Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain

OBJECTIVE: To determine whether multiple dosing of acetaminophen would result in drug accumulation in polymedicated elderly patients with rheumatic pain. METHODS: Twelve inpatients (11 women), aged 89 +/- 4 years, weight 59 +/- 10 kg, receiving 3 to 8 concomitant medications, entered the study. Their creatinine clearance according to the Cockroft-Gault formula was 42 +/- 12 ml/min. The pharmacokinetics of 1 g acetaminophen was evaluated after the first dose (D1) and after the last dose (D7) during a 3 times daily regimen of 1 g for 5 consecutive days. RESULTS: The plasma pharmacokinetic profile of acetaminophen did not change significantly at D7 compared to D1. No significant within-patient differences were observed, especially with respect to plasma elimination half-life (2.74 +/- 0.48 and 2.77 +/- 0.32 hours, respectively), area under the concentration-time curve (82.5 +/- 21.1 and 90.1 +/- 15.2 microg x h/ml, respectively), and apparent oral clearance (3.68 +/- 0.85 and 3.28 +/- 0.52 ml/min/kg, respectively). CONCLUSION: No drug accumulation occurred during multiple dosing with acetaminophen in these very old subjects. On the basis of pharmacokinetic data alone, a dose regimen of acetaminophen 1 g tid seems to be appropriate in such patients.     

The early bactericidal activity of amikacin in pulmonary tuberculosis.

SETTING: Stellenbosch University, a tertiary care hospital in Cape Town, South Africa. OBJECTIVE: To determine the early bactericidal activity (EBA) of amikacin in dosages of 5 mg/kg, 10 mg/kg and 15 mg/kg body weight in comparison to that of isoniazid 6 mg/kg body weight or no drug. DESIGN: An open, randomised trial. PATIENTS: Patients with previously untreated, sputum smear-positive pulmonary tuberculosis. INTERVENTION: Patients received amikacin 5 mg/kg (12 patients), 10 mg/kg (13 patients) or 15 mg/kg (15 patients), isoniazid 6 mg/kg (9 patients) or no drug (10 patients). RESULTS: The rate of decrease in log viable colony forming units of Mycobacterium tuberculosis per ml of sputum per day during the first 2 days of treatment with amikacin 5 mg/kg, 10 mg/kg and 15 mg/kg was 0.041 (SD 0.100), 0.045 (SD 0.144) and 0.052 (SD 0.096), respectively, 0.515 (SD 0.173) in the patients receiving isoniazid 6 mg/kg, and 0.041 (SD 0.113) in those receiving no drug. The EBA found in patients receiving amikacin did not differ significantly from that of the no drug group. However, as the EBA in the no drug group was the highest ever encountered at Stellenbosch University, the mean in patients receiving drug was tested against 0 and found to differ significantly (P = 0.03), suggesting minimal activity. Mean amikacin serum concentrations 1 hour after intramuscular drug administration were 13.5 microg/ml, 26.7 microg/ml and 39.2 microg/ml in the patients receiving 5 mg, 10 mg and 15 mg per kg body weight, respectively. CONCLUSION: Despite serum concentrations well in excess of the minimal inhibitory concentration of 2-4 microg/ml, the EBA of amikacin in patients with smear-positive pulmonary tuberculosis was only just detectable.     

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.     

Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: To determine the intra- and intersubject variability in and the effects of food or antacids on the pharmacokinetics of isoniazid (INH). DESIGN: Randomized, four-period cross-over Phase I study in 14 healthy male and female volunteers. Subjects ingested single doses of INH 300 mg under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of rifampin, pyrazinamide, and ethambutol. RESULTS: Serum was collected for 48 hours, and assayed by high performance liquid chromatography (HPLC). Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean INH Cmax of 5.53 +/- 2.92 microg/ml, Tmax of 1.02 +/- 1.10 hours, and AUC0-infinity of 20.16 +/- 12.45 microg x hr/ml. These findings are similar to those reported previously. Antacids did not alter these parameters significantly (Cmax of 5.62 +/- 2.53 microg/ml, Tmax of 0.71 +/- 0.56 hours, and AUC0-infinity of 20.27 +/- 11.39 microg x hr/ml). In contrast, the high-fat meal recommended by the Food and Drug Administration reduced INH Cmax by 51% (2.73 +/- 1.70 microg/ml), nearly doubled Tmax (1.93 +/- 1.61 hours), and reduced AUC0-infinity by 12% (17.72 +/- 10.32 microg x hr/ml). CONCLUSIONS: These changes in Cmax, Tmax, and AUC0-infinity can be avoided by giving INH on an empty stomach whenever possible.     

