Biomedical subjects

M Chacón

Publications and source records attributed to M Chacón.

10 recordsLinked to original sources

PubMed2001

A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients.

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Adult↗

PubMed2001

Effect of gonadectomy on cyclosporine pharmacokinetics in male and female rats.

The present paper reports about the effect of gonadectomy on cyclosporine (CyA) pharmacokinetics in rats. The oral administration of CyA (10 mg/kg b.w.) to male rats caused two-fold higher drug blood levels than those reached by females at 24 h after the last dose (334.10 +/- 126.70 vs. 161.49 +/- 53.39 ng/ml, p < 0.05). These levels increased by about 25% in orchiectomized male rats (419.47 +/- 132.63 ng/ml) but they returned to control values after testosterone treatment (330.99 +/- 130.80 ng/ml). On the other hand, CyA blood levels (90.66 +/- 22.25 ng/ml) decreased after ovariectomy, even more in the case of gonadectomized female rats receiving estradiol replacement (67.83 +/- 24.15 ng/ml). With regards to drug distribution, the concentrations of CyA in the liver, the kidneys and the spleen at 24 h after the last dose were about 8, 5 and 6-fold higher than blood levels, respectively, regardless of animal gender. These partition coefficients were increased to 11, 7 and 9-fold by male castration suggesting a more extensive drug distribution. Contrariwise, drug tissue levels in ovariectomized rats decreased. The changes of drug blood and tissue levels among groups were not associated to the variations of metabolite concentrations in the liver or blood. Therefore, gonadectomy exerts a complex effect on CyA pharmacokinetics in rats and makes complementary studies necessary to clarify how differences in sexual hormone secretion alter CyA disposition.

Algorithms↗

PubMed2000

Dependency of cyclosporine tissue distribution and metabolism on the age and gender of rats after a single intravenous dose.

In a previous study we demonstrated the dependency of cyclosporine (CyA) pharmacokinetics on the age and gender of Wistar rats given 10 mg/kg intravenously. The present study has been conducted under the same experimental conditions (10 mg/kg as a single intravenous dose) to identify the mechanisms behind such differences. On the one hand, drug distribution was studied by measuring the CyA levels in blood, liver, kidney, spleen, adipose tissue, skin and muscle at 48 h post-treatment by using a specific fluorescence polarization immunoassay (m-FPIA, Abbott Laboratories). Drug blood and tissue levels in male rats were significantly higher than the female counterparts except for adipose tissue where the concentrations were 2-fold higher in females. In males, the highest CyA concentrations were observed in the liver, followed in rank order by kidney and spleen, fat, skin, muscle, then blood. On the contrary, females showed the highest drug levels in fat, followed by liver, kidney, spleen, skin, muscle and blood. Age exerted a significant influence on CyA tissue levels in males but no effect was observed in females. The potential differences in drug metabolism were established by measuring (HPLC) the amounts of CyA and its metabolites accumulated in faeces after hepatic biotransformation and biliary excretion. The amounts of circulating metabolites in blood as well as those accumulated and excreted in the liver and urine were also estimated by using specific (m-FPIA) and non-specific fluorescence polarization immunoassay (p-FPIA, Abbott Laboratories), respectively. The analysis of faeces revealed that AM9 was the major identified metabolite with females excreting lower amounts of unchanged CyA than males. In addition, the comparison of the AUC values corresponding to parent CyA and total CyA derivatives suggested that blood concentrations of CyA metabolites were higher in females indicating higher biotransformation rates. Therefore, both CyA distribution and metabolism are responsible for the sex-associated differences in drug pharmacokinetics previously found in rats.

Aging↗

PubMed2000

Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer.

