Is Ramadan fasting safe in type 2 diabetic patients in view of the lack of significant effect of fasting on clinical and biochemical parameters, blood pressure, and glycemic control?

The study objective was to determine if Ramadan fasting was safe in patients with type 2 diabetes mellitus (T2D), based upon a determination of the effect of fasting on a broad range of physiological and clinical parameters, including markers of glycemic control and blood pressure. The study was carried out in Ramadan 1422 (December 2001-January 2002) at the Diabetology Services, Hopital Ibn Sina, Rabat, Morocco. One hundred and twenty T2D Moroccan patients (62 women, 58 men), aged 48-60 yrs with well-controlled diabetes through diet and/or oral hypoglycemic drugs (OHD), received dietary instructions and readjustment of the timing of the dose of OHD (gliclazide modified release) according to the fasting/eating periods. Anthropometric indices and physiological parameters (blood pressure, lipid, hematological, and serum electrolyte profiles, as well as markers of glycemic control, nutrition, renal and hepatic function) were measured on the day before Ramadan and then on the 15(th) and 29(th) day of fasting and thereafter 15 days later. Statistical analysis was done by standard methods. Ramadan fasting had no major effect on energy intake, body weight, body mass index, blood pressure, and liver enzymes. Fasting and post-prandial glucose levels decreased, while insulin levels increased. Diabetes was well controlled, as indicated by HbA1c, fructosamine, C-peptide, HOMA-IR, and IGF-1 values. There were fluctuations in some lipid and hematological parameters, creatinine, urea, uric acid, total protein, bilirubin, and electrolytes; however, all values stayed within the proper physiological range. In conclusion, diabetes was well-controlled in patients with dietary/medical management, without serious complications. With a regimen adjustment of OHD, diet control, and physical activity, most patients with T2D whose diabetes was well-controlled before Ramadan can safely observe Ramadan fasting.

Ethnopharmacological survey of plants used in the traditional treatment of hypertension and diabetes in south-eastern Morocco (Errachidia province).

This survey was undertaken in the Errachidia province in south-eastern Morocco in order to inventory the main medicinal plants used in folk medicine to treat arterial hypertension and diabetes mellitus. Four hundred individuals who knew about and/or had used the medicinal plants for the indicated diseases, including some herbal healers, were interviewed throughout different regions of the province. The inventory of medicinal plants is summarized in a synoptic table, which contains the scientific, vernacular and common name of the plant, its ecological distribution, the part of the plant and the preparation used and the therapeutic indication. Extensive investigations have brought to light 64 medicinal plants belonging to 33 families; of these, 45 are used for diabetes, 36 for hypertension, and 18 for both diseases. Of these plants, 34% grow in the wild, 44% are cultivated, and 22% are not indigenous to the area and are brought from other parts of Morocco or from outside the country. The survey shows that 78% of the patients regularly use these medicinal plants. In this region, the most frequently used plants to treat diabetes include Ajuga iva, Allium cepa, Artemisia herba-alba, Carum carvi, Lepidium sativum, Nigella sativa, Olea europaea, Peganum harmala, Phoenix dactylifera, Rosmarinus officinalis, and Zygophyllum gaetulum, and those to treat hypertension include Ajuga iva, Allium cepa, Allium sativum, Artemisia herba-alba Asso, Carum carvi, Nigella sativa, Olea europea, Rosmarinus officinalis, Origanum majorana, Peganum harmala, and Phoenix dactylifera. The local people recognize the toxic plants and are very careful in using such plants, which are Citrullus colocynthis, Datura stramonium, Nerium oleander, Nigella sativa, Peganum harmala and Zygophyllum gaetulum. Our survey shows that traditional medicine in the south-eastern Moroccan population has not only survived but has thrived in the transcultural environment and intermixture of many ethnic traditions and beliefs.

The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion.

The disposition of 5-[4-14C]azacytidine, administered i.v. as a bolus or continuous infusion, was studied in cancer patients. After bolus, plasma 14C levels exhibited as multiphasic disappearance pattern; half-life (t1/2, beta phase) = 3.4 to 6.2 hr. Of 14C in plasma, less than 2% was associated with 5-[4-14C]azacytidine 30 min after dose. The ratios of 14C levels were: red cells/plasma, approximately 0.8; leukocytes/plasma, 1.1 to 2.3; nucleic acids/leukocytes, 0.2 to 0.43; sputum/plasma, 0.05 to 0.17. Urinary excretion (3 days) accounted for 73 to 98% of 14C, LEss than 1% in feces. The relative concentration of 5-azacytidine in plasma with continuous infusion stayed higher than with bolus; urinary excretion was similar. Fewer side effects were observed with continuous infusion than with bolus. The stability of 5-azacytidine was determined in various media at several temperatures by thin layer chromatography and nuclear magnetic resonance. At 20 degrees in Ringer's lactate (pH 6.2), the t1/2 was 94 to 100 hr. Stability increased with lowering of temperature and pH. From our data we conclude that 5-azacytidine should be given by continuous infusion rather than as a bolus.