Azlocillin und Mezlocillin: Zwei neue semisynthetische Acylureidopenicilline

The pharmacokinetic parameters of two new ureido-penicillins (azlocillin and mezlocillin) were determined in 12 healthy subjects after a half-hour continuous infusion of 5,000 mg. The agar diffusion test (test strain Bacillus subtilis ATCC 6633) was used for the microbiological assays. The mean azlocillin serum concentration after the half-hour infusion was 431.0 +/- 75.0 microgram/ml; after eight hours it had fallen to a mean value of 4.7 +/- 2.6 microngram/ml. The mean elimination half-life was 77.5 +/- 10.4 minutes, and the relative distribution volume was 19.4 +/- 1.9% of the bodyweight. At the end of the infusion, mezlocillin showed a mean serum concentration of 426.0 +/- 61.0 microgram/ml and after eight hours an average of 1.1 +/-0.9 microgram/ml; the half-life was shorter (56.9 +/- 9.9 minutes) and the distribution volume lower (14.8 +/- 3.1%) than that of azlocillin. The renal clearance values measured in three subjects during a four-hour continuous infusion were: azlocillin 111.6 ml/min/1.73 m2, mezlocillin 121.5 ml/min/1.73 m2. The kinetic behaviour of the two ureido-penicillins was essentially very similar to that of ampicillin and carbenicillin, 38 patients with bronchopneumonia, cholangitis or urinary tract infections, which in some instances were severe, were treated for an average of 10 days with an average daily dosage of 3X4.0 g azlocillin or 3X5.0 g mezlocillin. 30 patients showed clinical improvement, and in 17 of these the pathogen was eliminated. These therapeutic results appear more favourable than those obtained with the newer aminoglycoside antibiotics (amikacin, sisomicin); in particular the drug was well tolerated.     

Epidemiological survey of hyperuricemia as an adverse reaction to antituberculous therapy with pyrazinamide

PURPOSE: Pyrazinamide is an antituberculous drug that is administered as a two-month course during treatment of pulmonary tuberculosis. Adverse reactions to pyrazinamide have been reported to include hyperuricemia. We performed a retrospective multicenter epidemiological survey to assess the relationship between various patient characteristics and the uric acid level, the changes of uric acid during pyrazinamide administration, and the use of medications for uric acid control as well as attacks of gout or arthralgia at the onset of hyperuricemia. A total of 226 patients who were admitted to four hospitals with pulmonary tuberculosis between January and December 2006 and received short-term intensive pyrazinamide therapy were studied. RESULTS: There were 172 men and 54 women with an average age of 59.5 years and an average body mass index of 19.8 kg/m2. The average serum uric acid concentration before pyrazinamide treatment was 4.73 +/- 1.78 mg/dl, while the average uric acid level after pyrazinamide treatment was 10.63 +/- 2.67 mg/dl, which was significantly higher than the pretreatment level (p<0.0001). During treatment, hyperuricemia (Serum uric acid > or = 8 mg/dl) was reported in 84.5% of patients and arthralgia developed in 4.42%. Although the therapy instituted in 51 patients (22.57%) had to be interrupted or discontinued due to liver dysfunction and skin rashes, which were probably caused by isoniazid and rifampicin, no patient ceased taking pyrazinamide due to an increase of uric acid. Drugs for uric acid control were administered to 21 patients (9.29%). Pyrazinamide is an important agent for intensive short-term antituberculous therapy. Hyperuricemia due to this drug can be managed by observation and does not require interruption of administration.     

Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery

OBJECTIVE: The aim was to study the pharmacokinetic parameters and biological activity of a single dose of human recombinant IGF-I (rhIGF-I) administered to patients following major gastrointestinal surgery. DESIGN: A double blind placebo controlled externally randomized study of 30 patients; the study commencing 24 hours after major colonic or gastric surgery. MEASUREMENTS: After a baseline blood sampling day, IGF-I (40 micrograms/kg by single subcutaneous dose, n = 20) or placebo (n = 10) was administered and serum and urine samples collected over the ensuing 72 hours. Serum IGF-I, IGF-II, IGF binding proteins (IGFBP-1, IGFBP-3), GH and insulin were measured by radioimmunoassay. Serum IGF bioactivity was assessed using a validated porcine cartilage bioassay. Serum and urinary electrolytes were measured by standard methodology. RESULTS: Serum immunoreactive IGF-I levels peaked at 4 hours following injection of IGF-I (1.09 +/- 0.12 U/ml mean +/- SEM), remained elevated for 15 hours and returned to basal levels by 24 hours after injection. IGF bioactivity was increased by 57% 6 hours after IGF-I injection. Mean levels of IGFBP-1 and IGFBP-3, IGF-II and GH were unaffected by IGF-I administration. Insulin levels were suppressed at 30 minutes following injection of IGF-I compared with the placebo group (16.9 +/- 3.0 mU/I vs 32.3 +/- 7.1, P = 0.02); thereafter, there were no differences in insulin levels. The mean change in serum creatinine following IGF-I (-6.3 +/- 3.0 mmol/l) was significantly different from that in the control group (+7.2 +/- 6.2, P = 0.03). Creatinine clearance rose from a mean of 71.6 +/- 7.5 ml/min to 83.2 +/- 7.6 ml/min after IGF-I treatment (P = 0.02). In the IGF treated patients, cholesterol levels consistently fell (-0.20 +/- 0.05 mmol/l); this was not observed in the placebo group (+0.20 +/- 0.14, P = 0.006). Basal serum potassium levels in the IGF treatment group (4.1 +/- 0.1 mmol/l) fell to 3.8 +/- 0.1 at 4 hours (P = 0.002) and 3.6 +/- 0.1 at 10 hours (P = 0.001) returning to a level of 4.0 +/- 0.1 (P = 0.293) at 24 hours after injection. There were no other observed differences in serum or urinary electrolytes or serum free fatty acids and triglycerides. Pharmacokinetic parameters derived from baseline adjusted IGF-I measurements revealed a slow absorption of the administered dose with a Tmax of 5.0 +/- 0.43 hours and an elimination half-life of 10.8 +/- 1.2 hours. The computed volume of distribution was 0.33 +/- 0.05 I/kg and the clearance on average 25 ml/min. CONCLUSION: A single subcutaneous dose of IGF-I normalized circulating IGF-I levels in post-operative patients, was well tolerated and without side-effects. IGF bioactivity was increased and associated with a fall in serum cholesterol, potassium and creatinine levels and a rise in creatinine clearance. Further long-term studies are now required to assess the anabolic effects of rhIGF-I in this type of patient group.     

Alteration of drug metabolism in Gilbert's syndrome.

The pathophysiology of Gilbert's syndrome was studied by investigating the metabolism of the drug tolbutamide, which is metabolised by the liver but does not undergo glucuronidation. Using rat liver cell supernatant, tolbutamide was shown to bind to the hepatic cytoplasmic Y protein in a manner similar to other organic anions, but not to Z protein. In 31 patients with Gilbert's syndrome the plasma disappearance (plasma half-life, mean +/- SD: 628+/-84 min) and metabolic clearance (7-9+/-1-8 ml/min) were significantly (P less than 0-0005) altered compared with the 13 controls (mean half-life 393+/-26 and mean clearance 13-4+/-1-5). The eight patients with hyperbilirubinaemia due to haemolytic disease showed no difference from the normal control subjects. In three patients with Gilbert's syndrome the cumulative urinary excretion of tolbutamide metabolites, 24 hours after the administration of the drug, was 30% lower than in the controls. In the five patients with Gilbert's syndrome, phenobarbital administration (100 mg/day) produced a significant increase in clearance of the drug from 8-8+/-0-8 to 13-4+/-1-9 ml/min; this was paralleled by a fall in serum bilirubin concentration. The plasma half-life of tolbutamide was similar in Gunn rats and Wistar rats. The results suggest that the metabolic defect(s) of Gilbert's syndrome affects compounds other than bilirubin and that defective uptake is probably the major factor.     

