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Biomedical subjects

M Guzmán

Publications and source records attributed to M Guzmán.

At least 19 recordsLinked to original sources
PubMed2006

A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.

Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15-33). Delta(9)-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

Adult↗
PubMed2005

Effects on cell viability.

Cannabinoids are known to control the cell survival/death decision, leading to different outcomes that depend on the nature of the target cell and its proliferative or differentiation status. Cannabinoids induce growth arrest or apoptosis in a number of transformed cells in culture. They do so by modulating key cell signalling pathways involved in the control of tumour cell fate. The best-characterised example is cannabinoid-induced apoptosis of glioma cells, which occurs via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid administration inhibits the angiogenesis and slows the growth of different types of tumours in laboratory animals. By contrast, most of the experimental evidence indicates that cannabinoids protect normal neurons and glial cells from apoptosis as induced by toxic insults such as glutamatergic overstimulation, ischaemia and oxidative damage. It is therefore very likely that cannabinoids regulate cell survival and cell death pathways differently in tumour and non-tumour cells. Regarding immune cells, cannabinoids affect proliferation and survival in a complex and still obscure manner that depends on the experimental setting. The findings reviewed here might set the basis for the use of cannabinoids in the treatment of cancer and neurodegenerative diseases.

Angiogenesis Inhibitors↗
PubMed2005

[Atherogenic lipid profile in children with subclinical hypothyroidism].

OBJECTIVE: To evaluate lipid profile in children with subclinical hypothyroidism. PATIENTS AND METHODS: Forty-six children of both sexes aged between 2 and 9 years old, 17 with subclinical hypothyroidism (study group) and 23 healthy children (control group), were studied. Subclinical hypothyroidism was diagnosed when levels of thyroid-stimulating hormone (TSH) were greater than 4.65 .U/mL and those of free thyroxin (fT4) were normal. Children with subclinical hypothyroidism were observed for 4 months with no interventions and TSH and fT4 were again determined to confirm the diagnosis. A complete medical history was taken and a blood sample was extracted for lipid determinations including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Anti-thyroglobulin antibodies (ATGA) and antithyroid peroxidase (anti-TPO) antibodies were also determined. RESULTS: Of the 17 children who initially presented elevated serum TSH levels, seven (41.2 %) had normal levels at 4 months and were consequently excluded. No significant differences were found in age, weight, height or body mass index between the study and the control groups. No differences were found between the two groups in levels of anti-TPO antibodies and ATGA. The mean plasma HDL-C level was significantly lower in children with subclinical hypothyroidism than in controls (p < 0.05) and a statistically significant association (p < 0.013) was found between the presence of subclinical hypothyroidism and a greater frequency of low HDL-C levels. CONCLUSION: Subclinical hypothyroidism may be transitory in a considerable percentage of children. Children with subclinical hypothyroidism had significantly lower HDL-C levels, suggesting an atherogenic lipid profile in this entity.

Arteriosclerosis↗
PubMed2003

Molecular variation of Potato yellow vein virus isolates.

To evaluate the variation of Potato yellow vein virus from potato fields, 12 isolates were collected from Colombia and one was collected from Peru. Double-stranded RNA was extracted from the plants and used as a template for RT-PCR amplification of the coat protein ( CP) gene and, in separate reactions the C-terminal region of the heat shock protein 70 homologue ( Hsp70h) gene and the N-terminal region of the p60 open reading frame. The CP amplicons were subjected to single-strand conformation polymorphism (SSCP) analysis and, together with the other amplicon, nucleotide sequence analysis. These analyses suggested that there is low genetic diversity in the PYVV isolates examined and that the Peruvian isolate of PYVV may have originated in Colombia.

Capsid Proteins↗
PubMed2001

Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor.

The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313-319, 2000). These compounds act on the brain and some other organs through the widely expressed CB(1) receptor. By contrast, the other cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist SR144528 but not the CB(1) antagonist SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the tumors; and (c) the absence of typical CB(1)-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB(2) receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administration at 50 microg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon JWH-133 challenge and showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.

Animals↗
PubMed2001

Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A.

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.

Acetyl-CoA Carboxylase↗
PubMed2001

The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes.

