Biomedical subjects

J Segura

Publications and source records attributed to J Segura.

At least 55 records · Page 3Linked to original sources

PubMed2001

A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease.

OBJECTIVE: To investigate in a random comparison the capacity of an angiotensin converting enzyme inhibitor (fosinopril), and that of a long-acting dihydropiridine (nifedipine GITS) to modify the decay in renal function in patients with primary renal disease, exhibiting a progressive increase in serum creatinine during the previous 2 years. METHODS: A randomized, open-label, multicenter study with a minimum follow-up of 3 years. A total of 241 patients were included in the study. All of them were hypertensive and had a 25% or at least 0.5 mg/dl increase in the value of serum creatinine during the 24 months prior to entering the study. Initial doses of fosinopril and nifedipine GITS were 10 and 30 mg respectively, and titration to 30 and 60 mg was performed if needed to obtain the expected blood pressure goal (< 140/90 mmHg). Furosemide, atenolol, and doxazosin were added as second, third, and fourth drugs if necessary, for blood pressure control. The primary end-point of the study was the appearance of double the serum creatinine values and/or the need to enter a dialysis programme. Secondary end-points were cardiovascular events, death, changes in 24 h proteinuria, and the evolution of serum creatinine. Data reflect the analysis performed by intention to treat. RESULTS: Mean age of the group was 54 +/- 14, and 59% were males. Primary glomerulonephritis (31%), nephrosclerosis (26%) and polycystic kidney disease (19%) were the three most frequent diagnostic findings. After 3 years of follow-up, 21% (27/127) of patients treated with fosinopril, and 36% (40/112) of those receiving nifedipine GITS presented a primary end-point, (OR 0.47, 95% confidence intervals 0.26-0.84, P = 0.01). Renal survival was significantly better when fosinopril constituted the first step therapy (P = 0.002). These results did not seem to be influenced by the type of primary renal disease. Proteinuria decreased at the end of the study by a mean of 57% in the fosinopril group and increased by 7% in the group receiving dihydropiridine. Blood pressure control did not differ among groups for diastolic values. During follow-up, however, the patients receiving ACEi showed systolic blood pressure values 4-6 mmHg lower. CONCLUSION: In patients with chronic renal failure and hypertension due to primary renal disease, fosinopril significantly differed from nifedipine GITS by its capacity to slow the progressive decay in renal function. The drugs also differed by their capacity to lower blood pressure. The better control, in particular of systolic blood pressure, in the fosinopril arm could have contributed in a relevant manner to the attainment of a better outcome when the ACEi was employed.

Adult↗

PubMed2001

ACE inhibitors and appearance of renal events in hypertensive nephrosclerosis.

Nephrosclerosis constitutes a major cause of end-stage renal disease. Independently of blood pressure control, ACE inhibitors (ACEIs) are considered to be more nephroprotective than other antihypertensive agents. We have reviewed the long-term evolution of renal function in our series of essential hypertensive patients diagnosed as having nephrosclerosis when first seen in our unit. The analysis was performed depending on whether or not their antihypertensive therapy contained an ACEI alone or in combination for the whole follow-up. The end point was defined as the confirmation of a 50% reduction in creatinine clearance or entry in a dialysis program. A historical cohort of 295 patients was included in the analysis. Mean follow-up was 7.4+/-3.9 years. Diabetes prevalence was higher in ACEI-treated patients (25.7% versus 7.1%, P=0.000), but the diagnosis of diabetic nephropathy could not be confirmed on clinical grounds, including renal biopsy. Twenty-three out of 183 (12.6%) patients in the ACEI group and 23 out of 112 (20.5%) patients in the non-ACEI group experienced a renal event (P=0.0104 by log rank test). Similar results were observed when only nondiabetic patients were considered for the analysis. Cox regression analysis showed that baseline serum creatinine, absence of ACEI administration, mean proteinuria during follow-up, and age were independent predictors for the development of a renal event. In hypertensive nephrosclerosis, therapy containing an ACEI alone or in combination significantly reduces the incidence of renal events. This effect is independent of blood pressure control.