The clearance of theophylline is increased during the initial period of tuberculosis treatment.

OBJECTIVE: To evaluate the effects of combined anti-tuberculosis treatment including isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and pyrazinamide (PZA), on the pharmacokinetics of theophylline during the initial phase of treatment. DESIGN: Prospective, controlled clinical study. PATIENTS AND METHODS: Twenty patients with pulmonary tuberculosis received 7.35 mg/kg/day of aminophylline intravenously combined with anti-tuberculosis agents. The first theophylline serum concentration was measured before administration of INH, RMP, EMB and PZA, and samples were obtained once daily for 6 consecutive days after initiation of treatment. All patients in this study were non-smokers with normal hepatic and renal function, and they were not given any other drugs that could affect the clearance of theophylline. RESULTS: The concentration and half-life of theophylline was decreased and its clearance was increased significantly at days 5-7 after administration of antituberculosis agents compared to before the therapy was started. CONCLUSIONS: These results suggest that patients with asthma or chronic obstructive pulmonary disease administered combinations of anti-tuberculosis agents and theophylline during the initial phase of tuberculosis treatment should be monitored closely for changes in theophylline concentration, and that the dose of theophylline should be adjusted accordingly.     

Enteric protein loss as a marker of intestinal inflammatory activity in Crohn's disease: comparability of enteric clearance and stool concentration of alpha-1-antitrypsin?

Intestinal alpha 1-antitrypsin (alpha 1-AT) clearance has been shown a reliable index of intestinal inflammatory activity in Crohn's disease (CD). For reasons of practicability, it has been repeatedly suggested to replace alpha 1-AT clearance by alpha 1-AT concentration in random stool samples. In 60 controls and in 70 patients with CD, in 21 patients before and after treatment, fecal alpha 1-AT concentration and the ratio of stool and serum alpha 1-AT concentration were compared with alpha 1-AT clearance. In 11 patients alpha 1-AT clearance, fecal concentration and stool/serum alpha 1-AT concentration ratio were compared with 51Cr-albumin clearance. alpha 1-AT clearance (104 +/- 14 vs. 17.5 +/- 2 ml/d, p < 0.0001) as well as fecal alpha 1-AT concentration (155 +/- 21 vs. 30 +/- 3 mg/100 ml, p < 0.0001) and stool/serum alpha 1-AT concentration ratio (45 +/- 6 vs. 12 +/- 1) were significantly higher in CD patients than in controls. alpha 1-AT clearance (60 +/- 9 vs. 37 +/- 4 ml/d, p < 0.01), fecal alpha 1-AT concentration (113 +/- 21 vs. 59 +/- 8 mg/100 ml, p < 0.01) and the stool/serum alpha 1-AT concentration ratio (27 +/- 4 vs. 18 +/- 2) decreased after treatment, but fecal alpha 1-AT concentration and the stool/serum alpha 1-AT concentration ratio failed to parallel the course of alpha 1-AT clearance in 33% and in 24% of patients, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of primary multidrug resistance to anti-tuberculosis drugs in Pakistan.

SETTING: Pakistan ranks sixth in the world in terms of tuberculosis (TB) burden, with a World Health Organization estimated incidence of 181 per 100000, or 286000 new cases annually. Hospital-based data indicate a significant problem of multidrug-resistant TB (MDR-TB) in the country and highlight the need to assess its extent at community level. In this cross-sectional study, sputum samples from 742 untreated newly diagnosed pulmonary TB patients from all over the country were used. OBJECTIVE: To assess the prevalence of primary drug resistance in Pakistan. RESULTS: Of 672 culture-positive patients, 76 (11.3%) showed resistance to one or more drugs. Resistance to streptomycin (10 microg/ml) was found in 36 (5.4%) patients, isoniazid (INH) (1 microg/ml) in 51 (7.6%), rifampicin (RMP) (5 microg/ml) in 15 (2.2%), ethambutol (10 microg/ml) in 12 (1.8%) and pyrazinamide in 22 (3.3%) samples. Forty-six (6.8%) of the isolates tested were resistant to a single drug, 10 (1.5%) to two drugs, 12 (1.8%) to three drugs, and 6 (0.9%) to four drugs, while 2 (0.3%) isolates were resistant to all five first-line agents. Primary MDR-TB was 1.8% (n=12) (INH 1 microg/ml, RMP 5 microg/ml). CONCLUSION: The results of this study show a prevalence of primary MDR-TB in Pakistan of <2%, which needs to be addressed through an effective DOTS strategy.     

