Comparative mathematical modelling of a green approach for bioaccumulation of cobalt from wastewater.

Cobalt is an essential element, but its wide use in industry generates important environmental and biological problems. The present study explores theoretical and empirical models of a green process for cobalt {Co2+} bioaccumulation from aqueous solutions. Two Gram-positive Bacillus subtilis species, strains CECT 4522 and LMM (the latter a former laboratory isolate from wastewater samples, which was phylogenetically characterized for the present work), were selected among others as the best Co2+ accumulation systems. Mathematical models representing kinetic and steady-state conditions for discrete and large amounts of bacterial biomass were expanded. In this way, it was possible to theoretically calculate the amount of Co2+ retained on the outer cell wall layer and incorporated inside the cell at any time. Theoretical and empirical hyperbolic-type models were suitable to fit the experimental bioaccumulation data for discrete amounts of bacteria biomass. In addition, kinetic relationships between the amount of Co2+ accumulated and the time before (or after) reaching steady state were established for large amounts of bacterial biomass. Other kinetic approaches were also satisfactorily tested. The two Gram-positive bacteria assayed are promising agents for developing heavy metal removal systems from industrial waste.

[Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy associated toxicity in treatment of peritoneal carcinomatosis]. / Toxicidad asociada a la cirugía citorreductora y quimioterapia intraperitoneal hipertérmica en el tratamiento de la carcinomatosis peritoneal.

INTRODUCTION: Peritoneal carcinomatosis is a form of intra-abdominal dissemination of several tumours, which is associated with a poor prognosis. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is an alternative treatment. The aim of this study is to describe the toxicity associated with this procedure in patients with peritoneal carcinomatosis. METHOD: We conducted a descriptive, retrospective, single-centre study, including all patients undergoing this procedure between December 2007 and January 2010. The following data were recorded: anthropometric data, personal and surgical events, indication, previous treatments, extent of carcinomatosis, intervention duration, hospital stay, and type of complications and/or adverse events following application of the multidisciplinary treatment. RESULTS: We performed 46 interventions on 45 patients diagnosed with peritoneal carcinomatosis from different causes, mainly ovarian cancer (83%). Paclitaxel was the most-used drug (35 interventions). There was no associated mortality, the average intervention time was 6.4 hours and the average hospital stay 7 days. We recorded adverse effects for 42 procedures, being grade 3-4 in 28.3% of the patients. The severe adverse events were: 10.9% gastrointestinal, 10.9% infectious, 6.5% haemorrhage or bleeding, 6.5% medullary toxicity, 4.4% respiratory, 2.2% coagulation and 2.2% hepatobiliary disorders. One patient developed grade III neutropaenia, probably associated with cisplatin. CONCLUSION: The morbidity and mortality is in line with the average of published studies, and has mainly been attributed to surgical complications. Toxicity data lower than other studies can be due to using more tolerable chemotherapy regimens, not including drug combinations and given that paclitaxel was the main drug.

[Experience using doxorubicin-loaded DC Beads® during hepatic chemoembolisation]. / Experiencia de uso de partículas DC Bead® cargadas con doxorrubicina en quimioembolización hepática.

INTRODUCTION: Hepatocellular carcinoma is the most common and aggressive liver and biliary tumour. Hepatic chemoembolisation with doxorubicin-loaded DC Beads(®) is a local therapy for patients with localised nodes, which are not suitable for surgery. The objective of this study is to describe the clinical situations in which this procedure has been used and its early toxicity. METHODS: Retrospective descriptive study of patients treated with doxorubicin-loaded DC Beads(®) undergoing hepatic chemoembolisation from October 2006 until July 2009. Data were taken from the Farhos Oncología(®) programme and clinical histories. RESULTS: Twenty-two patients were treated during the study period, 15 men and 6 women, with an average age of 66 years. This technique was used for patients diagnosed with unresectable liver cancer. Out of the patient total, 6 were on the liver transplant waiting list. Patients were assessed using the Child-Pugh score: 15 patients in group A, 5 in group B and 1 in group C; and according to Okuda staging system: 14 were in group I, 6 in group II and 1 in group III. The most common toxicity was post-chemoembolisation in 16 patients, which were treated with symptomatic medication. DISCUSSION: Using doxorubicin-loaded microspherical DC Beads(®) during transarterial chemoembolisation has been adapted to uses with scientific evidence and tolerated by all patients. Incidences during administration were mild and were resolved with symptomatic medication.