Adult↗

PubMed2001

Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome.

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1), CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2), GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI), 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS.

Adult↗

PubMed2001

Acute effects of 3,4-methylenedioxymethamphetamine alone and in combination with ethanol on the immune system in humans.

Cell-mediated immune response and release of cytokines after the administration of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") alone and in combination with ethanol were assessed in a double blind, randomized, crossover, controlled clinical trial. Six healthy male recreational users of MDMA participated in four different experimental sessions, with a washout interval between sessions of 1 week, in which single oral doses of MDMA (100 mg), ethanol (0.8 g/kg), the combination of both drugs, and placebo were tested. Acute MDMA administration produced a time-dependent immune dysfunction in association with serum concentrations of the drug as well as cortisol stimulation kinetics. Although total leukocyte count remained unchanged, there was a decrease in the CD4 T/CD8 T-cell ratio due to a decrease in both the percentage and absolute number of CD4 T-helper cells and simultaneous increase in natural killer (NK) cells. Ethanol consumption produced a decrease in T-helper cells and B lymphocytes. The combination of MDMA and ethanol caused the highest suppressive effect on CD4 T cells and increasing effect in NK cells. Drugs treatment produced a high increase of immunosuppressive cytokines (transforming growth factor-beta and interleukin-10) and a switch from Th1-type cytokines (interleukin-2 and interferon-gamma) to Th2-type cytokines (interleukin-4 and interleukin-10). Disregulation in the production of pro- and anti-inflammatory cytokines with an unbalance toward anti-inflammatory response was also observed. The immune function shows a trend toward baseline levels at 24 h after MDMA kinetics. This transient defect in immunological homeostasis, if temporarily repeated, might alter the immune response with a risk for the general health status.

Adult↗

PubMed2001

Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

BACKGROUND: Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. METHODS: Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. RESULTS: MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). CONCLUSIONS: Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

3,4-Methylenedioxyamphetamine↗

PubMed2001

What is the optimal blood pressure target in renal patients?

Chronic renal failure and arterial hypertension run in parallel. New goal BP levels have been established as 130/85 mm Hg and 125/75 mm Hg, depending on whether the level of proteinuria is less than or greater than 1 g/d. New and lower threshold BP (> 130/85 mm Hg) to initiate pharmacologic therapy is required in the presence of renal failure, to facilitate the strict BP control that is required. Hence, it is necessary to consider that both renal and cardiovascular protection are obtained with strict BP control, which otherwise seems to require blockade of angiotensin II effects when proteinuria above 1 g/d is present.

Blood Pressure↗

PubMed2000

Nonclassical photon statistics in single-molecule fluorescence at room temperature

The fluorescence of single terrylene molecules in a crystalline host is investigated at room temperature by scanning confocal optical microscopy. Photon arrival times are analyzed in terms of interphoton time distributions, second order correlation functions, and the variance of the photon number probability distribution. Antibunching at short times and bunching behavior for longer times is observed, associated with sub- and super-Poissonian statistics, respectively. A rate-equation analysis of the molecular level populations indicates an accelerated reverse intersystem crossing.

Journal Article↗

PubMed2000

Hair analysis and detectability of single dose administration of androgenic steroid esters.