Anti-arrhythmic effects of mexiletine

Mexiletine was used in 12 patients. Serum drug levels and the antiarrhythmic effects were studied in a therapeutic protocol comprising an initial intravenous administration (3,5 mg/Kg over 10 mins, then 450 mg in 5 hours) followed by oral administration (200 mg eight hourly). The serum drug levels of Mexiletine were high (1,46 +/- 0,47 microgram/ml) as from the first hour in all patients, and remained constant during intravenous administration (average: 1,59 +/- 0,72 microgram/ml). On oral therapy the average mexiletine level was 1,18 +/- 0,21 microgram/ml with two lows (1,02 microgram/ml) six to eight hours after the ingestion of the 200 mg gelules. Ventricular extrasystoles completely regressed after the initial rapid intravenous injection in 7 out of the 12 patients (58,3 p. 100) and this efficacity was maintained throughout the trial. In two patients with low serum mexiletine levels at the end of oral therapy (less than 1 microgram/ml), ventricular extrasystoles were much less frequent during the intravenous phases but reappeared during oral therapy. The clinical, electrocardiographic and hemodynamic tolerance was good (withdrawn in only one patient). The dose should be adapted to the patient's weight and hemodynamic status. When ineffective, the serum mexiletine level can be estimated and when less than 1 microgram/ml, the dose may be increased, in particular by adjusting oral dosage to 200 mg six hourly.     

Kinetics of antifibrillatory effects of bretylium: Correlation with myocardial drug concentrations

To determine the kinetics of the antifibrillatory effects of bretylium tosylate and to assess the relative importance of myocardial versus serum drug concentrations, studies were performed in 32 dogs after they received bolus injections of bretylium tosylate (6 mg/kg or 2 mg/kg body weight) or saline solution. Parallel determinations were made of drug concentrations in serum and myocardium, together with antifibrillatory and electrophysiologic effects, both with and without 2 minutes of coronary ischemia produced by temporary coronary ligation. Serum bretylium concentration decreased rapidly after intravenous injection, whereas myocardial concentrations increased gradually, peaking at 1.5 to 6 hours in both open and closed chest dogs. The ratio of myocardial to serum drug concentration increased to 6.4 to 12.6 at 12 hours. Parallel elimination of the drug in serum and myocardium occurred thereafter, with elimination half-life of 10.5 hours (closed chest dogs).Electrophysiologic and antifibrillatory effects paralleled myocardial rather than serum drug kinetics with peak effects at 3 to 6 hours. The ventricular effective refractory period was 24 to 26 ms greater at 3 hours in dogs treated with the drug than in those receiving saline solution. The ventricular fibrillation threshold increased 6 to 10-fold after 2 mg/kg of the drug was given at 3 to 6 hours in dogs both with and without ischemia in comparison with that in control animals treated with saline solution. The average increase in threshold exceeded 12-fold after administration of 6 mg/kg of the drug (2 minutes to 12 hours). The repetitive ventricular response threshold 3 hours after drug administration increased 5-fold after 2 mg/kg and 18-fold after 6 mg/kg of the drug was administered in dogs with or without ischemia.These studies elucidate canine serum and myocardial drug kinetics of bretylium, quantify the prolonged antifibrillatory effect of this drug with its delayed maximal effect and emphasize the importance of tissue levels of bretylium in determining drug action.     

