RESUMEN
We undertook a cross-sectional study in rural Jehlum and urban Karachi to evaluate the prevalence of vitamin D deficiency in Pakistani pregnant women and neonates and to assess any association of serum 25(OH) vitamin D [25(OH)D] concentration with vitamin D binding protein (Gc) genotypes. Altogether, 390 women and 266 neonates were recruited from urban and rural sites, respectively. Serum 25(OH)D was measured by an immunoassay, while Gc genotypes were identified using polymerase chain reaction followed by restriction fragment length polymorphism or PCR-RFLP. One-way analysis of variance or ANOVA and linear regression were used for statistical analysis. In urban Karachi, 99.5% of women and 97.3% of neonates were vitamin D deficient (< 50 nmol/L), while 89% of women and 82% of neonates were deficient in rural Jehlum. Gc genotypes were not associated with serum 25(OH)D concentrations in both women and their neonates. We conclude that vitamin D deficiency is highly prevalent in Pakistani women and their neonates, and Gc genotypes are not associated with serum 25(OH)D concentrations.
Asunto(s)
Deficiencia de Vitamina D/epidemiología , Proteína de Unión a Vitamina D/genética , Adolescente , Adulto , Calcifediol/sangre , Estudios Transversales , Femenino , Humanos , Recién Nacido , Pakistán/epidemiología , Embarazo , Prevalencia , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/genética , Adulto JovenRESUMEN
BACKGROUND AND AIM: Pakistani people belong to an ethnic group which has the highest rate of coronary artery disease (CAD). We investigated the possible correlation between deficiency of vitamins B6, B12 or folic acid and hyperhomocysteinemia in Pakistani patients with acute myocardial infarction (AMI). A case-control study was carried out involving 224 AMI patients (age 30-70 years; 55 females and 169 males) and 126 normal healthy subjects (age 31-70 years; 35 females and 91 males). METHODS AND RESULTS: Fasting venous blood was obtained from cases and controls. Serum was analyzed for folic acid and B12 using radioassays. Plasma was analyzed for pyridoxal phosphate (PLP; coenzymic form of B6) using a radioenzymatic assay and for total homocysteine using a fluorescence polarization immunoassay. Mean serum B12 concentration in AMI patients was found to be significantly lower than the mean for controls (241+/-185 pg/ml vs 608+/-341 pg/ml; p < 0.001). Mean serum folate level in patients was also found to be lower than controls (3.35+/-3.78 ng/ml vs 4.93+/-2.93 ng/ml), however, the differences were not statistically significant. Similarly, mean PLP concentration in plasma of cases (19.4+/-24.4 nmol/l) was lower than the concentration in controls (23.2+/-17.6 nmol/l), but the difference was not statistically significant. Mean plasma homocysteine level in AMI cases (18+/-8.36 micromol/l) was higher than the mean level in controls (16.4+/-4.9 micromol/l), but not to a significant extent. However, this mean homocysteine concentration in normal healthy subjects was among the highest reported in the literature and was significantly more than mean values reported in most Eastern and Western studies. Compared to controls, there was significantly greater deficiency of folate (32.5% vs 67.1%), B12 (3.2% vs 63.4%) and PLP (49.2% vs 74.1%) in AMI patients. Deficiencies of folate, B12 and PLP were defined as serum folate levels less than 3.5 ng/ml, serum levels of B12 less than 200 pg/ml and plasma PLP levels less than 20 nmol/l. Mean plasma homocysteine levels in smokers were found to be significantly higher in both cases and controls. Similarly, mean serum folate levels in smokers (compared to nonsmokers) were significantly lower in both cases and controls. CONCLUSIONS: Substantial nutritional deficiencies of these three vitamins along with mild hyperhomocysteinemia, perhaps through an interplay with the classical cardiovascular risk factors (highly prevalent in this population), could be further aggravating the risk of CAD in the Pakistani population.
