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1.
Diabetes Metab ; 37(2): 90-6, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21236717

ABSTRACT

Digestive disorders (diarrhoea, vomiting) represent the most common metformin side-effects (around 30%) with this first-line drug treatment for type 2 diabetes. In healthy individuals, metformin affects glucose, vitamin B12 and the digestive uptake of bile salts. In the colon, it acts locally by modifying glucose cell metabolism. Different pathophysiological hypotheses have been proposed to explain the metformin-induced diarrhoea and vomiting, which can sometimes cause the patient to stop an effective treatment. These theories include stimulation of intestinal secretion of serotonin, changes in incretin and glucose metabolism, and bile-salt malabsorption. However, none of these hypotheses can be considered an adequate pathophysiological explanation of metformin digestive side-effects. In addition, there is a lack of experimental data to explain these highly patient-dependent adverse effects.


Subject(s)
Digestive System Diseases/chemically induced , Metformin/adverse effects , Bile Acids and Salts/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diarrhea/chemically induced , Digestive System Diseases/epidemiology , Glucose/metabolism , Humans , Intestinal Mucosa/metabolism , Intestines/drug effects , Metformin/pharmacokinetics , Serotonin/metabolism , Vomiting/chemically induced
2.
Anticancer Res ; 30(10): 4297-301, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21036755

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) patients whose tumours have microsatellite instability (MSI) do not benefit from adjuvant 5-fluorouracil. However, the predictive value of MSI is not known for FOLFOX, now recommended in adjuvant setting. PATIENTS AND METHODS: MSI phenotype was assessed by the pentaplex method. Three-year relapse and disease-free survival (DFS) of patients treated for CRC with FOLFOX 4 in an adjuvant setting were compared according to MSI phenotype. RESULTS: A total of 105 patients (19 MSI, 86 microsatellite stable, MSS) were included. Stage II patients more frequently exhibited MSI (58%) than MSS (21%); (p=0.002). Patients with MSI relapsed significantly less than those with MSS (10.5% vs. 35.0%; p=0.04). DFS was similar for MSI and MSS (p=0.1). In univariate analysis, stage (p=0.0006) and MSI status (p=0.017) were significant predictors of DFS. CONCLUSION: MSI status was associated with significantly fewer relapses and a better prognosis. FOLFOX4 did not alter survival of patients with MSI and can be administered to them.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Microsatellite Instability , Adult , Age Factors , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Chemotherapy, Adjuvant , Colorectal Neoplasms/surgery , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Organoplatinum Compounds/administration & dosage
3.
Parasite ; 17(4): 329-35, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21275239

ABSTRACT

Head lice are endemic worldwide. Resistance to permethrin and doubts about the safety of pesticides promoted the use of physical therapies (wet-combing, dry-on suffocation). The aim of our study was to test the pediculicidal and ovicidal effects of one application of a silicon-oil complex composed of dimethiconol and castor oil. The study was a prospective cohort of 108 infested patients (11 males, 97 females; 58 children, 50 adults), in Sri-Lanka. Pediculicidal efficacy was evaluated as the percentage of patients free of live lice one hour after the application of the treatment and at day 1 (wet combing). Ovicidal efficacy was calculated as the proportion of subjects without larval stages at days 1 and 7 among subjects followed up all over the study. In normal conditions of use, in this open cohort, a pediculicidal effect of a dimethiconol-castor-oil lotion was.shown one hour after application in 99/108 (91.7%) treated subjects and at day 1 in 86/99 (87%) subjects and an ovicidal effect at day 7 in 79/108 (73.2%) treated subjects. A second application of the same product was necessary to increase the cure rate to 79.6% (86/108) at day 8. In our study, the second application of the same product was performed seven days later, but the best time for additional applications should be defined in further studies. However, the efficacy of this safe physical treatment was similar to that of chemical pediculicides (malathion, permethrin).