BACKGROUND: Although not clearly defined, 'hormone refractory' prostate cancer implies disease progression after orchiectomy +/- antiandrogens. Patients in this setting are usually offered chemotherapy protocols which often lead to significant toxicity and expense. In search of a well-tolerated, active, third-line treatment, we have attempted to prolong hormonal maneuvers by using low-dose estrogen therapy. DESIGN: Thirty-eight patients with evidence of disease progression (as indicated by 2 consecutively rising PSA determinations) after > or = 2 hormonal treatments (including surgical or chemical orchiectomy and a median of 3 prior treatment lines) received fosfestrol 100 mg t.i.d. per os in a continuous schedule until the appearance of progressive disease or excessive toxicity. Response was assessed by serial PSA levels. Complete response (CR) was defined as normalisation and partial response (PR) as a > or = 50 decrease of PSA levels for longer than one month. The median duration of prior treatment was 20 months and the median PSA at fosfestrol start was 126 ng/ml (range 8-12,800); symptoms (pain) were present in 73% of patients. RESULTS: CR + PR were observed in 79% (95% confidence interval: 66%-92%). The median time to progression was seven months. Pain remained stable or improved in 34% and 53%, respectively, of symptomatic patients with PSA response. Toxicity included worsening of gynecomastia, peripheral edema, and deep vein thrombosis (8%). No treatment-related deaths occurred. Uni- and multivariate analyses failed to identify predictive factors for response. PSA response was associated with significantly longer survival (13 vs. 7 months, P < 0.05 by Mantel-Haentzel). CONCLUSIONS: FOSF produces high rates of PSA-determined and symptomatic response in 'hormone-refractory' prostate cancer. Toxicity and ease of administration compare favorably with those reported for CHT regimens used in this setting. The role of estrogens in prostate cancer should be redefined.

Administration, Oral↗

PubMed1999

A polycaprolactone nanoparticle formulation of cyclosporin-A improves the prediction of area under the curve using a limited sampling strategy.

Therapeutic monitoring of Cyclosporine (CyA) by using area under the curve (AUC) from abbreviated kinetic profiles is of recent trend in clinical practice due to the potential improvement in transplant and clinical outcome with costs reduction in mind. Several papers describe successful use of the limited sampling strategy to predict AUCs in different transplant populations when treated with Sandimmun or Sandimmun Neoral. However, the same predictive potential is achieved for the latter formulation with lesser effort. The present paper describes the application of the limited sampling strategies to demonstrate the advantages of using CyA incorporated in polymeric nanoparticles (CyA-NP) as compared to two reference Sandimmun formulations which consisted of an emulsion of the oily solution in milk (SIM-EM) and a microemulsion (SIM-Neoral) formerly tried on rats. Two independent data batches were used: group 1 which included 36, 31 and 10 animals receiving SIM-EM, CyA-NP and SIM-Neoral, respectively, and group 2 made of nine and eight rats treated with SIM-EM and CyA-NP. Several limited sampling equations were derived for each formulation from group 1 by stepwise multiple linear regression. Statistical analysis disclosed that CyA concentrations 8 and 32 h after dose administration vouched for 88 and 69% variability in AUC (0-48 h) for CyA-NP and SIM-EM, respectively. When summed up, these two concentrations revealed nearly 97% of AUC (0-48 h) variability. CyA concentrations 8 h post-treatment with SIM-Neoral explained 89% variability in AUC (0-48 h). This value raised to 98% when a second CyA concentration (24 h) was introduced. The equations derived from group 1 were then employed to predict AUCs in group 2. CyA blood levels at 8 h post-treatment confirmed AUC for CyA-NP (r(2)=0.98) to be very precise and unbiased (error=1. 46%, interval -16.2 to 21.33%), while the results for SIM-EM obtained with the CyA concentration at 32 h were r(2)=0.93 plus error=5.71%, interval -44.33 to 105.94%. Similar results were obtained when the study period was reduced to 24 h. The use of these limited sampling models manifested the coincidence between CyA-NP and SIM-Neoral as well as the advantages of both formulations over SIM-EM when it comes to CyA monitoring.

Animals↗

PubMed1999

Stability and freeze-drying of cyclosporine loaded poly(D,L lactide-glycolide) carriers.