Detection of anabolic steroids in hair samples has been possible only in fatal cases or in cases of high-continuous dosages. In order to verify the possibility of detecting an acute administration, a sensitive and specific assay has been developed for the simultaneous determination of testosterone, nandrolone and some of their esters in hair. The analytes were extracted from finely cut hair with methanol-trifluoroacetic acid overnight. After the incubation, the mixture was evaporated to dryness, redissolved and extracted with hexane. The dried organic layer was silanised and analysed by GC-MS and GC-MS-MS. A sensitivity of at least 20 pg injected was obtained for all the analytes. In guinea pigs treated with a single intramuscular dose of 10 mg/kg nandrolone decanoate, neither nandrolone decanoate nor nandrolone were found in hair collected after 13 days, while both compounds were clearly detectable after four repeated doses (each dose every 3-4 days) of 20 mg/kg nandrolone decanoate. Neither nandrolone decanoate nor nandrolone could be detected in hair from a male healthy volunteer 1 month after treatment with 50 mg nandrolone decanoate, while his urine still tested highly positive for the main nandrolone metabolite (> 100 ng/ml). Testosterone esters could not be detected in hair of healthy subjects collected respectively 3, 2 and 1 month after a single intramuscular administration of 250 mg testosterone enanthate (five subjects), a single intramuscular coadministration of 25 mg testosterone propionate plus 110 mg testosterone enanthate (one subject), or a single oral administration of 120 mg testosterone undecanoate (three subjects). Otherwise, hair analysis revealed an increase of testosterone concentration corresponding to the period of treatment. Analysis of blood and urine samples confirmed the absorption of those compounds. At the sensitivity achieved by the present method, no detection of nandrolone, nandrolone decanoate nor testosteron esters in hair seems to be obvious after a single dose administration.

Adult↗

PubMed2000

Derivatization procedures for the detection of beta(2)-agonists by gas chromatographic/mass spectrometric analysis.

An evaluation of derivatization procedures for the detection of beta(2)-agonists is presented. The study was performed with the beta(2)-agonists bambuterol, clenbuterol, fenoterol, formoterol, salbutamol, salmeterol and terbutaline. Different derivatizating agents were employed, aiming to obtain derivatives with high selectivity to be used in the gas chromatographic/mass spectrometric analysis of beta(2)-agonists in biological samples. Trimethylsilylation was compared with different agents and the role of some catalysts was evaluated. Acylation, combined trimethylsilylation and acylation, and the formation of cyclic methylboronates were also studied. Sterical hindrance caused by different substituents at the nitrogen atom of the beta-ethanolamine lateral chain of beta(2)-agonist molecules is mainly responsible for differences in the abundances of the derivatives obtained. The use of catalysts produces an increase in the derivatization yield, especially for compounds with low steric hindrance (substituents with primary and secondary carbon atoms). The formation of trimethylsilyl (TMS) ethers is not influenced by structural molecular differences when only hydroxy groups are involved in derivatization. Combined trimethylsilylation and acylation showed that compounds with a secondary carbon atom linked to the nitrogen atom form mainly N-TFA-O-TMS derivatives, with a small amount of N-TMS-O-TMS derivatives. Compounds with tert-butyl substituents at the amino group (bambuterol, salbutamol and terbutaline) formed O-TMS derivatives as the main products, although a limited amount of trifluoroacylation at the nitrogen atom also occurred. Cyclic methylboronates were formed with bambuterol, clenbuterol, formoterol, salbutamol and salmeterol. Owing to hydroxy substituents in unsuitable positions for ring formation, this procedure was not effective for fenoterol and terbutaline. Mass spectra of different derivatives and tentative fragmentation profiles are also shown. For screening purpose (e.g. sports drug testing), derivatization with MSTFA or BSTFA alone is recommended as a comprehensive derivatization technique for beta(2)-agonists owing to minimal by-product formation; formation of cyclic methylboronates can be useful for confirmation purposes. Detection limits were obtained for the TMS and cyclic methylboronate derivatives using the derivatizing reagents MSTFA and trimethylboroxine, respectively. For most of the compounds, lower detection limits were found for the TMS derivatives.

Acetamides↗

PubMed2000

Transcatheter occlusion of complex atrial septal defects.