Subject(s)
Lice Infestations/drug therapy , Pediculus/drug effects , Permethrin/therapeutic use , Adult , Aged , Animals , Castor Oil/administration & dosage , Castor Oil/therapeutic use , Child , Child, Preschool , Drug Tolerance , Female , Hair/parasitology , Humans , Insecticides/therapeutic use , Male , Middle Aged
4.
Anticancer Res ; 27(4C): 2715-9, 2007.
Article in English | MEDLINE | ID: mdl-17695437

ABSTRACT

BACKGROUND: Microsatelite instability (MSI) is the consequence of the inactivation of a mismatch repair gene and is observed in approximately 15% of colon cancer cases. Patients with MSI colon cancer do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. A current treatment of reference for colon cancer is a combination of 5-FU and oxaliplatin (FOLFOX). The aim of this study was to determine the efficiency of the FOLFOX treatment in patients with metastatic MSI colon cancer. PATIENTS AND METHODS: Tumour specimens were collected from patients with metastatic colon cancer treated with FOLFOX 4 modified or FOLFOX 6; these two regimens are based on 85 mg/m2 and 100 mg/m2 oxaliplatin, respectively. The MSI status was assessed by measuring the length of five monomorphic mononucleotide markers. The FOLFOX regimen was evaluated as a first-line treatment according to WHO criteria. RESULTS: Forty patients (22 men, 18 women), median age 63.5 years (27-83 years) were treated with FOLFOX 4 or 6. Nine patients had tumours exhibiting high MSI (MSI group) and 31 patients had tumours exhibiting microsatellite stability (MSS group). In the MSS group, 11 partial responses (36%) were observed, while there were only two in the MSI group (22%) (no significant difference). The two patients who were responders in the MSI group were treated with FOLFOX 6. The overall survival was not significantly different for MSI and MSS patients. CONCLUSION: No significant differences in the overall response rate or overall survival between the two groups of patients were observed. However, these results suggest that patients with MSI colon cancer are more sensitive to a higher dose of FOLFOX.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Microsatellite Instability , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Oxaliplatin
5.
Ann Endocrinol (Paris) ; 68(5): 332-6, 2007 Oct.
Article in French | MEDLINE | ID: mdl-17707761

ABSTRACT

Sunitinib inhibits numerous tyrosine kinase receptors involved in tumor growth, angiogenesis, and metastatic invasion. It is indicated in case of metastatic renal carcinomas and gastrointestinal stromal tumors (GIST) resistant to imatinib. Prospective and retrospective studies have shown association between use of sunitinib and hypothyroidism affecting more than 50% of patients in some series. More amazing, was the non-visualisation of thyroid tissue evaluated with thyroid ultrasonography in two cases. Mechanisms of this side effect are not elucidated. Some studies have suggested destructive thyroiditis but no evidence of autoimmunity has been demonstrated. Anti angiogenic effect could be another hypothesis. Recently antithyroperoxidase activity of sunitinib has been demonstrated. Because hypothyroidism is easily accessible to treatment, screening of thyroid abnormalities is mandatory every three months to improve quality of life of these patients. This unique thyroid side effect of sunitinib with the non-visualisation of thyroid suggests a possible and promising antitumor activity in thyroid cancer.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Hypothyroidism/drug therapy , Indoles/therapeutic use , Pyrroles/therapeutic use , Clinical Trials as Topic , Humans , Sunitinib
6.
Br J Cancer ; 94(12): 1823-32, 2006 Jun 19.
Article in English | MEDLINE | ID: mdl-16773076

ABSTRACT

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.


Subject(s)
Adenocarcinoma/blood supply , Adenocarcinoma/mortality , Colorectal Neoplasms/blood supply , Colorectal Neoplasms/mortality , Neovascularization, Pathologic , Vascular Endothelial Growth Factor A/biosynthesis , Adenocarcinoma/metabolism , Aged , Antigens, CD34/biosynthesis , Capillaries , Colorectal Neoplasms/metabolism , Disease-Free Survival , Factor VIII/biosynthesis , Female , Humans , Immunohistochemistry , Male , Middle Aged , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Prognosis , Survival Analysis , Survival Rate
7.
Antimicrob Agents Chemother ; 42(4): 849-56, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9559795

ABSTRACT

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL[CR]) are proposed: for patients with normal renal function (CL[CR] of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL[CR], 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.