Asunto(s)
Ácido Fólico/sangre , Hiperhomocisteinemia/complicaciones , Infarto del Miocardio/sangre , Vitamina B 12/sangre , Vitamina B 6/sangre , Adulto , Anciano , Envejecimiento , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Inmunoensayo de Polarización Fluorescente , Deficiencia de Ácido Fólico/complicaciones , Deficiencia de Ácido Fólico/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Obesidad/complicaciones , Pakistán/epidemiología , Fosfato de Piridoxal/sangre , Fumar/sangre , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/epidemiología , Deficiencia de Vitamina B 6/complicaciones , Deficiencia de Vitamina B 6/epidemiologíaRESUMEN
OBJECTIVE: To investigate changes in total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides in serum of Pakistani patients with AMI due to age, gender, body mass index (BMI), diabetes, hypertension, and smoking, and also find out the prevalence of hypercholesterolemia, hypertriglyceridemia, "low HDL-cholesterol" and "isolated low-HDL cholesterol" in them. PATIENTS AND METHODS: Serum samples from 451 consecutive AMI patients (250 from National Institute of Cardiovascular Diseases, Karachi and 201 from Armed Forces Institute of Cardiology, Rawalpindi) were analyzed for total cholesterol, HDL-cholesterol and triglycerides using kit methods. LDL-cholesterol was determined using the Friedewald formula. RESULTS: Mean serum concentrations of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides in AMI patients were found to be 181 +/- 50 mg/dl, 35.7 +/- 11.3 mg/dl, 110 +/- 47 mg/dl and 177 +/- 127 mg/dl, respectively. Mean levels of total cholesterol and HDL-cholesterol were not significantly affected by age, gender, BMI, diabetes mellitus, hypertension and smoking. Mean LDL-cholesterol concentration, however, was found to be significantly increased in diabetes mellitus (p=0.047), while age, gender, BMI, hypertension and smoking had no significant effect on the levels of this lipoprotein. Mean levels of triglycerides were significantly decreased in older patients (>50 years) compared to younger (<50 years) ones (p=0.019). Gender, BMI, diabetes mellitus, hypertension and smoking, however, had no effect on triglyceride levels The frequencies of hypercholesterolemia, hypertriglyceridemia, "low HDL-cholesterol" and "isolated low-HDL-cholesterol" were found to be 30.6%, 30.1%, 48.6% and 34.1%, respectively. CONCLUSION: High prevalence of hypertriglyceridemia and low HDL-cholesterol (which constitute a component of metabolic syndrome) in Pakistani AMI patients is suggestive that these two lipid abnormalities could be playing a major role in the development of atherosclerosis in Pakistani population.
Asunto(s)
Lipoproteínas HDL/sangre , Infarto del Miocardio/sangre , Anciano , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Angiopatías Diabéticas/sangre , Femenino , Humanos , Hipercolesterolemia/epidemiología , Hipertrigliceridemia/epidemiología , Masculino , Persona de Mediana Edad , Pakistán/epidemiología , Estudios Seroepidemiológicos , Triglicéridos/sangreRESUMEN
OBJECTIVE: Glutathione (GSH) has a central role in the defence against oxidative damage. This study was carried out to investigate any change in erythrocyte GSH levels in a population of patients with acute myocardial infarction (AMI) and compare them with levels in normal healthy subjects. METHOD: GSH levels were determined in erythrocytes of one hundred and seventy six patients with AMI (age: 30-70 years; 131 males and 45 females) admitted to the National Institute of Cardiovascular Diseases, Karachi. These levels were compared with eryrocyte GSH levels obtained from 95 normal healthy subjects (controls). RESULTS: Mean +/- SD erythrocyte GSH levels in AMI patients and controls were found to be 2.34 +/- 0.62 micromol/ml of packed cells and 2.08+/- 0.62 micromol/ml of packed cells, respectively. The two values when compared with one way ANOVA were found to be significantly different (p=0.001). Age had little effect on erythrocyte GSH levels in both AMI patients and normal healthy subjects. CONCLUSION: Increased production of reactive oxygen species is a feature of cardiovascular disease, such as AMI and cells can respond to mild oxidative stress by upregulating antioxidant defence in terms of increased production of GSH.
