior laxity, knee extension strength (concentric at 60°/s) and single leg hop performance (single hop, crossover triple hop and 6 m timed hop test) were evaluated pre-surgery and at 6, 9,12 and 24 months post-surgery. We calculated the symmetry index for individual and four performance tests pooled. Mixed linear model analyses were used with confidence interval set at 95%. The change over 2 years for the pooled performance-based tests was comparable between the two treatment arms. At 2 years, 70% (38/54) of all patients returned to >85% symmetry in overall functional performance. A decrease in functional performance at 6 months following ACI resulted in slower recovery at 9 and 12 months compared to microfracture. Rehabilitation following both cartilage repair procedures is a lengthy process. At 2 years after surgery, ACI patients have similar overall functional outcome compared to microfracture patients.     

Ankylosing enthesitis, dactylitis, and onychoperiostitis in male DBA/1 mice: a model of psoriatic arthritis

OBJECTIVES: To further characterise spontaneous arthritis in aging male DBA/1 mice as a model of spondyloarthropathy and psoriatic arthritis with particular attention to signs of inflammation and nail involvement. MATERIALS AND METHODS: Aging male DBA/1 mice from different litters were caged together (4-6 mice per cage) at the age of 12 weeks, checked twice a week for signs of arthritis, and killed at different times. Hind paws were dissected and processed for histology. RESULTS: Disease incidence varied between 50% and 100% in four different experiments. Besides clinical signs of arthritis, nail abnormalities were noticed. Pathological examination showed the occurrence of dactylitis characterised by diffuse neutrophil infiltration in 6 of 50 paws examined. Onycho-periostitis with progressive destruction of the nail bed and the underlying distal phalanx was seen in 5 of 50 paws examined. CONCLUSIONS: Although dactylitis and onychoperiostitis are rare manifestations of the disease process, these data strongly suggest that spontaneous arthritis in aging male DBA/1 mice shares important features with human psoriatic arthritis. This model may therefore be an important tool to study links between stress, sex, inflammation, and new bone formation with particular relevance to human psoriatic arthritis.     

Peripheral blood T lymphocyte subpopulations determined by monoclonal antibodies in active rheumatoid arthritis

The introduction of an automated flow cytofluorograph has facilitated the detection of T lymphocyte subsets because it enables a larger number of cells to be analyzed. Many authors have reported a decrease of cytotoxic/suppressor T lymphocytes in rheumatoid arthritis (RA), in contrast to the results of other workers. We believe that the discrepancy between the various studies is due to the fact that different methods and different criteria for patient selection were used. Our study comprised a larger number of patients which makes the results suitable for statistical inference. Disease activity is clearly defined and all drugs that could alter the results were excluded. The use of a flow cytometer enhances the reliability of T lymphocyte subset determination by monoclonal antibodies (OKT series). Our study confirms the reports, which suggested that the number of suppressor/cytotoxic T lymphocytes (OKT8+ cells/mm3) is decreased in patients with active RA, resulting in a high T helper/inducer lymphocyte/T suppressor/cytotoxic lymphocyte ratio (OKT4+:OKT8+). This immune balance represents an interesting feature of the disease, since several active antirheumatic drugs share a common immunomodulatory action, which normalizes the OKT4+:OKT8+ ratio. Finally, we found a good correlation between the OKT4+ cells and OKT8+ cells in the normal control population. This observation enabled us to isolate a subgroup of active patients with RA not responding to slow acting antirheumatic drugs and characterized by a low OKT4+:OKT8+ ratio.