Subject(s)
Amikacin/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Fever/metabolism , Neutropenia/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Amikacin/administration & dosage , Anti-Bacterial Agents/administration & dosage , Creatinine/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Kidney Diseases/metabolism , Male , Middle Aged , Models, Biological , Population
8.
J Hepatol ; 26(1): 96-102, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9148029

ABSTRACT

BACKGROUND/AIMS: The incidence of hepatocellular carcinoma is higher in males, presumably due to the influence of sex steroids. Therefore, to further assess the role of sex steroids in the occurrence of hepatocellular carcinoma, this study investigated the predictive value of different sex hormones and their binding protein. METHODS: Among 101 male patients with cirrhosis included in a prospective screening study, 29 developed hepatocellular carcinoma. We assessed the predictive value of 17 clinico-biological and 4 serum hormonal variables collected at enrollment, by the log-rank test and the Cox model. RESULTS: Age (p = 0.003), bilirubin (p = 0.04), sex-hormone-binding-globulin (p = 0.006) and albumin (p = 0.08) were predictive using the log-rank test, while estradiol and total and free testosterone were not. The Cox model showed age (p = 0.0003; relative risk = 7.52), sex-hormone-binding globulin (p = 0.001, relative risk = 3.37) and albumin (p = 0.02, relative risk = 2.94) as the most predictive parameters. CONCLUSION: We conclude that high serum sex-hormone-binding-globulin levels have an independent predictive value for the occurrence of hepatocellular carcinoma. Serum sex-hormone-binding-globulin could be used to define patients at high risk for hepatocellular carcinoma and could hypothetically play a role in hepatocarcinogenesis.


Subject(s)
Carcinoma, Hepatocellular/diagnosis , Liver Cirrhosis/complications , Liver Neoplasms/diagnosis , Sex Hormone-Binding Globulin/metabolism , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Liver Cirrhosis/blood , Liver Neoplasms/blood , Liver Neoplasms/complications , Liver Neoplasms/epidemiology , Logistic Models , Male , Mass Screening/methods , Middle Aged , Predictive Value of Tests , Prospective Studies
9.
J Clin Endocrinol Metab ; 81(12): 4278-89, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8954028

ABSTRACT

Osteoporosis is the main cause of spine and hip fractures. Morbidity, mortality, and costs arising from hip fractures have been well documented. Thyroid hormones (TH) are widely prescribed, mainly in the elderly. Some studies (but not all) found a deleterious effect of suppressive TH therapy on bone mass. These conflicting data raised a controversy as to the safety of current prescribing and follow-up habits, which, in turn, raised major health-care issues. To look for a detrimental effect on bone of TH therapy, we performed a meta-analysis (by pooling standardized differences, using a fixed effect model) of all published controlled cross-sectional studies (41, including about 1250 patients) concerning the impact of TH therapy on bone mineral density (BMD). Studies with women receiving estrogen therapy were excluded a priori, as were studies with a high percentage of patients with postoperative hypoparathyroidism, when no separate data were available. We decided to stratify the data according to anatomical site, menopausal status, and suppressive or replacement TH therapy, resulting in 25 meta-analysis on 138 homogeneous subsets of data. The main sources of heterogensity between studies that we could identify were replacement or suppressive TH therapy, menopausal status, site (lumbar spine, femoral neck, Ward's triangle, greater trochanter, midshaft and distal radius, with various percentages of cortical bone), and history of hyperthyroidism, which has recently been found to impair bone mass in a large epidemiological survey. To improve homogeneity, we excluded a posteriori 102 patients from 3 studies, who had a past history of hyperthyroidism and separate BMD data, thus allowing assessment of the TH effect in almost all 25 subset meta-analyses. However, controls were usually not matched with cases for many factors influencing bone mass, such as body weight, age at menarche and at menopause, calcium dietary intake, smoking habits, alcohol intake, exercise, etc. For lumbar spine and hip (as for all other sites), suppressive TH therapy was associated with significant bone loss in postmenopausal women (but not in premenopausal women), whereas, conversely, replacement therapy was associated with bone loss in premenopausal women (spine and hip), but not in postmenopausal women. The detrimental effect of TH appeared more marked on cortical bone than on trabecular bone. Only a large long term prospective placebo-controlled trial of TH therapy (e.g. in benign nodules) evaluating BMD (and ideally fracture rate) would provide further insight into these issues.