Asunto(s)
Antioxidantes , Eritrocitos/metabolismo , Glutatión/metabolismo , Infarto del Miocardio/metabolismo , Enfermedad Aguda , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A mouse-model was used to investigate the effect of methotrexate (MTX) and folinic acid on accumulation of iron in young growing mice. Four equal groups of Balb/c young male mice were treated (subcutaneously) with either MTX, or folinic acid, or MTX plus folinic acid, or physiological saline on every second day. After 3 weeks of treatment, liver, spleen, kidney, small intestine, brain, skeletal muscle and heart were removed and analyzed for iron contents using a spectrophotometric method. When the mean values of iron in liver of four groups were compared using one way ANOVA followed by Tukey's HSD test, the group receiving MTX alone was found to have significantly (p=0.004) more accumulation of iron in liver. The group receiving MTX plus folinic acid had iron accumulation in the liver similar to the placebo group. However, the mean values of iron in brain, kidney, small intestine, skeletal muscle, heart and spleen in all the groups, were not found to be statistically different. The data indicate that MTX shifts iron from being utilized in hemoglobin synthesis to liver stores. Folinic acid administration 8 h post-MTX, however, prevents this shift of iron to liver. Decreased levels of iron in plasma in mice treated with MTX alone suggest decreased availability of iron to other tissues for their normal growth and development.
Asunto(s)
Antagonistas del Ácido Fólico/farmacología , Hierro/metabolismo , Leucovorina/farmacología , Metotrexato/farmacología , Animales , Hemoglobinas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos TeóricosAsunto(s)
Enfermedad Coronaria/genética , Predisposición Genética a la Enfermedad , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Polimorfismo Genético , Adulto , Distribución por Edad , Anciano , Estudios de Casos y Controles , Enfermedad Coronaria/epidemiología , Femenino , Genotipo , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Persona de Mediana Edad , Mutación , Prevalencia , Medición de Riesgo , Sensibilidad y Especificidad , Distribución por SexoRESUMEN
AIM: To investigate whether chronic administration of medium doses of methotrexate (MTX) causes suppression of skeletal growth in young mice and to determine whether folinic acid supplementation could reverse this effect. METHODS: Four equal groups of Balb/c young male mice (6 animals in each group; mean body weight 11.9 +/- 0.25 g, in their rapid growth phase) were subjected to the following drug treatment for a period of 3 wk. Group 1 was given intraperitoneal MTX (3.5 mg kg(-1) body weight) every second day. Group 2 received folinic acid (7.0 mg kg(-1) body weight) intraperitoneally every second day. Group 3 was given both drugs (MTX every second day and folinic acid 8 h post-MTX injection). Group 4 was injected with physiological saline every other day to serve as a control group. Total body weight of the animals in each group was monitored every second day for the entire study period. The animals were sacrificed, the bilateral femurs and tibias of each animal were harvested and X-rays of the bones were taken. The length of each femur and tibia was measured using a micrometer. Measurements from the radiographs were also recorded using image analysis software. The MTX concentrations in the plasma and the folate levels in erythrocytes were determined. The heights of the distal femoral and the proximal tibial growth plate for each animal were measured on histological tissue sections. RESULTS: Mean lengths of both the tibia and femur of animals were compared in the four treatment groups. A significant decrease in the mean lengths (one-way ANOVA, p < 0.005) was observed in the group receiving MTX alone. Similarly, there was a significant decrease (p < 0.001) in the height of the femoral and tibial growth plate in this group when compared with the other groups. The main effect of MTX seemed to be on the hypertrophic proliferative zone of chondrocytes in the growth plate. Furthermore, animals in this MTX-treated group also showed increased levels of MTX in plasma and low levels of erythrocyte folate. CONCLUSION: These data show that chronic administration of MTX induces suppression of skeletal growth in mice, possibly through the inhibition of the pathway of de novo DNA synthesis. Folinic acid treatment following MTX administration appears to reverse this growth inhibition. Based on these observations, children suffering from juvenile rheumatoid arthritis, osteosarcoma or acute lymphoblastic leukaemia and receiving MTX over long periods of time could be at risk of short-term suppression of skeletal growth. If this is the case, it is possible that they could benefit from dietary supplementation with folinic acid.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antirreumáticos/farmacología , Desarrollo Óseo/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Leucovorina/farmacología , Metotrexato/farmacología , Animales , Antimetabolitos Antineoplásicos/efectos adversos , Antirreumáticos/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Eritrocitos/química , Fémur/crecimiento & desarrollo , Ácido Fólico/sangre , Placa de Crecimiento/efectos de los fármacos , Leucovorina/administración & dosificación , Masculino , Metotrexato/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Tibia/crecimiento & desarrolloRESUMEN
The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.