Percutaneous device occlusion of secundum atrial septal defects (ASDs) is becoming an accepted alternative to surgical closure. This method allows us to evaluate patients with complex conditions for treatment. From a total of 70 patients with ASD evaluated for percutaneous closure, we selected for analysis 28 who had complex conditions. The mean age was 36+/-23 yr (range, 4-72). Six had heart failure, and of these six, three had atrial fibrillation. At cardiac catheterization, the pulmonary pressure was 47+/-24 mm Hg, and the QP/QS was 1.7+/-0.4; two patients had bidirectional shunt and systemic pulmonary pressure. Two patients received a buttoned device and 26 an Amplatzer septal occluder. The groups of patients with complex conditions were separated into the following groups. Group I (n = 4) underwent combined treatment of associated anomalies. Two patients had pulmonary stenosis, one had mitral stenosis, and one had an aortic root-left atrium fistula. They were treated in or during with the same procedure by combined transcatheter techniques (balloon valvuloplasty and fistula occlusion) before ASD occlusion. Group II (n = 9) had multiple defects (cribiform or two separate holes). They were treated with a single device in five instances and with two separate devices in four cases. Group III (n = 14) had large (32+/-3 mm) single defects. Nine of them underwent successful implantation using a device 33+/-3 mm in diameter; in the remaining five patients the device was removed because of instability. Group IV (n = 3) had residual defects after previous partial device occlusion. All three defects were successfully occluded with a second device. No movement or interference with the first device was observed. Group V (n = 6) had severe pulmonary hypertension (86+/-16 mm Hg). Immediately after ASD occlusion we observed significant relief in these patients (67+/-14 mm Hg; P<0.01). There were no major complications; all 23 patients with successful implants were discharged without symptoms 2-7 days later; one patient with atrial fibrillation recovered sinus rhythm. The follow-up (8+/-5 mo) Doppler echo study showed complete ASD occlusion in 22 patients and a peak pulmonary pressure of 30+/-14 mm Hg. We conclude that transcatheter occlusion of ASDs is an effective and safe treatment for patients with complex anatomic or physiopathologic conditions, as evaluated by short-term follow-up.

Adolescent↗

PubMed2000

Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy.

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.

Animals↗

PubMed2000

Engineering pancreatic islets.

Pancreatic islets are neuroendocrine organs that control blood glucose homeostasis. The precise interplay of a heterogeneous group of cell populations (beta, alpha, delta and PP cells) results in the fine-tuned release of counterbalanced hormones (insulin, glucagon, somatostatin and pancreatic polypeptide respectively). Under the premises of detailed knowledge of the physiological basis underlying this behaviour, two lines of investigation might be inferred: generating computational and operational models to explain and predict this behaviour and engineering islet cells to reconstruct pancreatic endocrine function. Whilst the former is being fuelled by new computational strategies, giving biophysicists the possibility of modelling a system in which new "emergent" properties appear, the latter is benefiting from the useful tools and strategic knowledge achieved by molecular, cell and developmental biologists. This includes using tumour cell lines, engineering islet cell precursors, knowledge of the mechanisms of differentiation, regeneration and growth and, finally, therapeutic cloning of human tissues. Gaining deep physiological understanding of the basis governing these processes is instrumental for engineering new pancreatic islets.

Animals↗

PubMed2000

Specific c-K-ras gene mutations as a tumor-response marker in locally advanced rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: Forty percent of patients with colorectal cancer develop mutations in the K-ras gene. OBJECTIVE: Our objective was to evaluate whether the presence of c-K-ras gene mutations is a useful tumor-response marker in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. MATERIAL AND METHODS: Thirty seven patients with locally advanced rectal cancer were treated with preoperative chemoradiotherapy. Four to six weeks later, surgery was performed. Specimens were classified according to the UICC-AJC classification. A segment of the tumor was obtained to analyze specific c-K-ras gene mutations. Restriction fragment length polymorphism (RFLP) and single strand confirmation polymorphism (SSCP) techniques were used with a set of probes to detect specific c-K-ras mutations in codons 12, 13, and 61. The 37 patients were divided into Group A (with mutations) and Group B (without mutations). RESULTS: All 37 patients completed the scheduled treatment. Group A consisted of 12 patients, whose tumors were classified and specific c-K-ras mutations were located as follows: eight in codon 12, two in codon 13, and one in codon 61. Group B consisted of 25 patients. The tumors were classified and there were more early-stage tumors in Group A, whereas in Group B there were more advanced-stage tumors (P = .05, respectively). The mean follow-up was 36.2+/-18.3 months. All Group A patients survived, whereas 8 of the 25 patients in Group B died due to progressive metastatic disease. Survival in Group A was 100%, whereas in Group B it was 59% (P = .03). CONCLUSIONS: The presence of specific c-K-ras mutations is an indicator of tumor response in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy and surgery. Therefore, responding patients may be more amenable to less radical surgical procedures based on c-K-ras mutations.