Subject(s)
Bone Density/drug effects , Thyroid Hormones/adverse effects , Adult , Aged , Cross-Sectional Studies , Female , Humans , Male , Middle Aged
10.
AIDS ; 9(8): 901-7, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7576325

ABSTRACT

OBJECTIVE: Intravenous pentamidine induces hypo- and hyperglycaemia (dose-dependent toxicity on islet beta cells), pancreatitis and nephrotoxicity. Conversely, aerosolized pentamidine (AP) is usually devoid of systemic side-effects: few reports of hypo- or hyperglycaemia have been published. Our study aimed to assess the influence on glucose homeostasis and insulin secretion of long-term exposure to AP used for prophylaxis of Pneumocystis carinii pneumonia in HIV-positive patients, and to compare the impact on insulin secretion of AP, whether administered for the first time or after prolonged monthly exposure. DESIGN: Retrospective cross-sectional controlled study (main objective) and non-randomized prospective controlled study. PATIENTS: We compared glucose homeostasis and C peptide response to 1 mg intravenous glucagon in patients who had previously inhaled > or = 10 prophylactic aerosols (group 1, n = 21) and in HIV-positive controls (groups 2 and 3, n = 28) who had received none. Both groups were comparable for age and body-mass index, but CD4 T-lymphocyte counts and Karnofsky scores were both significantly higher in the control group. RESULTS: Fasting (T0) blood glucose, fructosamine and response to the first glucagon test were similar in both groups, but postprandial glucose, glycated haemoglobin and fasting C peptide were significantly higher (P < 0.05) in the pentamidine group. A second glucagon test was performed on the same day, 3 h (T3) after AP inhalation in 35 patients (in 21 after > or = 10 aerosols, group 1; in 14 after the first, group 2) and in 14 HIV-positive controls (group 3). The only significant difference between the three groups in C peptide response to this second test was a lower peak T3/peak T0 ratio in group 1. Plasma amylase and creatinine were not altered by the aerosol. CONCLUSION: Long-term prophylactic exposure to AP had minor but significant effects on glucose homeostasis and insulin secretion but did not modify pancreatic and renal function. The detrimental effects induced by long-term exposure to AP found in our study are probably not clinically relevant, but a more prolonged exposure to AP might conceivably induce more severe alterations.


Subject(s)
Glucose/metabolism , HIV Infections/drug therapy , Insulin/metabolism , Pentamidine/administration & dosage , Pentamidine/adverse effects , AIDS-Related Opportunistic Infections/prevention & control , Administration, Inhalation , Adult , Aerosols , C-Peptide/blood , Cross-Sectional Studies , Female , HIV Infections/physiopathology , Homeostasis/drug effects , Humans , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/physiopathology , Male , Pneumonia, Pneumocystis/prevention & control , Prospective Studies , Retrospective Studies , Time Factors
11.
Ann Otol Rhinol Laryngol ; 102(7): 496-501, 1993 Jul.
Article in English | MEDLINE | ID: mdl-8333670

ABSTRACT

The causes of transient hypocalcemia after thyroid surgery are not fully understood. In 95 consecutive patients undergoing total thyroidectomy (n = 30), subtotal thyroidectomy (n = 14), or hemithyroidectomy (n = 51), we serially measured total calcium, parathyroid hormone (PTH), and proteins before surgery and 6, 24, 48, 72, and 96 hours after surgery, and we calculated the corresponding ionized calcium levels. In the whole population, there was a statistically significant decrease of PTH, total calcium, and proteins at nearly every time of blood withdrawal, when compared with the preoperative levels. The PTH decreased earlier and total calcium levels were significantly lower after total thyroidectomy than after hemithyroidectomy (at 48, 72, and 96 hours). Ten patients had on 2 occasions serum calcium levels below or equal to 2 mmol/L and were defined as having severe hypocalcemia. Severe hypocalcemia was found in 8 patients after total thyroidectomy, compared with 2 after hemithyroidectomy (p < .05), and was present in 3 of the 5 patients with thyroid carcinoma, compared with 7 of the 90 patients with nonmalignant thyroid diseases (p < .01). Despite careful preservation of the parathyroid glands and their blood supply, thyroidectomy was often followed by transient hypocalcemia, the determinants of which are hypoparathyroidism and hemodilution. No patients had persistent symptoms of hypocalcemia from 2 to 3 months after surgery.


