Cis-dichlorodiammineplatinum (II) and VP 16–213 combination chemotherapy for non-small cell lung cancer

Twenty-three patients with non-small cell lung cancer were treated with a combination of cis-dichlorodiammineplatinum(II) 100 mg/m² IV on day 1 and VP 16–213 80 mg/m² IV on days 1–3. Eighteen patients are evaluable for response. Seven partial remissions with a median duration of 3 months (range, 1–13+) have been observed. Three patients exhibit stable disease, and eight patients show tumor progression. Overall survival was 5+ months (range, 1–13+); 7.5 months (range, 3–13+) for responders and 3+ months (range, 1–9+) for non-responders. Hematologic toxicity was acceptable, but poor subjective tolerance (nausea, vomiting, loss of appetite) was the main factor limiting treatment duration.     

SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.     

Venous imprint on the superior infundibulum

International Urology and Nephrology - Venous imprints on the upper urinary tract are common urographic findings but are rarely documented by renal angiography. The authors describe an unusual...     

Solid lipid micro-particles carrying insulin formed by solvent-in-water emulsion-diffusion technique

The study aimed to produce solid lipid insulin-loaded micro-particles by the solvent-in-water emulsion-diffusion technique, using isobutyric acid as solvent phase, glyceryl monostearate or cetyl palmitate as lipid, soya lecithin and taurodeoxycholate as emulsifiers. Isobutyric acid, a partially water-miscible solvent with low toxicity, was used due to its high insulin-solubilization capacity. Solid lipid micro-particles of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogeniser was used. Insulin encapsulation efficiency was about 80%. Analysis of microsphere content after processing showed that insulin did not undergo any chemical modification within the micro-particles. The in vitro release of insulin from the micro-particles was very low, and an initial burst effect of 20% of the dose was observed. After treatment of the solid lipid micro-particles with pepsin solution, an insulin loss of about 24% of the total englobed insulin was observed. The solid lipid micro-particles appear to have interesting possibilities as delivery systems for oral administration of insulin.     

Scale-up and optimization of an evaporative drying process applied to aqueous dispersions of solid lipid nanoparticles

An apparatus to dry aqueous dispersions of solid lipid nanoparticles (SLNs) was designed. Optimal running conditions were evaluated to obtain minimum process time and produce dried SLNs characterized by small size variation. To achieve process optimization, SLN average diameter, SLNs polydispersity index, and drying time were related to three operative variables: process temperature, SLN concentration in the original aqueous dispersions, and nitrogen flow rate as the physical means of the drying process. An experimental design procedure and a multicriteria optimization method, targeting desirability functions, enabled us to obtain the optimal conditions for all responses. Drying time, average diameter, and polydispersity index of dried SLN batches were more favorable than those obtained by freeze-drying identical SLN aqueous dispersions with the same initial nanoparticle concentration.     

Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues

The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.     

Effect of a new oral antiandrogen-estrogen combination on the endometrium: histological and ultrastructural scanning electron microscopy study

Endometrial biopsies were obtained in 12 volunteers between 18 and 35 years old who had used SHB 209 AE oral contraceptive during the previous six months. Three main types of endometrial patterns were observed: proliferative, very similar to a normal proliferative phase; early secretory: similar to early postovulatory endometrium; late secretory: characterized by diffuse predecidual changes in the stroma. At SEM after one week a great prevalence of nonciliated cells was observed. During the 2nd and the 3rd week, the endometrial surface appears still flattened with scanty glandular outlets.     

Proposing phase I studies: Patients', relatives', nurses' and specialists' perceptions

Purpose:As of now the primary objective of studies on informedconsent in phase I trials has been to assess patients' expectations andreasons for participation. We have previously shown that the quantity ofinformation provided through a procedure of subsequent oral interviews withpatients was adequate while the attention paid by the physician to theemotional needs and concerns of patients was not. We wanted therefore toassess and compare the perceptions of the information provided about theinvestigational study of patients, relatives, the research nurse and theinvestigator responsible for the phase I trial and the impact this informationhad on the patients' level of anxiety and depression. Patients and methods:The participation to a phase I study wasproposed to patients through two subsequent interviews, the latter attendedalso by patients' relatives, the research nurse and the investigatorcoordinating the phase I trial. After the second interview, attendees wererequested to complete a questionnaire assessing the principal reason forparticipating in the study and the informative, emotional and interactivedimension of the information. Patients were also requested to complete theHospital Anxiety and Depression (HAD) scale before and after the secondinterview. Results:The completed questionnaires of 31 of 42 patients wereretrieved and analysed. The possibility to benefit from the study wasindicated as the main reason for participating by 59% of the patientswhile it was judged to be the case in 78% and 86% of thepatients by the nurse and the investigator, respectively. The information wasjudged to be clear and sufficient in almost all cases by all attendees, whilethe investigator judged that a lower percentage of patients felt at ease andcould express their main worries during the interview, had been helped andwere less worried after it than it was judged by the nurse and the relatives.Patients' state of anxiety and depression was not adversely affected by theinformation provided. Conclusions:Informing patients on the option of receiving aninvestigational treatment within a phase I study is feasible and can be donein a way felt appropriate by patients and relatives, nursing and medicalprofessionals. Providing information in an appropriate manner does notincrease patients' anxiety and depression. Divergence between the aims andinterests of the investigators and patients might explain the difference inthe evaluation of physician, a problem which could perhaps be partiallyovercome by the application of innovative phase I designs.