Adenocarcinoma↗

PubMed2000

Modeling study of exocytosis in neuroendocrine cells: influence of the geometrical parameters.

Exocytosis in neuroendocrine cells is a process triggered by Ca(2+). A Monte Carlo simulation of secretion has been developed which, together with the diffusion of calcium, buffered by endogenous and/or exogenously added chelators, also accounts for the dynamics of exocytosis for a pool of readily releasable vesicles. Different distributions of channels and vesicles (random or correlated) are studied. A local study of exocytosis is carried out by obtaining capacitance time courses for the different types of release-ready vesicle pools (correlated or not with Ca(2+) channels). Also, depending upon the kinetic constants for the exocytotic process, we study the levels of local Ca(2+) needed to trigger secretion. Our simulations show that a strong heterogeneity in the calcium concentrations at the different sites of exocytosis is a requirement for reproducing the experimentally observed biphasic response in chromaffin cells in situ (Voets, T., E. Neher, and T. Moser. 1999. Neuron. 23:607-615). Correlated nonuniform distributions of channels and vesicles and the existence of diffusion barriers are shown to quantitatively explain the experimental data on chromaffin cells in situ. The first description requires a deeply heterogeneous distribution, with vesicles attached to the channels or far from them, but never at middle distances. The second description is able to reproduce biphasic release even for uniformly (readily releasable) distributed vesicles. We quantify the degree of inhomogeneity in the distribution of vesicles and how porous the diffusion barriers should be to account for the observed biphasic response.

Animals↗

PubMed2000

Monte carlo simulation of 3-D buffered Ca(2+) diffusion in neuroendocrine cells.

Buffered Ca(2+) diffusion in the cytosol of neuroendocrine cells is a plausible explanation for the slowness and latency in the secretion of hormones. We have developed a Monte Carlo simulation to treat the problem of 3-D diffusion and kinetic reactions of ions and buffers. The 3-D diffusion is modeled as a random walk process that follows the path of each ion and buffer molecule, combined locally with a stochastic treatment of the first-order kinetic reactions involved. Such modeling is able to predict [Ca(2+)] and buffer concentration time courses regardless of how low the calcium influx is, and it is therefore a convenient method for dealing with physiological calcium currents and concentrations. We study the effects of the diffusional and kinetic parameters of the model on the concentration time courses as well as on the local equilibrium of buffers with calcium. An in-mobile and fast endogenous buffer as described by, Biophys. J. 72:674-690) was able to reach local equilibrium with calcium; however, the exogenous buffers considered are displaced drastically from equilibrium at the start of the calcium pulse, particularly below the pores. The versatility of the method also allows the effect of different arrangements of calcium channels on submembrane gradients to be studied, including random distribution of calcium channels and channel clusters. The simulation shows how the particular distribution of channels or clusters can be of relevance for secretion in the case where the distribution of release granules is correlated with the channels or clusters.

Animals↗

PubMed2000

Truncated active matrix metalloproteinase-8 gene expression in HepG2 cells is active against native type I collagen.