Fatty acids induce apoptosis in primary astrocytes by enhancing ceramide synthesis de novo. The possible role of the AMP-activated protein kinase (AMPK) in the control of apoptosis was studied in this model. Long-term stimulation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevented apoptosis. AICAR blunted fatty acid-mediated induction of serine palmitoyltransferase and ceramide synthesis de novo, without affecting fatty acid synthesis and oxidation. Prevention of ceramide accumulation by AICAR led to a concomitant blockade of the Raf-1/extracellular signal-regulated kinase cascade, which selectively mediates fatty acid-induced apoptosis. Data indicate that AMPK may protect cells from apoptosis induced by stress stimuli.

AMP-Activated Protein Kinases↗
PubMed2001

Control of the cell survival/death decision by cannabinoids.

Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.

Animals↗
PubMed2001

Ceramide: a new second messenger of cannabinoid action.

Cannabinoids, the active components of Cannabis sativa (marijuana), and their endogenous counterparts exert their effects by binding to specific G(i/o)-protein-coupled receptors that modulate adenylyl cyclase, ion channels and extracellular signal-regulated kinases. Recent research has shown that the CB(1) cannabinoid receptor is coupled to the generation of the lipid second messenger ceramide via two different pathways: sphingomyelin hydrolysis, and ceramide synthesis de novo. Ceramide in turn mediates cannabinoid-induced apoptosis, as shown by in vitro and in vivo studies. These findings provide a new perspective on how cannabinoids act, and raise exciting physiological and therapeutic questions.

Animals↗
PubMed2001

Cyclosporine-loaded polycaprolactone nanoparticles: immunosuppression and nephrotoxicity in rats.

AIM: The nephrotoxicity and immunosuppressive ability of cyclosporine (CyA) incorporated into polycaprolactone nanoparticles (CyA-NP) was assessed in vitro and in vivo and compared to the effects caused by free drug (Sandimmun. METHODS: The in vivo study included four groups (12 Wistar rats each) receiving oral CyA (10 mg/kg/day for 3 days) as an emulsion of Sandimmun in whole milk or CyA-NP and equivalent doses of empty NP or cremophor in milk as controls. CyA concentrations in blood, urine, liver, spleen and kidney at 24 h post-dosing were measured by fluorescence polarization immunoassay (FPIA). The nephrotoxicity induced by each drug treatment was determined by measuring creatinine plasma levels, malonyl dialdehyde production, and H(2)O(2) and reduced glutathione contents in glomeruli. On the other hand, the immunosuppressive effect was estimated in vivo by incubating lymphocyte suspensions obtained from CyA-, CyA-NP- and control-treated rats, as well as in vitro on lymphocyte suspensions from non-treated healthy animals. RESULTS: Significantly higher blood, urine and tissue levels were achieved with CyA-NP compared to free CyA. However, no changes in creatinine plasma levels were detected due to either CyA or CyA-NP treatment. Only the production of H(2)O(2) in the glomeruli exhibited a significant increase as compared to control groups, but no differences could be ascribed to the different drug treatments. In vivo, the immunosuppressive activity was also comparable for both drug treatments. In contrast, CyA-NP showed a better drug uptake in vitro at concentrations above 25 microM. No immunosuppression was detected in control groups. CONCLUSION: NP improve the oral bioavailability of CyA and its uptake by lymphocytes in vitro above 25 microM. On the contrary, specific immunosuppression and adverse effects were not simultaneously increased. Further studies are needed to clarify the results.

Animals↗
PubMed2001

Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat.