Subject(s)
Calcium/blood , Hypocalcemia/blood , Hypocalcemia/etiology , Parathyroid Hormone/blood , Thyroidectomy/adverse effects , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Postoperative Care , Preoperative Care , Prospective Studies , Severity of Illness Index , Thyroidectomy/classification , Time Factors
13.
J Cardiovasc Pharmacol ; 19(4): 473-8, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1380587

ABSTRACT

Because surprising similarities exist between the cardiac effects of amiodarone and those observed during hypothyroidism, we tested three different mechanisms of action in rats to determine whether amiodarone might act by inducing a tissular hypothyroidism: (a) a decrease in thyroid secretion, (b) an inhibiting effect on the conversion of thyroxine (T4) to 3,5,3' triiodothyronine (T3), and (c) a direct antagonistic effect on the cellular action of T3. Five groups of rats, treated orally for 7 or 13 days, were studied: I, control (0.5 ml saline for 7 or 13 days, n = 14); II, amiodarone (50 mg/kg for 7 days, n = 5); III, iopanoic acid (100 mg/kg for 13 days, n = 7); IV, control + T3 (0.5 ml saline for 13 days and 0.5 mg/kg T3 for the last 6 days, n = 5); V, amiodarone + T3 (amiodarone 50 mg/kg for 13 days and 0.5 mg/kg T3 for the last 6 days, n = 5). Cardiac beta-adrenoceptor density (CBARD) and heart rate (HR) were the two endpoint parameters investigated. Thyroid status was evaluated by serum thyrotropin (TSH), T4, T3, rT3 concentrations and liver type I 5'-deiodinase (5'D-I) activity. Amiodarone (group II) decreased CBARD (-22%, p less than 0.05) without altering thyroid secretion and T3 serum level, whereas 5'D-I was strongly inhibited (-90%, p less than 0.01). Iopanoic acid had no effect on CBARD and HR, but deeply inhibited 5'D-I.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Amiodarone/pharmacology , Heart/drug effects , Receptors, Adrenergic, beta/drug effects , Triiodothyronine/antagonists & inhibitors , Animals , Heart Rate/drug effects , Iodide Peroxidase/metabolism , Iopanoic Acid/pharmacology , Liver/drug effects , Liver/metabolism , Male , Radioimmunoassay , Rats , Rats, Inbred Strains , Thyrotropin/blood , Thyroxine/blood , Triiodothyronine/blood
14.
J Cardiovasc Pharmacol ; 19(4): 541-5, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1380596

ABSTRACT

To assess if the anti-beta-adrenergic effect and the bradycardia induced by amiodarone were mediated by thyroid hormone, we investigated these effects of amiodarone in euthyroid and hypothyroid rats. We studied control rats, thyroidectomized rats, control rats treated with amiodarone (50 mg/kg for 8 days), and thyroidectomized rats treated with amiodarone. At the end of the treatment, free thyroid hormone levels (FT4 and FT3) were determined, and cardiac beta-receptor density (Bmax) and affinity (Kd) were assayed by using (-)-[125I]iodocyanopindolol as radioligand. Resting heart rate (rHR) was also assessed every day in control and thyroidectomized rats, before and after amiodarone. In hypothyroid rats, in which free thyroxine (FT4) was not detectable and free 3,5,3'-triiodothyronine (FT3) was only 16% that of euthyroid rats, Bmax (14.1 +/- 2.5 fmol/mg, n = 7) and rHR (259 +/- 9.7 beats/min, n = 6) were significantly lowered compared with euthyroid rats (Bmax:18.4 +/- 3.4 fmol/mg, n = 7; rHR:277 +/- 4.1 beats/min, n = 5). Amiodarone treatment decreased Bmax (13.6 +/- 2.9 fmol/mg, n = 8) and rHR (252 +/- 5.5 beats/min, n = 5) only in euthyroid rats and did not produce significant cardiac effects in hypothyroid rats. (Values are given as mean +/- SD.) We conclude that a minimum serum thyroid hormone concentration is a necessary condition for amiodarone to produce some of its cardiac effects. An antagonistic reaction to thyroid hormones at the cellular level can be postulated as a mechanism of the cardiac anti-beta-adrenergic action of amiodarone.


