Regional differences in risk factors and clinical presentation of diabetic foot lesions.

BACKGROUND: Problems associated with the diabetic foot are worldwide. However, there may be regional variation among risk factors and clinical presentation. Prospective comparative data concerning this topic are rare. AIM: To determine differences in underlying risk factors and clinical presentation of foot problems among people with diabetes in different regions. PATIENTS AND METHODS: Six hundred and thirteen consecutive patients with diabetic foot lesions from three centres [Soest-Germany (GER), Dar-es-Salaam, Tanzania (TAN) and Chennai, India (IND)] were included during the period June 1998 through December 1999. Diabetes-related data, risk-factor profiles, and lesion-related data were collected for each patient. Due to varying proportions of recurrent lesions among the centres, only data from patients with newly presenting diabetic foot lesion were analysed. RESULTS: Of the 613 patients sampled, 368 (60%) were treated for newly presenting diabetic foot lesion. In all three centres, patients were predominately male and had Type 2 diabetes. The average diabetes duration until the onset of the initial foot lesion was 14 years in GER and 12 years in IND, but only 5 years in TAN. The corresponding patient ages were 71, 56 and 51 years. Neuropathy was common to patients in all three centres. Peripheral vascular disease (PVD) was a frequent risk factor in GER (48%). In TAN and IND it was far less common (12 and 13%), probably due to younger patient populations, shorter diabetes duration and lower proportions of smokers. Inadequate footwear was the most common cause of foot lesions in GER (19%), while lack of footwear, irregular foot care and burns were the primary precipitating factors among patients in TAN and IND. CONCLUSION: Similarities in different regions of the world among people with diabetes suffering newly presenting foot lesions include a predominance of males and patients with Type 2 diabetes, as well as a high frequency of diabetic neuropathy. However, differences concerning age, diabetes duration, peripheral vascular disease, and precipitating factors contributing to injury are also observed.

Nitrazepam clearance unimpaired in patients with renal insufficiency.

Eight patients with mild to moderate renal insufficiency (mean serum creatinine: 2.4 mg/100 ml) and 9 matched control subjects with normal renal function received a single 5-mg oral dose of nitrazepam, cleared mainly by hepatic nitroreduction. Serum nitrazepam levels were determined by gas chromatography during the 72 hours after dosage. Renal patients and controls were well-matched for age (74 vs. 63 years), height (165 vs. 164 cm), and weight (68 vs. 64 kg). Patients and control subjects did not differ significantly in nitrazepam elimination half-life (32 vs. 24 hour) or volume of distribution (4.2 vs. 3.6 liters/kg). Clearance was higher in patients than in controls (4.2 vs. 1.7 ml/min/kg), but the difference was not significant. Nitrazepam free fraction in serum was increased in renal patients (16.8 vs. 15.0% unbound, p = 0.08). After correction for individual values of free fraction, the two groups still did not differ in kinetic variables for nitrazepam. Thus, mild to moderate renal insufficiency does not alter the kinetics of nitrazepam.

Contribution of the gastrointestinal tract to lorazepam conjugation and clonazepam nitroreduction.

Domestic pigs received single intravenous and oral doses of lorazepam or clonazepam (1 mg/kg), benzodiazepine derivatives biotransformed by glucuronide conjugation and nitroreduction, respectively. Blood samples were simultaneously drawn from portal venous and systemic venous sampling sites during 8 h after dosage. After intravenous dosage with either drug, the area under the serum concentration curve (AUC) for the intact drug, as well as for the principal metabolites (lorazepam glucuronide and 7-aminoclonazepam, respectively), was nearly identical between portal and systemic serum. After oral dosage, absolute systemic availability (relative to intravenous administration) of both lorazepam and clonazepam was incomplete (mean values: 29 and 49%, respectively); however, metabolite levels were also correspondingly lower between oral and intravenous dosages. First-pass hepatic extraction also occurred for both drugs, with mean systemic/portal AUC ratios of 0.60 for lorazepam and 0.74 for clonazepam. Pretreatment with neomycin (1.0 g) had a minimal effect on portal or systemic AUC for intact clonazepam after oral dosage, but 7-aminoclonazepam concentrations were reduced by neomycin pretreatment. Thus incomplete absorption, together with first-pass hepatic biotransformation, appears to explain the incomplete systemic availability of orally administered lorazepam or clonazepam. Biotransformation within the gastrointestinal tract or during absorption through the gastrointestinal mucosa contributes minimally.