Hepatic ischemia-reperfusion (I/R) injury associated with liver transplantation and hepatic resections are an unresolved problem in the clinical practice. Preconditioning is known to preserve energy metabolism in liver during sustained ischemia, but the molecular mechanisms underlying this effect are still unclear. Different metabolic signals, including adenosine monophosphate (AMP) and nitric oxide (NO), have been implicated in preconditioning. AMP-activated protein kinase (AMPK) protects cells by acting as a low-fuel warning system, becoming switched on by adenosine triphosphate (ATP) depletion. NO synthesis is induced by AMPK in the heart during ischemia. The aim of this study was to investigate: 1) whether preconditioning induces AMPK activation; and 2) if AMPK activation leads to ATP preservation and reduced lactate accumulation during prolonged ischemia and its relationship with NO. Preconditioning activated AMPK and concomitantly reduced ATP degradation, lactate accumulation, and hepatic injury. The administration of an AMPK activator, AICAR, before ischemia simulated the benefits of preconditioning on energy metabolism and hepatic injury. The inhibition of AMPK abolished the protective effects of preconditioning. The effect of AMPK on energy metabolism was independent of NO because the inhibition of NO synthesis in the preconditioned group and the administration of the NO donor before ischemia, or to the preconditioned group with previous inhibition of AMPK, had no effect on energy metabolism. Both preconditioning and AICAR pretreatment, through AMPK activation, may be useful surgical and pharmacologic strategies aimed at reducing hepatic I/R injury.

AMP-Activated Protein Kinases↗
PubMed2001

The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan.

Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.

Adenylate Cyclase Toxin↗
PubMed2001

Neuropsychological test scores, academic performance, and developmental disorders in Spanish-speaking children.

Limited information is currently available about performance of Spanish-speaking children on different neuropsychological tests. This study was designed to (a) analyze the effects of age and sex on different neuropsychological test scores of a randomly selected sample of Spanish-speaking children, (b) analyze the value of neuropsychological test scores for predicting school performance, and (c) describe the neuropsychological profile of Spanish-speaking children with learning disabilities (LD). Two hundred ninety (141 boys, 149 girls) 6- to 11-year-old children were selected from a school in Bogotá, Colombia. Three age groups were distinguished: 6- to 7-, 8- to 9-, and 10- to 11-year-olds. Performance was measured utilizing the following neuropsychological tests: Seashore Rhythm Test, Finger Tapping Test (FTT), Grooved Pegboard Test, Children's Category Test (CCT), California Verbal Learning Test-Children's Version (CVLT-C), Benton Visual Retention Test (BVRT), and Bateria Woodcock Psicoeducativa en Español (Woodcock, 1982). Normative scores were calculated. Age effect was significant for most of the test scores. A significant sex effect was observed for 3 test scores. Intercorrelations were performed between neuropsychological test scores and academic areas (science, mathematics, Spanish, social studies, and music). In a post hoc analysis, children presenting very low scores on the reading, writing, and arithmetic achievement scales of the Woodcock battery were identified in the sample, and their neuropsychological test scores were compared with a matched normal group. Finally, a comparison was made between Colombian and American norms.

Achievement↗
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

The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt.

Cannabinoids exert most of their effects in the central nervous system through the CB(1) cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin and wortmannin blocked the CB(1) receptor-evoked activation of PKB, pointing to the sequential involvement of a G(i)/G(o) protein and phosphoinositide 3'-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB(1) receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB(2) receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB(1) receptor.

Adenylate Cyclase Toxin↗
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

Increasing anther culture efficiency in rice (Oryza sativa L.) using anthers from ratooned plants.

Anther culture response for the variety Taipei-309 was compared using anthers of ratooned and non-ratooned plants. Anthers were plated onto N6 liquid media with 0, 2, 5, and 10 mg l(-1) ABA, respectively. After 5 days in culture, the media were removed and N6 medium without ABA was added. A higher number of pre-mitotic P-pollen grains were observed in anthers from ratooned plants. A significant synergistic effect was found between anthers from ratooned plants/ABA concentrations and the increase in embryogenic-like structures (ELS) induction and green plant regeneration efficiency. The highest frequency of anthers producing ELS was found in N6 medium (6% Sucrose and 2 mg l(-1) 2,4-D) with 5 and 10 mg l(-1) ABA for anthers derived from ratooned plants. Mean green plant regeneration efficiencies were raised from 24.2 to 42% (non-ratooned), and from 30 to 70%, (ratooned donor plants) using a combination of 10 mg l(-1) ABA in induction media, and MS with 2 mg l(-1) BAP, 1 mg l(-1) NAA, 2 mg l(-1) kinetin and 0.45% agarose. The highest number of green shoots per ELS were obtained from ratooned-derived anthers (up to 82). The use of ratooned plants in anther culture, its importance and relative advantages are also discussed.

Journal Article↗