Duration of hydralazine action in hypertension.

The effect on blood pressure of giving hydralazine orally, 300 mg per day divided into 2, 3, and 4 doses, was studied in 4 hypertensive patients. There was no significant difference in average mean arterial pressure for the 3 regimens. Fluctuations of mean arterial pressure with time were not significantly different for the regimens as indicated by coefficient of variation. The mean coefficient of variation for the 2 days prior to initiation of hydralazine dosing was 4.0% +/- 0.3 (SEM) and for the 3 dosing regimens ranged from 4.1% to 4.8%. Heart rate was used as an index of vasodilator-induced increase in sympathetic tone and therefore as a measure of possible side effects. Fluctuations in heart rate were small and were not associated with symptoms. After discontinuation of hydralazine, the time for blood pressure to return halfway between initial placebo value and end treatment value varied from 30 to 140 hr. A tracer dose of hydralazine 14C. HCl was administered intravenously to the patients. The urinary excretion of 14C showed a multiexponential pattern of elimination with a previously undescribed prolonged terminal phase. Under the conditions of the present study, a daily dose of 300 mg of hydralazine was as effective and free of side effects given in 2 as in 4 divided doses.

The effect of the interaction of pyrazinamide and probenecid on urinary uric acid excretion in man.

Complex interactions occur between pyrazinamide (PZA) and probenecid in man involving both the metabolism and distribution of the drugs, and their effects on renal tubules. Pretreatment with PZA prolonged the half-life (T 1/2) of probenecid without changing its plasma-binding. As the rate of probenecid metabolism is decreased, its uricosuric action tends to be prolonged and the effect of PZA lessened. The PZA-suppressible urate level is increased to values well above control after the administration of probenecid; it is less after alkalinization of urine, although still larger than the value for PZA-suppressible urate after the administration of PZA alone. Urinary probenecid excretion is much greater when urine is alkalinized. These observed drug interactions, plus the known effect of probenecid to block secretion of PZA, have to be considered in evaluating the effect of the two drugs given together, compared to the effect of each drug given separately.

A nonmetabolized analogue of phenytoin.

Nine novel analogues of 5,5-diphenylhydantoin bearing a CF3 group(s) in the meta or para position of one or both rings were synthesized. Preliminary evaluation of all the analogues (performed by the ADD Program, NIH) indicated no significant anticonvulsant activity against electrical or chemical shock in mice at doses of less than or equal to 100 mg/kg. The analogue 5,5-bis[4-(trifluoromethyl)phenyl]hydantoin (1) was synthesized labeled with 14C in the 4 position of the hydantoin ring. Certain physicochemical properties (pKa, partition ratio, protein binding, etc.) and the LD50 of 1 in mice (40 mg/kg, ip; 100 mg/kg, po) were determined. The disposition of [14C]1 was determined in rodents. The compound was excreted unchanged in rat feces (94% in 18 days), urinary excretion less than 0.5%. The half-life of elimination of [14C]1 from plasma was 67-72 h (ip and iv) in rats and 115 h (ip) in mice. Studies of tissue distribution and biliary excretion of [14C]1 indicate low tissue/plasma ratios (due to high plasma binding, 97%) and low biliary excretion. The lack of metabolism of [14C]1 may possibly be explained by (1) the strong electron-withdrawing effects of CF3 substituents, (2) the preemption of the primary metabolic sites, (3) the accompanying steric hindrance, and (4) the apparent inability of the CF3 group to undergo the NIH shift.

Specificity of an antibody directed against d-methamphetamine. Studies with rigid and nonrigid analogs.

The specificity of an antibody directed against d-(S)-methamphetamine (MA) was determined by competitive binding assay with more than 50 compounds-metabolites, homologs, and analogs of amphetamine. The antibody appears to be specific both for the side chain and the aromatic ring of d-(S)-amphetamine (A). The basic requirements for a compound to be bound to the antibody are (a) an aromatic ring, (b) a basic nitrogen, and (c) a two-carbon chain between the aromatic ring and the nitrogen. A transoid conformation for the phenethylamine skeleton is preferred. The interaction of the antibody with compounds differing from MA or A in side-chain substitutions was directly proportional to the closeness of their structure to MA and/or A. The antibody exhibited greatly reduced affinity for ring-substituted analogs of A; the p-hydroxy metabolite of A did not bind to the antibody. A radioimmunoassay of A is described; it was utilized to study the disposition of A in dogs.

Clinical pharmacokinetics of probenecid.