[Therapeutic use and profile of toxicity of the FOLFOX4 regimen]. / Uso terapéutico y perfil de toxicidad del esquema FOLFOX4.

INTRODUCTION: Since the publication of the MOSAIC test results in 2004, the FOLFOX4 regimen has been established as an adjuvant treatment which is recommended in stage III colorectal cancer. The aim of this study is to assess the use of this regimen in our field and to describe its toxicity. METHODS: Descriptive study of treatments with FOLFOX4 prescribed between April 2005 and March 2007. The data was obtained from the Farhos Oncología programme and clinical records. The following data was collected: age, gender, diagnosis, stage of the illness (TNM classification) and adverse reactions, expressing severity according to Common Toxicity Criteria 2.0. RESULTS: The FOLFOX4 regimen was prescribed for 39 patients (24 men and 15 women) with an average age of 59. The diagnoses were: 28 colon cancer (4 stage II, 17 stage III, and 7 stage IV), 10 rectal cancer (1 stage II, 4 stage III, and 5 stage IV) and 1 stage IV gastric cancer. The most frequent adverse reactions were peripheral neuropathy (82 %), neutropenia (56.4 %) and diarrhoea (53.9 %.) When the study was completed, 9 patients continued active treatment with the regimen (average 6.8 cycles.) Of the 30 remaining patients only 16 people completed the 12 planned cycles. 14 patients stopped their treatment (an average of 8.1 cycles) due to toxicity in 10 cases, clinical progression in 3 cases and one patient died. Of the total 368 cycles administered, 68 suffered administration delays and 22 had the dosage reduced. CONCLUSION: The use of the FOLFOX4 regimen has been adjusted to uses with some solid scientific evidence, but its toxicity has limited its use and has made administering the planned dosage levels difficult.

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients.

CYP2D6 has been suggested to be functionally similar to the dopamine transporter. The present study was aimed at analysing the frequency of CYP2D6 alleles and genotype among schizophrenic patients compared to healthy volunteers. CYP2D6 *3, *4, *5, *6, *10 and duplicated alleles were analysed in 128 unselected schizophrenia inpatients (SP) and 142 unrelated white European Spanish healthy volunteers (HV). SP and HV with >2, 2, 1 or 0 CYP2D6 active genes were 4.7, 64.8, 28.1 and 2.3%, and 6.3, 52.1, 33.1 and 8.5%, respectively. The frequency of homozygous for CYP2D6 inactive alleles or poor metabolizers (PMs) was lower (P<0.05) in SP than in HV. Furthermore, the frequency of CYP2D6 inactive alleles was also lower in SP than in HV (16.8 vs 25.7; P<0.05), specifically the CYP2D6*6 allele was not found among patients. The present study shows a lower frequency of PMs in schizophrenic patients than in healthy volunteers supporting the hypothesis of a potential role of CYP2D6 in the vulnerability to schizophrenia.

The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions.

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

CYP2C9 gene and susceptibility to major depressive disorder.

Alteration of monoaminergic neurotransmission has been implicated in the pathophysiology of mood disorders, and CYP2C9 enzyme activity has been shown to be modulated by serotonin in vitro. The present study was aimed at analysing the frequency of CYP2C9 alleles (*1, *2, *3) among patients suffering from major depressive disorder. In all, 70 such suffering psychiatric outpatients were studied. The CYP2C9 genotypes were determined by allele-specific PCR. The CYP2C9*3 allele frequency was higher (P<0.01) among the patients suffering from major depression than in a population of 89 schizophrenic patients (odds ratio=3.3) and 138 healthy volunteers (odds ratio=2.8). The results suggest that CYP2C9 genetic polymorphism may be related to a major depressive disorder due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out.

Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients.