Asunto(s)
Antídotos/farmacología , Antagonistas del Ácido Fólico/toxicidad , Trastornos del Crecimiento/inducido químicamente , Trastornos del Crecimiento/prevención & control , Leucovorina/farmacología , Metotrexato/antagonistas & inhibidores , Metotrexato/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Trastornos del Crecimiento/patología , Intestino Delgado/patología , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
OBJECTIVE: Granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) are frequently used in cancer patients to overcome the granulocytopenic effects of chemotherapy, and also to mobilize the stem cells. The mobilized stem cells are collected from the peripheral blood and used for transplantation following high doses of chemotherapy. However, the molecular mechanism by which these colony stimulating factors (CSFs) bring about proliferation of myeloid precursor cells is not clearly known. Dihydrofolate reductase (DHFR), which has an established role in DNA synthesis, could be a link between administration of CSF and stem cell proliferation. The purpose of this study was to investigate whether CSFs induce white cell proliferation by producing multiple forms of DHFR. METHODS: Twelve patients with non-haematological malignancies were treated with either G-CSF or GM-CSF to mobilize stem cells. Nine healthy subjects were treated with placebo as controls. Blood samples were obtained before and after stimulation with CSFs or placebo. White blood cells were separated and concentrations of both active DHFR and immunoreactive nonfunctional form of DHFR were determined in their cytoplasm using methotrexate-binding assay and enzyme-linked immunosorbent assay, respectively. Total leucocytes count (TLC) was also monitored before and after stimulation with CSFs or placebo. RESULTS: There was a significant (P < 0.05) increase in concentration of immunoreactive nonfunctional form of DHFR and TLC following stimulation with CSFs. There was an increase in concentration of active DHFR as well, however, this did not reach statistical significance. In the placebo-treated subjects, no significant increase in active DHFR, immunoreactive nonfunctional form of enzyme or TLC was observed. However, it was noticed that the base-line values of active DHFR and immunoreactive nonfunctional form of enzyme in leucocytes of cancer patients were higher than the base-line values in leukocytes of normal healthy subjects. CONCLUSION: Our data suggest that colony stimulating factors induce white cell proliferation by increasing levels of multiple forms of DHFR.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Leucocitos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Tetrahidrofolato Deshidrogenasa/efectos de los fármacos , Adolescente , Adulto , Femenino , Movilización de Célula Madre Hematopoyética , Humanos , Recuento de Leucocitos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean +/- SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 +/- 0.4 ng/mg protein and 0.99 +/- 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 +/- 0.32 ng/mg protein and 1.18 +/- 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P < 0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 +/- 97 ng/mg protein and 605 +/- 475 ng/mg protein before and after stimulation with GM-CSF, and 115 +/- 165 ng/mg protein and 1,054 +/- 1,095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Neoplasias/sangre , Neutropenia/metabolismo , Tetrahidrofolato Deshidrogenasa/metabolismo , Adolescente , Adulto , División Celular/efectos de los fármacos , Niño , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Isoenzimas/biosíntesis , Isoenzimas/metabolismo , Recuento de Leucocitos , Leucocitos/efectos de los fármacos , Leucocitos/enzimología , Leucocitos/patología , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neutropenia/sangre , Neutropenia/inducido químicamente , Tetrahidrofolato Deshidrogenasa/biosíntesisRESUMEN
The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antagonistas del Ácido Fólico/farmacología , Crecimiento/efectos de los fármacos , Indometacina/farmacología , Metotrexato/farmacología , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Interacciones Farmacológicas , Ingestión de Alimentos/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tetrahidrofolato Deshidrogenasa/metabolismoRESUMEN