The present paper describes the stability of poly (D, L-lactide-glycolide) nanoparticles (PLGA NP) and microspheres (MS), either alone or loaded with cyclosporine (CyA), stored at 8 degrees C and room temperature (RT). Freeze-drying of these formulations was evaluated as an alternative method to achieve long term stability. A significant polymer rupture was detected during PLGA MS preparation by solvent evaporation, which correlated with the stirring rates used for the formation of the primary emulsion. On the other hand, the polymer remained unchanged during NP formation. After 6 months of storage, PLGA NP of a size below 80 nm aggregated when stored at RT whereas no changes of particle size were observed for the remaining formulations and experimental conditions. Drug entrapment significantly increased by about 9.5% only during PLGA NP storage at RT. The PLGA molecular weight of NP dropped at RT being these changes related to the initial particle size and amount of CyA incorporated. The same effect was observed at 8 degrees C but only the particle size showed a significant influence. The drop of PLGA molecular weight observed during storage of MS was not dependent on the storage temperature but it was directly related to the molecular weights obtained after MS preparation. Freeze-drying studies revealed that it was not feasible to maintain the initial PLGA NP characteristics after reconstitution. On the other hand, MS lyophilized in the absence of cryoprotectants retained the drug initially entrapped; however, the presence of at least 5% cryoprotectant was essential to keep the initial particle size. Therefore, PLGA NP and MS show a significant instability when stored as suspensions. Freeze-drying offers a good alternative to stabilize polymeric MS but the preservation of the PLGA NP characteristics by freeze-drying needs for further investigations.

Calorimetry, Differential Scanning↗

PubMed1997

[Clinical correlation between the premortem study and autopsy].

BACKGROUND: Lately, autopsies are performed less frequently in hospitals, despite their importance as a diagnostic tool. AIM: To study the concordance between clinical diagnosis and postmortem study in patients that died in a teaching hospital. MATERIAL AND METHODS: Autopsy findings in 57 patients (aged 16 to 85 years old, 28 female) that died at a University hospital were analyzed. Clinical diagnoses were compared with those of the postmortem examination and the degree of concordance between both diagnoses was calculated. RESULTS: Seven major omissions (12.3%), whose knowledge could have changed the clinical course of patients, were detected. These omissions occurred in patients with complex diseases or due to limitations of diagnostic procedures. Also, seven omissions, found in severely ill patients, whose knowledge would not change the patient's evolution, were also detected. CONCLUSIONS: Autopsy still is a valuable tool to assess the quality of care for patients that die during their hospitalization.

Adolescent↗

PubMed1996

Determination of ipriflavone and its synthetic impurities by high-performance liquid chromatography using diode-array detection.

A simple, accurate and rapid method for the determination of ipriflavone and its synthetic impurities has been developed. It consists in RP-HPLC separation and identification of the impurities from their UV spectra using photodiode-array detection. The method has been validated and shows good specificity, accuracy, precision and sensitivity.

Chromatography, High Pressure Liquid↗

PubMed1995

Traumatic dislocation of the tibialis posterior tendon: a new surgical procedure to obtain a strong reconstruction.

Traumatic dislocation of the tibialis posterior tendon (TPT) is an uncommon condition. The diagnosis is difficult and may be delayed, impairing the activity level. The authors present a case, wherein the diagnosis was clinical, supported by magnetic resonance imaging. Treatment was surgical; reconstruction of the retinaculum was performed with a medial slip of the Achilles tendon that was detached proximally and attached to the medial malleolus. A full functional recovery to a highly competitive activity was obtained after 12 weeks.

Adult↗

PubMedDate not supplied

Stability of cyclosporine-loaded poly-sigma-caprolactone nanoparticles.

The aim was to evaluate the long-term stability of cyclosporin A-loaded nanoparticle suspensions, stored at 8 and 25 degrees C. The stability of freeze-dried samples was also investigated. Nanoparticles (NP) of poly-sigma-caprolactone (P sigma CL), a biodegradable polymer, were obtained by a modified nanoprecipitation method. A central composite experimental design was used to investigate the simultaneous effect of technological factors (temperature of the aqueous phase and needle gauge) and formulation variables (volume of acetone and the amount of polymer and surfactant). The effect of these variables on the stability of the 100-220 nm particles obtained was evaluated. The percentage of cyclosporin A (CyA) encapsulated in the NP suspensions stored at 8 and 25 degrees C for at least 3 months remained unaltered. Moreover, there was no change in the size of NP. After 4 months storage, the physical stability of the preparation was affected. NP aggregates could be observed by light microscopy. Reconstituted freeze-dried preparations showed a mean increase of 1% in the incorporated drug and also a considerable increase in mean size and size distribution. Additional experiments investigated the effect of freezing temperature (-70 and -196 degrees C) and of 5, 10 and 20% (w/v) cryoprotector (mannitol, sorbitol, glucose and threalose) on 100 nm particles. The addition of glucose and threalose at concentrations > 10% permitted adequate reconstitution of the freeze-dried product with conservation of the encapsulated CyA.

Cold Temperature↗