The implication of cytochrome P450 CYP2D6 enzyme activity in the metabolism of the antipsychotic drug risperidone has been reported in vitro and in studies of healthy volunteers. Around 7 % of Caucasians have inherited impaired capacity of this enzyme (poor metabolisers). These subjects might be prone to higher plasma concentrations of risperidone. The aim of the study was to determine the relationship between the debrisoquine metabolic ratio (MR), a marker of CYP2D6 enzyme activity, and risperidone plasma levels in psychiatric patients. A population of 40 Spanish and Hungarian schizophrenic patients was studied. The possible inhibition of CYP2D6 enzyme was also evaluated in a subgroup of patients co-medicated with inhibitors of CYP2D6. The risperidone/9-hydroxy-risperidone ratio correlated significantly with debrisoquine MR (p < 0.001). In patients co-medicated with strong inhibitors of CYP2D6, the plasma levels of risperidone (p < 0.05) and debrisoquine MR (p < 0.01) and risperidone/9-hydroxy-risperidone ratio were higher compared to patients with monotherapy. According to the present data, the evaluation of the risperidone/9-hydroxy-risperidone ratio may reflect the actual enzyme activity of CYP2D6. Therefore, the use of this ratio may help to assess potential pharmacokinetic interactions and to improve risperidone treatment.

El síndrome iliotibial o rodilla del corredor. Revisión de casos / Iliotibial syndrome or runner's knee. Review of cases

El síndrome iliotibial o rodilla del corredor es una de las lesiones más habituales entre los practicantes de la carrera y el ciclismo, y su diagnóstico se basa en el hallazgo de dos signos clínicos específicos: el test de Renne y el test de Noble. El estudio de 30 casos muestra el importante papel de la Fisioterapia en el tratamiento y curación del mismo mediante el empleo de estiramientos miotendinosos y el uso de ortesis plantares correctoras (AU)

Determination of clozapine and its N-desmethyl metabolite by high-performance liquid chromatography with ultraviolet detection.

A rapid high-performance liquid chromatographic method has been developed for the simultaneous determination of the atypical antipsychotic drug clozapine and its principal metabolite, N-desmethyl clozapine in human plasma. After liquid-liquid extraction the compounds were separated in a reversed-phase column and measured by ultraviolet absorption at 230 nm. For both compounds inter-day variations were <3.8%, and, based on a plasma sample volume of 2 ml, the limits of quantification were 25 ng/ml. Analytical interference from coadministered psychoactive drugs and their metabolites was also studied, and no interference was found from the most commonly used antidepressants and antipsychotic drugs. The assay is sufficiently sensitive and easy to use for the analysis of plasma samples in human clinical trials and therapeutic drug monitoring.

Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes.

Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.

Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity.

Thioridazine is metabolized in humans by CYP2D6 to mesoridazine, which is an active metabolite. Two or more CYP2D6 substrates are seldom given simultaneously to elderly patients because potentially dangerous metabolic interactions may occur. It may be valuable to know the CYP2D6 metabolic capacity of such patients to avoid drug interactions, which depend on the metabolic phenotype. The goal of this study was to evaluate the use of the mesoridazine/thioridazine ratio for the estimation of CYP2D6 enzyme capacity. A sensitive and reliable method has been developed for the determination of thioridazine and its metabolites, mesoridazine and sulforidazine. Commonly used central nervous system (CNS) comedications do not interfere with the method. A group of 27 chronic patients with mental illness receiving monotherapy with thioridazine were studied. There were 23 men and 4 women between 37 and 80 years old (mean +/- SD: 61.2 +/- 10.2). The thioridazine/mesoridazine ratio correlated with the debrisoquine metabolic ratio (r = 0.74, p < 0.001). Therefore, the authors suggest that the measurement of thioridazine and its metabolite might be a useful tool to assess CYP2D6 activity during treatment.

Clozapine withdrawal symptoms after change to sertindole in a schizophrenic patient.

A 30-year-old male patient with paranoid schizophrenia was on clozapine therapy for more than five years. Discontinuation of clozapine and an attempt to change his medication to sertindole has led to serious psychotic and somatic symptoms. After readministration of clozapine the psychotic symptoms rapidly disappeared. The patient was monitored by BPRS and PANSS positive and negative scale. Also clinical and labor parameters of the patient were monitored. The change of his medication from clozapine to sertindole was unsuccessful. This case report suggests that although atypical antipsychotics may be generally different from the classical neuroleptic drugs, there are also significant differences among the atypical antipsychotic drugs in their effects on the receptors of the central nervous system. Therefore the change of clozapine to another atypical antipsychotic medication in the clinical practice should be cross-tapered and the symptoms of withdrawal closely monitored.