In this study we report our two years experience of methotrexate (MTX) in the management of rheumatoid arthritis (RA) at the Aga Khan University Hospital, Karachi. We studied the clinical course of 124 RA patients. The mean age was 44 +/- 11 years (range 19-72) and mean duration of RA was 5 +/- 4 years (range 0.3-25). Female to male ratio was 10:2.4 (100F:24M). All of them were diagnosed according to the criteria set by American Rheumatism Association. The mean value of ESR was 60 +/- 30 (Range 3-128). Fifty one percent had severe disease (> 10 joints involved and evidence of erosions and deformities). Twenty-one patients had extra-articular manifestations. None of them had received MTX previously. Their kidney and liver functions were assessed to be normal. Patients were divided into two groups. One group (n = 92) received MTX (7.5-10 mg/week) as initial treatment, while the other group (n = 32) was given other disease modifying anti-rheumatic drugs (penicillamine, salazopyrin, gold, or chloroquine) followed by MTX. Assessment of the treatment outcome and development of any adverse reactions was carried out at 3-month interval over an average period of 1 year. Assessment of the treatment outcome in the group which received MTX as initial drug revealed the response to be excellent in 13%, good in 70%, fair in 11% and variable in 4%. In the group which received MTX as second-line of therapy, 59% of the patients had the response from good to excellent, while 25% of the patients exhibited poor to fair response. Regarding side-effects of MTX treatment, 57% exhibited none, while 35% had nausea and vomiting. Alopecia was the next common toxicity in these patients. Two individuals had abnormal liver function tests (value twice more than normal), while one developed lung fibrosis. MTX despite its adverse effects in some of the patients is still an effective, well tolerated and inexpensive disease modifying drug in RA.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Adulto , Anciano , Artritis Reumatoide/diagnóstico , Cloroquina/uso terapéutico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Oro/uso terapéutico , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Penicilamina/uso terapéutico , Estudios Retrospectivos , Sulfasalazina/uso terapéutico , Resultado del TratamientoRESUMEN
We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently taking the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, diclofenac, naproxen, indomethacin, and ibuprofen. The area under the curve, the total systemic clearance, the distribution volume, and the half-life of methotrexate in patients receiving concurrent NSAID therapy did not change significantly (at p < 0.05). Concurrent treatment with NSAIDs resulted in increased inter-patient variability of methotrexate concentration, possibly as a result of biochemical interactions; however, it does not appear clinically relevant. The data suggest that the NSAIDs do not significantly affect the disposition of methotrexate, contrary to some of the earlier reports.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Metotrexato/farmacocinética , Metotrexato/uso terapéutico , Adolescente , Adulto , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Antirreumáticos/efectos adversos , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Metotrexato/efectos adversos , Persona de Mediana EdadRESUMEN
Excretion of urinary N-acetyl beta-D-glucosaminidase (NAG) and its isoenzyme patterns were studied in two groups of patients with rheumatoid arthritis (RA) and in normal control subjects. Urine samples were collected from 30 seropositive RA patients, 19 seronegative RA patients, and 15 normal healthy subjects. All the patients and normal subjects were assessed to have normal liver and kidney functions. A small portion of the urine sample was dialyzed against 0.01 M phosphate buffer, pH 7.0 and NAG activity was monitored. Mean +/- SD values of urinary NAG in seropositive RA patients, in seronegative RA patients and in normal healthy subjects were found to be 4.20 +/- 3.73 U/g creatinine, 2.96 +/- 2.11 U/gm creatinine, and 1.71 +/- 0.6 U/g creatinine, respectively. The mean urinary, NAG value in RA patients was found to be significantly higher (P < 0.05) in seropositive RA compared to the mean NAG value in normal healthy subjects and patients with seronegative RA when analyzed by one way ANOVA and Tukey-HSD test. The mean proportion of isoenzyme form B to isoenzyme form A in seropositive RA patients was also found to be significantly different (P < 0.05) from the mean proportion of these forms in normal healthy subjects and seronegative RA patients. There also appears to be a correlation between the concentration of urinary NAG and severity of the disease in seropositive RA.