Reduced systemic absorption of intrabronchial lidocaine by high-frequency nebulization.

Serum lidocaine concentrations were measured in a series of patients during and after topical administration of lidocaine used to anesthetize the nasal mucosa, pharynx, and larynx for diagnostic fiberoptic bronchoscopy. In one group of patients (N = 9) the trachea and bronchi were sprayed with a 2% lidocaine solution administered in 2 mL volumes. Another group (N = 14) received a 2% lidocaine solution which was administered by inhalation of lidocaine dispensed by a high-frequency nebulizer. Multiple serum samples drawn over a 1-hour period were analyzed by gas chromatography with nitrogen-phosphorous detection. In the spray group versus the inhalation group, there were no differences in mean age (54 vs 55 years), total lidocaine dose (572 vs 525 mg), or time of peak serum lidocaine concentration (43 vs 41 minutes after dose). However, the peak serum lidocaine concentrations were significantly lower in the inhalation group vs the spray group (1.40 vs 3.63 micrograms/mL). Thus, administration of lidocaine via inhalation by ultrasonic nebulization results in lower peak serum concentrations, and a reduction in the likelihood of toxicity, than when administered by conventional topical spray.

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Chronic treatment with fluvoxamine, clovoxamine, and placebo: interaction with digoxin and effects on sleep and alertness.

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self-rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half-life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half-life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P less than .05). Self-ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

Age and gender effects on chlordiazepoxide kinetics: relation to antipyrine disposition.

Twelve normal subjects aged 24-41 years, and 12 subjects aged 62-79 years, received single 50-mg doses of chlordiazepoxide hydrochloride by mouth and by intravenous injection on two occasions. Chlordiazepoxide volume of distribution was significantly correlated with body weight (r = 0.63, p less than 0.001), but was not related to age or sex. Among male subjects, elimination half-life was prolonged (20 vs. 8 h, p less than 0.025) and clearance reduced (20 vs. 43 ml/min, p less than 0.05) in elderly as opposed to young volunteers. Among women, there was no significant difference between elderly and young subjects in elimination half-life (12 vs. 13 h) or clearance (29 vs. 22 ml/min). Absolute bioavailability of oral chlordiazepoxide was not less than 100%, and was unrelated to age or sex. Among 20 subjects who received a single 1.0- to 1.2-gram intravenous dose of antipyrine on another occasion, clearance of chlordiazepoxide and of antipyrine were significantly correlated (r = 0.62, p less than 0.01). Like many other low-clearance oxidatively metabolized compounds, chlordiazepoxide clearance is reduced and half-life prolonged in elderly men, but not elderly women. Individual variations in chlordiazepoxide clearance are significantly correlated with those of antipyrine, a drug commonly used as an index of hepatic oxidizing capacity.

Pharmacodynamic comparison of L-bunolol with propranolol, metoprolol, and placebo.

Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.

Quantitation of flurazepam and three metabolites by electron capture gas liquid chromatography.

Flurazepam and three of its metabolic products (desalkyl, hydroxyethyl, and aldehyde metabolites) can be simultaneously quantitated without derivatization by gas chromatography with electron capture detection. After addition of a suitable internal standard, unknown biological samples and calibration standards are extracted at neutral pH into benzene/isoamyl alcohol. The reconstituted extract is chromatographed at 275 degrees C with a 10% OV-101 liquid phase, which allows resolution of all 5 compounds. In some cases a 1% OV-225 liquid phase is used for quantitation of hydroxyethylflurazepam. The method is sufficiently sensitive and reproducible for use in clinical and experimental pharmacokinetic studies.

