BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma.

High-dose melphalan is considered the current standard of care among the preparative regimens used in peripheral blood autologous SCT (ASCT) for multiple myeloma (MM). We report the results of a single ASCT in 79 MM patients using the BU/CY conditioning regimen, with BU 1 mg/kg p.o. or 0.8 mg/kg i.v. every 6 h x 16 doses, and CY 60 mg/kg per day i.v. for 2 days. ASCT was carried out in first (62%) or subsequent remission/refractory disease (38%). For an overall RR of 86%, 48 and 20 patients achieved PR and CR, respectively. At a median follow-up of 41 months (range 2-132 months), the estimated median OS and PFS were 45 months (95% confidence interval (CI)=38-92) and 20 months (95% CI=15-25), respectively. The BU/CY regimen was well tolerated, and transplant-related mortality was 4%. Clinical outcomes of the BU/CY regimen are not superior to those obtained in historical controls with high-dose melphalan followed by a single ASCT. Therefore, considering even the greater complexity of administration of the BU/CY regimen compared with that of single-agent melphalan, we believe the latter should remain the conditioning regimen of choice for ASCT in MM.

The release and percutaneous permeation of anthralin products, using clinically involved and uninvolved psoriatic skin.

The release and permeation of 1% Westragel and 1% Westrastick and three commercial 1% anthralin products were investigated in vitro with the use of a Franz diffusion cell unit. An inert Teflon membrane with a mesh opening of 74 mu was used for measuring the rate of release. Involved psoriatic and uninvolved human skin collected from the same subjects were used for the permeation study. The permeation of danthron and dianthrone, the major degradation products of anthralin, was also studied with the use of microemulsion gels of 1% danthron and 1% dianthrone, which were prepared in the same way as 1% Westragel. The penetrating anthralin, danthron, and dianthrone were stabilized by a modified receptor fluid, and sample solutions were analyzed by a high-power liquid chromatography method. Involved psoriatic skin was found to be much more permeable to anthralin than was uninvolved psoriatic skin. The slow permeation rate of anthralin, danthron, and dianthrone through normal skin and uninvolved skin indicates that the stratum corneum is the rate-limiting barrier. In involved psoriatic skin, the release rate of anthralin from the topical product becomes the rate-determining step. Large individual variations were found in the permeation of anthralin through involved psoriatic skin, suggesting that the permeation rate of anthralin also may depend on the disease state of psoriatic patients. The anthralin molecule, possessing both hydrophilic and lipophilic centers, diffused significantly faster than did danthron and dianthrone. Westragel, 1%, showed the highest diffusion rate as well as the highest driving force when compared to other commercial 1% anthralin products. This suggests that 1% Westragel may be an optimal design, especially for short-contact anthralin therapy.

Pharmacokinetics of 14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage.

The pharmacokinetics of isotretinoin and 4-oxoisotretinoin in blood, as well as the blood concentrations and urinary, biliary, and fecal excretion of carbon-14 were studied using liquid scintillation counting techniques and reverse phase HPLC methods following a single 80-mg oral suspension dose of 14C-isotretinoin to four healthy male subjects and two patients with biliary T-tube drainage. Approximately 80% of the dose was recovered as 14C in excreta during the course of the study of which about equal fractions were in the urine and feces. Secondary peaks in blood concentrations of 14C were observed in the healthy subjects whereas they were not seen in the patients with T-tubes. The harmonic mean apparent half-life for isotretinoin in the blood of the healthy subjects was 13.6 hr, whereas the corresponding value for the 14C was 90 hr. Although a rigorous comparison of pharmacokinetic parameters between healthy subjects and T-tube patients was not feasible due to the limited number of subjects studied, comparisons of certain trends in the pharmacokinetic profiles gave some possible insights into the role of biliary excretion and enterohepatic cycling on the disposition of isotretinoin. The data for isotretinoin and 4-oxoisotretinoin coupled with the total carbon-14 data suggest that the oral dose of 14C-isotretinoin is absorbed to a similar extent by the healthy subjects and T-tube patients, whereas T-tube patients clear the drug more rapidly. The biliary excretion and possible enterohepatic circulation of isotretinoin and its metabolites may have significant impact on the pharmacokinetic profile of isotretinoin in man.

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

International studies of the efficacy of etretinate in the treatment of psoriasis.

International studies evaluating the efficacy of etretinate (Ro 10-9359) in psoriatic patients are reviewed. Double-blind, placebo controlled studies uniformly have demonstrated the therapeutic effect of the retinoid. Both single therapy and combination therapy studies confirm the efficacy of this new form of treatment, especially in patients with the rarer and more severe forms of psoriasis.