Asunto(s)
Acetilglucosaminidasa/orina , Artritis Reumatoide/enzimología , Artritis Reumatoide/orina , Adulto , Artritis Reumatoide/inmunología , Cromatografía Liquida/métodos , Femenino , Humanos , Isoenzimas , Masculino , Valor Predictivo de las Pruebas , Índice de Severidad de la EnfermedadRESUMEN
Methotrexate concentration was analyzed in a number of tissues of a patient of osteogenic sarcoma who had been on high-dose methotrexate therapy for nearly 6 months. Gall bladder and kidney contained the highest concentration of the drug, followed by testis, small intestine, skeletal muscle, bone marrow, lung, spleen, heart and liver. Although, compared to kidney the liver contained relatively small amount of the drug, yet nearly 1/5th of the total drug in liver was in bound form. This bound form of methotrexate is most likely associated with multiple forms of dihydrofolate reductase. The total concentration of methotrexate in kidney is 80 fold higher than the concentration of the drug in liver and 28 fold higher than the concentration in bone marrow. This suggests that in high-dose methotrexate therapy, nephrotoxicity is the more immediate threat to the patient than hepatotoxicity and bone marrow suppression.
Asunto(s)
Antimetabolitos Antineoplásicos/metabolismo , Neoplasias Óseas/metabolismo , Metotrexato/metabolismo , Osteosarcoma/metabolismo , Adolescente , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Vesícula Biliar/metabolismo , Humanos , Riñón/metabolismo , Hígado/metabolismo , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Músculo Esquelético/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/secundario , Distribución TisularRESUMEN
The successful outcome of ovarian cancer therapy with alkylating agents and cisplatin is seriously hampered by the development of acquired drug resistance. An increase in intracellular glutathione (GSH) levels in cancer cells is one of the major mechanisms involved. Depletion of GSH overcomes drug resistance and restores the chemosensitivity of malignant cells. Ifosfamide (IFEX), an alkylating agent, has been demonstrated to decrease intracellular GSH levels in vitro in malignant cell lines and in vivo in peripheral blood lymphocytes (PBL) obtained from patients with cancer. We studied the effect of IFEX on intracellular GSH levels in PBL isolated from patients with advanced ovarian cancer who were receiving chemotherapy. A total of 14 patients received IFEX plus mesna as a continuous infusion (1 g/m2 per day) for 6 consecutive days and cisplatin (100 mg/m2) as a 24-h continuous infusion on the 6th day. PBL were isolated prior to the initiation of chemotherapy and on the 3rd and 6th days of IFEX infusion. Intracellular GSH levels were determined by a modification of Tietze's method. IFEX caused a 20% or greater suppression of intracellular GSH levels in nine patients, eight of whom achieved complete remission of their disease. Six patients responded poorly to this chemotherapeutic regimen, five of whom showed no significant suppression of GSH levels. These data suggest that IFEX suppresses intracellular GSH levels in PBL from patients with ovarian cancer and that this suppression correlates closely with the subsequent clinical outcome.