Second lethal events associated with treatment for Hodgkin's disease: a review of 2980 patients treated in a single Mexican institute.

Presence of second neoplasms and cardiac toxicity has been recognized as potential late lethal second events in patients treated for Hodgkin's disease. However, most reports analyze these association independently. We reviewed 2980 cases of patients treated during 1970-1995 with long-term follow-up (> 4 years) in an attempt to identify all late events in Hodgkin's disease secondary to the treatment or those which are unrelated. Three hundred and ten patients died, and of these 156 were secondary to relapse and tumor progression. Death associated second tumors and cardiac events were increased 37 fold and 29 fold respectively compared to the general population. The risk factors for this complications did not differ to previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 61 patients died secondary to non-related events. Nevertheless, at 20-years overall survival was 90 % (95 % confidence interval (CI): 78 % to 97 %) and event free survival was 88 % (95 % CI: 76 % to 96 %) for these patients. Thus, second events, fatal in most cases, should be considered as an expected risk to the treatment in patients with Hodgkin's disease; the proposed modifications of therapy may indeed be useful to avoid or diminish these complications in the future.

High dose chemotherapy with G-CSF in refractory Hodgkin's disease.

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non-myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with high doses: BCNU, 300 mg/m2, on day 1, vincristine 1.4 mg/m2, and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m2, i.v., on days 14 and 15; and ifosfamide 4 g/m2, and epirubicin 180 mg/m2, on day 29. G-CSF 5 ug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m2, i.v., on days 1 and 8; vincristine 1.4 mg/m2, i.v. on days 1 and 8; prednisone 60 mg/m2, p.o., daily, days 1 to 14 and procarbazine 100 ng/m2, p.o., daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58% (50 out of 86 patients) being 38 and 76% in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44% of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autologous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.

Treatment of refractory low grade lymphoma with chlorambucil alternating with interferon and radiotherapy.

We report the results of a clinical trial of chlorambucil (CB) alternating with interferon alfa 2b (IFN) in previously treated patients with low-grade lymphoma who were refractory to previous treatment. Patients received CB 10 mg/m2, po, daily, days 1-14, alternating with IFN 5.0 MU three times a week days 15-28 (six doses) by six monthly cycles. If partial response was achieved, patients received extended field radiotherapy to sites of nodal residual postchemotherapy disease. Forty-three patients were enrolled into the study, and 30 were evaluable for response and toxicity. Nineteen out of 39 (40%) achieved complete remission and 14 out of 39 (35%) had partial remission, thus the overall response was observed in 83% of the cases. Ten patients with partial response and residual nodal disease received radiotherapy and achieved complete response criteria. The median duration of response has not been achieved, yet, 23 patients remain in complete response after a median follow-up of 98.5 months. Toxicity was mild and 95% of the patients received the planned dose of CB and IFN. These results suggest that combination of CB and IFN and addition of radiotherapy to residual postchemotherapy nodal disease may be effective in patients with low-grade lymphoma without excessive toxicity and adequate quality of life.

Application of a sensorial response model to the design of an oral liquid pharmaceutical dosage form.

In this paper, we discuss the application of a compartmental model to study the sensorial response, in terms of taste intensity versus time, in an oral solution for pharmaceutical use. The numerical model was developed from sensorial response curves obtained by a panel of three trained individuals. Parameter identification was carried out by means of a least-squares procedure that obtained the linear coefficients in the model by solving an exact linear least-squares problem conditional on the values of the nonlinear parameters for each iteration. Thus, nonlinear estimation was done in terms of the first-order kinetic parameters only, and ill-conditioning of the Hessian matrix present in these models was solved. Results of modeling for a set of formulations were used to determine the effects of various ingredients (sweeteners and an essence) on a baseline unflavored formulation of acetaminophen in a mixture of cosolvents. The first moment of the area under the curve of taste intensity versus time was found to be the best global indicator of taste for the purpose of product design. It was found that a mixture of sweeteners and an essence was the most efficient way of masking the bitter taste of this active ingredient.

Application of a mixed optimization strategy in the design of a pharmaceutical solid formulation at laboratory scale.

The objective of this work was to develop an optimization strategy for the design of pharmaceutical formulations. The mixed strategy was used to optimize a dry powder blend containing 500mg of alpha methlyl dopa to be filled into hard gelatin capsules. The experimental plan consisted of assessing blend flow and dissolution rate using formulations manufactured at small laboratory scale, selecting the optimum formulation, and confirming the data. Two optimization techniques were used in the solid pharmaceutical product design: a genetic algorithm (GA) and a downhill simplex technique. The genetic algorithm used in this work was implemented in an interactive form. Data for each generation of formulations were introduced to the computer with the corresponding values of a fitness function, which was determined in experimental form for each individual formulation. The fitness function used to evaluate product performance (capsule) was defined in terms of the dissolution rate multiplied by a weight function that penalizes those formulations with flow index outside a predefined range. The formulation design contained variable concentrations and types of lubricants/ glidants. There were 64 combinations of seven agents with discrete ranges of concentrations codified into a 16-bit chromosome. Crossing and mutation operations were implemented with relatively high probabilities, for generations with a relatively small number of individuals, due to the restrictions imposed by the experimental cost. The mixed formulation strategy based on genetic algorithms and downhill simplex was used to obtain sequentially improved formulations based on two desired targets: in vitro dissolution rate and flow properties. The basic downhill simplex method was used to obtain an optimal, formulation on the regression response surface obtained from the genetic algorithm data. The results obtained in this work clearliy illustrate the potential of the proposed mixed optimization strategy to obtain optimal formulations.