Subject(s)
Amiodarone/pharmacology , Heart Rate/drug effects , Receptors, Adrenergic, beta/drug effects , Thyroxine/physiology , Triiodothyronine/physiology , Animals , Male , Rats , Rats, Inbred Strains , Receptors, Adrenergic, beta/physiology , Thyroidectomy , Thyroxine/blood , Triiodothyronine/blood
15.
Methods Find Exp Clin Pharmacol ; 13(8): 557-63, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1956211

ABSTRACT

Calcium antagonists are known to decrease insulin release in vitro. In vivo, their effects on insulin secretion and glucose tolerance are more controversial. We carried out a double-blind, double-dummy, controlled trial to study the effects of nifedipine (40 mg/day; n = 9), nitrendipine (20 mg/day; n = 9) and placebo (n = 10) on insulin release in 3 parallel groups of obese patients with mild or transient hypertension and a normal oral glucose tolerance test. The treatment lasted one week. Patients were asked not to modify their diet throughout the trial, and their body weight did not vary significantly. A 2-hour i.v. glucose tolerance test was performed twice in every patient, just before the first drug intake and one hour after the last one. The following parameters were measured or calculated during each test: basal, peak and early phase levels of blood glucose, insulin and C-peptide; glucose disappearance rate; and glucose, insulin and C-peptide incremental areas under the time-curves. On day 1, the 3 groups of patients were comparable for age, sex, body weight and every biological parameter. One-way analysis of variance did not show any significantly different evolution of those parameters between the 3 treatment groups, but calcium antagonists tended to slightly reduce the early phase of insulin release compared with placebo.


Subject(s)
Insulin/metabolism , Nifedipine/pharmacology , Nitrendipine/pharmacology , Obesity/metabolism , Adolescent , Adult , Aged , Double-Blind Method , Female , Glucose/metabolism , Humans , Insulin Secretion , Male , Middle Aged
17.
Fundam Clin Pharmacol ; 5(6): 513-26, 1991.
Article in English | MEDLINE | ID: mdl-1955196

ABSTRACT

Serum TSH levels are moderately but significantly (P ANOVA: 0.05) decreased by troleandomycin (T; 1 g bid over a 10-day period) compared with josamycin (J) (same doses) and placebo (P) in healthy volunteers. T also significantly increases serum estradiol concentration (P ANOVA: 0.03). This effect may be related to a T-induced inhibition of some P450 monooxygenase isoenzymes and more specifically P 450 NF, determined in our study by a decrease in urinary excretion of 6-beta-hydroxy-cortisol. Troleandomycin and josamycin both show poor upper GI tolerance. Liver enzymes (SGOT, SGPT, alkaline phosphatase and gGT) are significantly altered by T compared with J and P (P ANOVA: 0.007, 0.001, 0.09 and 0.04 respectively). After J, liver function tests are very close to control values (placebo). Liver enzymes are significantly more altered by T than by J (P 0.004, 0.001 and 0.06 for SGOT, SGPT and gGT respectively). Using 6 volunteers in a latin-square designed study, some established effects of oral macrolides were confirmed (poor upper GI tolerance; liver toxicity of T). Some other effects of T were also elicited, which were either unknown (decrease in serum TSH) or expected but which had not previously been assessed in man (increase in serum estradiol; decreased urinary excretion of 6-beta-hydroxy-cortisol).


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Hormones/blood , Josamycin/pharmacology , Liver/drug effects , Troleandomycin/pharmacology , Adult , Biological Availability , Double-Blind Method , Gonadotropins/blood , Humans , Liver Function Tests , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Radioimmunoassay , Thyroid Hormones/blood , Thyroid Hormones/metabolism
18.
Fundam Clin Pharmacol ; 5(7): 583-93, 1991.
Article in English | MEDLINE | ID: mdl-1778536

ABSTRACT

Very often, an impact on the intracellular metabolism of iodothyronines and more precisely on microsomal deiodinases is evoked to explain thyroid hormone (TH) serum level alterations occurring with numerous drugs. Among them, three at least are also known to interfere with other hepatic microsomal enzymes, amiodarone (AMI), phenobarbital (PHE) and propranolol (PRO). Starting from this statement, we have examined the effects of 5 macrolides on TH serum level and on hepatic 5' type 1 deiodinase (5'DI) in vivo in rat. Rats were treated orally for eight days either with 200 mg/kg macrolides--erythromycine (ERY), troleandomycine (TRO), josamycine (JOS), midecamycine (MID) and spiramycine (SPI)--, or with AMI (45 mg/kg), PHE (50 mg/kg) or PRO (20 mg/kg), these 3 latter drugs for comparative purpose. Total T4, T3 and rT3 were determined by RIA. Hepatic 5'DI was evaluated by measuring released radioactive iodide from a reverse T3 monolabelled with 125I used substrate. Compared to control group, ERY and TRO decreased T4 (respectively by 28 and 16%) and from these two, only TRO decreased T3 (23%). With JOS, the only major modification was an increment of T3 (26%). AMI gave a typical alteration with a high T4 (130%), a low T3 (26%) and a high rT3 (376%). 5'DI was statistically inhibited by AMI (85%), JOS (49%), TRO (43%) and ERY (35%). The other drugs showed no significant effect. So, three macrolides have both altered TH serum level and 5'DI, findings which have never been reported before. The precise mechanism of this action remains unknown and the resulting effect, being far from the one observed with AMI, tends to demonstrate, for macrolides, an absence of correlation between the extent of 5'DI inhibition and TH serum profile. Besides, comparative analysis of the results observed with macrolides, AMI, PHE and PRO argues against any relationship between 5'DI and cytochrome-P450 monooxygenases.