BACKGROUND/AIMS: Excess type I collagen accumulation is a major feature of fibrotic diseases such as liver cirrhosis. Reversion of this disease has not been fully accomplished. Physiologically, collagen is degraded by interstitial collagenases, neutrophil collagenase (MMP-8) being the most active against type I collagen. Introduction of MMP-8 gene into liver cells could be an advantageous tool to potentiate fibrosis degradation. METHODS: We cloned latent and active MMP-8 genes in prokaryotic and eukaryotic expression vectors and an adenoviral vector. Transfection of MMP-8 in HepG2 was effectuated by CaPO4, polylysine-lactose (P-L) and adenoviral transduction, and cells and culture supernatant were harvested 72 h after transfection for analysis of MMP-8 expression by reverse transcription-polymerase chain reaction and collagenolytic activity. RESULTS AND CONCLUSIONS: We show that a truncated neutrophil collagenase (tMMP-8) lacking a portion of the carboxy terminus and with an intact aminoterminus (latent; l-tMMP-8) or a truncated amino terminus (active; a-tMMP-8) has enzymatic activity against native type I collagen, and the activity was inhibited by EDTA, 1,10-phenanthroline and TIMP-1. Both MMP-8 mRNA (latent and active) were detected by polymerase chain reaction in cells transfected with CaPO4, P-L and adenoviral transduction; however, relative expression of MMP-8 was enhanced when the plasmid was delivered as a P-L complex and increased by adenoviral infection. Finally, a-tMMP-8 cDNA was cloned in a vector under transcriptional control of a regulated promoter (PEPCK-a-tMMP-8). HepG2 cells transfected with the PEPCK-a-tMMP-8 plasmid DNA up-regulated expression of a-tMMP-8 after incubation of the cells with butyryl-cAMP and glucagon, while stimulation with insulin slightly down-regulated its expression. Recombinant MMP-8 expressed by HepG2-transduced cells can efficiently degrade soluble type I collagen, which is potentially useful for gene transfer therapies.

Collagen↗

PubMed2000

Non-linear pharmacokinetics of MDMA ('ecstasy') in humans.

AIMS: 3,4-Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers. METHODS: A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA) and 4-hydroxy-3-methoxy-amphetamine (HMA). RESULTS: As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent. CONCLUSIONS: It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.

3,4-Methylenedioxyamphetamine↗

PubMed2000

Comparative study of home and office blood pressure in hypertensive patients treated with enalapril/HCTZ 20/6 mg: the ESPADA study.

The introduction and generalization of 24-h ambulatory blood pressure (BP) monitoring has shown the clinical relevance of home BP. The aim of this study was to assess the validity of home-measured BP for monitoring and controlling patients with arterial hypertension while on a homogeneous treatment. An additional objective was to establish the degree of office BP control obtained. This was a prospective, longitudinal, observational and multicenter study in a cohort of 156 patients of both sexes, aged over 18 years and with essential hypertension. All of them received the fixed combination enalapril/HCTZ 20/6 mg as the only hypertensive agent for at least 4 weeks previously. Office BP was the average of three measurements. For home BP, a semi-automated device (OMRON HEM 705 CP) was used. The patients measured their BP twice a day for 2 consecutive days. The average differences between the two measuring methods were low, but significant: 3.99 mmHg for systolic BP (SBP; p < 0.05), 2.02 mmHg for diastolic BP (DBP; p < 0.05). Pearson's regression coefficient between the office and home values was highly significant (p < 0.0001) for SBP, DBP and heart rate. Home BP measurement was highly reproducible as shown by the high within-class correlation coefficient for individual measurements on the first day compared with the second: 0.88 (95% confidence interval, CI 0.82-0.92; p < 0.00001) for SBP and 0.89 for DBP (95% CI 0.83-0.93; p < 0.00001). The percentage of patients with strict office DBP and SBP control (< 140/90 mmHg) was 61.3% and with DBP control (<90 mmHg) 92%. In conclusion, in the ESPADA study, the application of home BP measurement is valid, reproducible and shows a high correlation with office BP.

Age Factors↗