Pharmacokinetics of oxaprozin in women receiving conjugated estrogen.

The kinetics of a single 1200 mg oral dose of oxaprozin, a nonsteroidal antiinflammatory agent of the propionic acid class, was studied in 22 healthy female volunteers aged 21 to 64 years. Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects served as control women who were not taking conjugated estrogens. Mean pharmacokinetic variables in control and conjugated estrogen groups were: volume of distribution, 15.1 vs 14.1 l; elimination half-life, 59.8 vs 54.2 h; clearance, 3.2 vs 3.1 ml/min; peak plasma concentration, 84.8 vs 90.7 micrograms/ml, respectively. None of the differences were significant. However, the time of peak concentration (8.9 vs 4.0 h) was significantly longer in the control group than in the conjugated estrogen group, respectively (p less than 0.05). Oxaprozin clearance, accomplished by a combination of oxidation and conjugation, is unimpaired by coadministration of conjugated estrogens.

Pharmacokinetics and CSF entry of flurazepam in dogs.

Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 l/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

Hepatic vs. gastrointestinal presystemic extraction of oral midazolam and flurazepam.

An experimental model was developed to elucidate the site of presystemic extraction of drugs with incomplete bioavailability due to high extraction after p.o. dosage. Domestic pigs received single i.v. or p.o. doses of midazolam (1 mg/kg) or flurazepam (2 mg/kg), two benzodiazepine derivatives with high presystemic extraction after p.o. dosage. Multiple blood samples were simultaneously drawn from the portal vein and from a systemic vein during 8 hr after dosage. After i.v. administration, both drugs had high systemic serum clearance, averaging 24 ml/min/kg. Area under the serum concentration curve (AUC) for systemic vs. portal sites was nearly identical for midazolam (769 vs. 737 ng/ml x hr); for flurazepam, systemic AUC exceeded portal AUC (1035 vs. 778 ng/ml x hr, P less than .01). After p.o. dosage, the systemic/portal AUC ratio averaged 0.15 for midazolam and 0.11 for flurazepam; for both drugs, portal AUC after p.o. dosage did not differ significantly from systemic AUC after i.v. administration. Thus, the extensive presystemic extraction of orally administered midazolam and flurazepam are mainly attributable to hepatic biotransformation rather than metabolism either within the gastrointestinal tract or during absorption into the portal circulation.

Trazodone kinetics: effect of age, gender, and obesity.

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15-30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml-1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half-life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min-1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.

Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol.

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age- and weight-matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half-life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half-life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half-life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.

The interactions of propranolol and ketanserin.

Ten healthy volunteers received a single 10 mg intravenous dose of the 5-hydroxytryptamine-2 serotonin antagonist ketanserin in the control state and again during coadministration of propranolol, 80 mg b.i.d. There were no differences between control and propranolol treatment conditions in ketanserin volume of distribution (5.2 vs. 3.8 L/kg), elimination half-life (6.6 vs. 4.7 hours), clearance (9.7 vs. 10.0 ml/min/kg), or 72-hour excretion of intact ketanserin (0.7% vs. 0.7% of dose) or ketanserinol (21.8% vs. 24.9% of dose). In a second study, eight volunteers received a 160 mg oral dose of propranolol hydrochloride in the control state and again during treatment with ketanserin, 40 mg b.i.d. There were no significant differences between control and ketanserin conditions in the time of peak serum propranolol concentration (2.1 vs. 1.5 hours after dosage) or elimination half-life (3.8 vs. 4.1 hours). However, ketanserin increased peak serum propranolol concentrations (169 vs. 233 ng/ml) and reduced oral clearance (39 vs. 27 ml/min/kg); the differences were not statistically significant (0.05 less than P less than 0.1) with a sample size of eight. Thus therapeutic doses of propranolol in healthy volunteers do not alter the kinetics of a single dose of ketanserin. Therapeutic doses of ketanserin may impair oral clearance of propranolol, leading to increased area under the serum concentration curve and higher peak serum levels.