Subject(s)
Anti-Bacterial Agents/pharmacology , Iodide Peroxidase/metabolism , Liver/enzymology , Thyroid Hormones/blood , Amiodarone/pharmacology , Animals , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/metabolism , Body Weight/drug effects , Liver/metabolism , Macrolides , Male , Phenobarbital/pharmacology , Propranolol/pharmacology , Rats , Rats, Inbred Strains , Thyronines/blood
19.
Fundam Clin Pharmacol ; 5(6): 491-5, 1991.
Article in English | MEDLINE | ID: mdl-1659555

ABSTRACT

The influence of 2 different routes of amiodarone (AMIO) administration, oral gavage (OG) and subcutaneous injection (SC), on the density of cardiac beta-adrenoceptors (Bmax), hepatic type I 5' iodothyronine deiodinase (5' DI) and thyroid hormone serum concentrations was studied. Compared with respective control values, AMIO treatment (50 mg/kg per day, 7 days) via both OG and SC routes significantly lowered Bmax (OG: 14.6 +/- 1.92 vs 18.2 +/- 1.03 fmol/mg and SC: 16.6 +/- 2.34 vs 19.1 +/- 2.05 fmol/mg) and 5' DI activity (from 409 to 85 and 340 to 47 fmol I-/mg per min, respectively). The SC route induced a fall in thyroid secretion and a generalized hypothyroidism (decreased serum FT4 and FT3, inhibition of body weight gain. The OG route did not modify thyroid secretion. These results demonstrated that the effects on cardiac beta-receptor density in the SC group might be due to the generalized hypothyroidism and that AMIO produced its specific cardiac effects only after oral route medication, suggesting that the oral route is the best choice for studying AMIO cardiac effects on beta-receptor density.


Subject(s)
Amiodarone/pharmacology , Iodide Peroxidase/metabolism , Myocardium/chemistry , Receptors, Adrenergic, beta/analysis , Thyroid Hormones/blood , Administration, Oral , Amiodarone/administration & dosage , Animals , Body Weight/drug effects , Injections, Subcutaneous , Liver/enzymology , Male , Rats , Rats, Inbred Strains
20.
J Cardiovasc Pharmacol ; 18 Suppl 1: S91-3, 1991.
Article in English | MEDLINE | ID: mdl-1723467

ABSTRACT

Data on the influence of calcium antagonists on glucose tolerance and insulin release in humans are conflicting. The present double-blind, double-dummy, controlled trial was designed to investigate the effect of a short-term (7 days) treatment with nitrendipine, 20 mg b.i.d.; nitrendipine, 20 mg once daily; or placebo on blood glucose and plasma insulin and C-peptide response to an intravenous glucose load in mildly or transiently hypertensive nondiabetic obese patients. No statistically significant differences were found in fasting glucose, insulin, and C-peptide, or in the glucose disappearance rate and in any of the parameters for insulin and C-peptide response after i.v. glucose, between the three groups of patients. However, a slight decrease in early insulin response to glucose was observed in the nifedipine and the nitrendipine groups. This study confirms that calcium antagonists have no clinically relevant effect on glucose homeostasis even if a slight alteration of insulin release after glucose load cannot be ruled out.


Subject(s)
Hypertension/drug therapy , Insulin/metabolism , Nifedipine/therapeutic use , Nitrendipine/therapeutic use , Obesity/metabolism , Adult , Analysis of Variance , Blood Glucose/drug effects , C-Peptide/blood , Double-Blind Method , Female , Humans , Hypertension/complications , Hypertension/metabolism , Insulin/blood , Insulin Secretion , Male , Middle Aged , Obesity/complications , Time Factors
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