A review of the clinical applications and of the disposition of probenecid in man, including drug interactions, is presented. Probenecid is the classical competitive inhibitor of organic acid transport in the kidney and other organs. There are 2 primary clinical uses for probenecid: as a uricosuric agent in the treatment of chronic gout and as an adjunct to enhance blood levels of antibiotics (such as penicillins and cephalosporins). Adsorption of probenecid is essentially complete following oral administration. The drug is extensively metabolised by glucuronide conjugation and by oxidation of the alkyl side chains; oxidation of the aromatic ring does not occur. The half-life of probenecid in plasma (4 to 12 hours) is dose-dependent. Renal excretion is the major route of elimination of the metabolites; excretion of the parent drug is minimal and is dependent on urinary pH. Probenecid and its oxidised metabolites are extensively bound to plasma proteins, mainly to albumin. Tissue concentrations (based on animal studies) are generally lower than plasma concentrations. Most of the drug-drug interactions involving probenecid are due to an effect on the kidney-block of transport of acidic drugs. Similarly probenecid affects the tubular secretion of a number of acidic endogenous substances by the kidney. Probenecid is also involved in the block of transport of acidic metabolites of catecholamines, for example homovanillic and hydroxyindoleacetic acids, in the brain. There are a number of analytical procedures for the assay of probenecid. These are based on spectrophotometry, spectrofluorometry, gas and liquid chromatography and radioimmunoassay.

Probenecid in CSF and plasma of rabbits and dogs measured by radioimmunoassay.

Probenecid (P) in CSF of rabbits and dogs was investigated using a new radioimmunoassay technique. In rabbits, under steady-state conditions, CSF/free plasma concentration ratios of P were found to be similar to those reported in man. The ratios were concentration dependent and less than 0.5 suggesting an inhibition of transport of the drug in CNS. Under nonsteady-state conditions, no clear evidence of a transport system was found in dogs.

Pharmacokinetics of antituberculosis drugs in patients.

The pharmacokinetics of rifampin, isoniazid, and ethambutol were determined in 26 ambulatory male patients (aged 49.5 +/- 9.9 yr) with tuberculosis. Rifampin and isoniazid were given individually or together, with or without ethambutol; studies were done after a single dose and after chronic administration. Under the study conditions, with large variability in the extent of disease and physical status and history of alcohol and tobacco abuse and narrow age range, the pharmacokinetics of these three antituberculosis drugs were not modified significantly by patient age. Furthermore, appreciable drug-drug interactions did not occur when the three drugs were administered concurrently. Self-induction of rifampin clearance by chronic dosing with the drug may lead to subtherapeutic levels of rifampin. Administration of isoniazid and ethambutol in two divided doses resulted in peak plasma concentrations below the accepted therapeutic levels of the two drugs. Our findings indicate that at least in the middle-aged patients with tuberculosis, the current single daily dose, multiple-drug regimen is therapeutically sound pharmacokinetically, and clinicians do not have to make adjustments in dosages of these drugs for age and the extent of disease.

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension.

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE

ACE inhibitors. Differential use in elderly patients with hypertension.

High blood pressure (BP) in the elderly must not be ignored as a normal consequence of aging. The criteria for the diagnosis of hypertension and the necessity to treat it are the same in elderly and younger patients. The aim of treatment of elderly hypertensive patients is to decrease BP safely and to reduce risk factors associated with cerebrovascular, cardiovascular and renal morbidity and mortality. The treatment of elderly hypertensive patients should be adjusted according to the needs of the individual, based upon age, race, severity of hypertension, co-existing medical problems, other cardiovascular risk factors, target-organ damage, risk-benefit considerations and costs. In addition to the elevated BP, other cardiovascular risk factors include smoking, glucose intolerance, hyperinsulinaemia, dyslipidaemia, hypercreatininaemia, peripheral vascular disease, left ventricular hypertrophy, and microalbuminuria (or albuminuria). Thus, the choice of initial antihypertensive therapy in elderly hypertensive patients should be based not only on the expected response, but also on the effects of therapy on lipid, potassium, glucose and uric acid levels, and left ventricular anatomy and function. Co-existing medical conditions (such as asthma, diabetes mellitus, heart failure, renal failure, gout, coronary artery disease, hyperlipidaemia and peripheral vascular disease) are major determinants for the selection of antihypertensive medications. With previous therapies (diuretics, beta-blockers, etc.), good BP control in the elderly was associated with clear and statistically significant reductions in stroke-related morbidity and mortality, but the overall effects on cardiovascular and renal complications of hypertension was either more variable or less obvious. Angiotensin converting enzyme (ACE) inhibitors are not only efficacious antihypertensive agents in the elderly, but also appear promising in counteracting some of the cardiovascular and renal consequences of hypertension. They are well tolerated and have a relatively low incidence of adverse effects. ACE inhibitors possess ancillary characteristics that are potentially beneficial for many elderly patients, including reduction of left ventricular mass, lack of metabolic and lipid disturbances, no adverse CNS effects, no risk of induction of heart failure, and a low risk of orthostatic hypotension. Since ACE inhibitors may improve perfusion to the heart, kidney and brain, they are well worth considering for the treatment of elderly patients with hypertensive target organ damage, especially in patients with heart failure, and diabetic patients with early nephropathy.

New spectrophotofluorometric assay for probenecid.

A new spectrophotofluorometric assay for probenecid is presented based on conversion of the drug to a fluorescent anthranilic acid derivative. The assay is especially applicable with "clean" biological fluids such as cerebrospinal fluid and offers severalfold greater sensitivity than the commonly used UV method.