The disposition of 6-deoxyacyclovir, a xanthine oxidase-activated prodrug of acyclovir, in the isolated perfused rat liver

The antiviral drug, acyclovir, has been used in the treatment of chronic type B hepatitis. High serum concentrations of acyclovir are required to achieve inhibition of hepatitis B viral replication. Because only 15 to 20% of an oral dose is absorbed, it is necessary to administer acyclovir by intravenous infusion. 6-Deoxyacyclovir, an analog of acyclovir, is well absorbed when given orally, and is converted to acyclovir by xanthine oxidase which is present in the gut and liver. This study has examined the hepatic disposition of 6-deoxyacyclovir in a 100 ml recirculating (12 ml per min) perfused rat liver system. Following administration of a bolus dose of 5 mumoles 6-deoxyacyclovir to the reservoir, perfusate concentrations of 6-deoxyacyclovir declined monoexponentially, as the metabolite acyclovir appeared in the perfusate. Addition of the xanthine oxidase inhibitor allopurinol (5 mg) to the perfusate reservoir prior to the administration of 6-deoxyacyclovir resulted in impaired hepatic metabolism of 6-deoxyacyclovir, as demonstrated by a 47% reduction in systemic clearance rate (4.5 +/- 0.4 to 2.4 +/- 0.9 ml per min; p less than 0.05) (mean +/- S.E., n = 6) and a 1.8-fold increase in terminal elimination half-life of 6-deoxyacyclovir (23.5 +/- 2.7 to 42.7 +/- 4.1 min; p less than 0.05), accompanied by a 30% reduction in appearance of acyclovir. The efficient hepatic conversion of 6-deoxyacyclovir to the active antiviral drug, acyclovir, provides a rationale for trials of oral 6-deoxyacyclovir in the treatment of chronic type B hepatitis.     

Pharmacokinetics of human leptin in mice and rhesus monkeys

OBJECTIVE: The pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BL/6J mice fed a normal chow or a high-fat diet. DESIGN: For the monkey study, in nine rhesus monkeys (body weight 12.4 +/- 2.4 kg; mean +/- s.d.), recombinant met-human leptin was injected intravenously or subcutaneously (1 mg/kg). For the mouse study, after 6 months of feeding C57BL/6J mice a high-fat diet (body weight 32.9 +/- 3.6 g; n = 8) or a control diet (24.5 +/- 1.2 g; n = 6), recombinant met-human leptin was administered intraperitoneally (10 microg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration. MEASUREMENTS: Plasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed. RESULTS: Disposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 +/- 16.5 min and clearance of 1.8 +/- 0.2 ml/min/kg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BL/6J mice, the absorption and elimination of human leptin were both first-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 +/- 26.4 min in mice fed a high-fat diet and 49.5 +/- 12.0 min in mice fed a control diet. CONCLUSION: The kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion.     

Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload

We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus injection of deferoxamine and after 12 hours of subcutaneous continuous infusion of the drug in 27 patients with iron overload (mean age, 55.7 years). In most patients, the iron overload was due to multiple transfusions administered during chemotherapy or as part of supportive care for a hematologic or oncologic disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis and spherocytosis. Similar urinary iron excretion was observed with the 2 methods of administration; mean +/- SD values were 6935.3 +/- 3832.3 microg/48 hours with subcutaneous bolus injection and 6630.4 +/- 3606.9 microg/48 hours with subcutaneous continuous infusion (P =.3). Twenty-six patients (96.3%) chose to continue therapy with bolus injection. The long-term efficacy of bolus injection was evaluated by measuring the serum ferritin concentration at regular intervals for a follow-up time of 20.1 +/- 4.5 months. Ferritin concentration decreased to below 1000 microg/L in 73% of the patients and to below 500 microg/L in 42% and became normal in 26%. Best results were obtained in patients who were no longer receiving blood transfusions when chelation therapy was initiated. Three of 26 patients (11.5%) had mild, transient side effects after bolus injection. Larger prospective, randomized studies must be conducted before deferoxamine bolus injection can be routinely recommended for patients with iron overload. (Blood. 2000;95:2776-2779)     

Pharmacokinetics and pharmacodynamics of milrinone in chronic congestive heart failure

The acute hemodynamic effects and pharmacokinetics of bolus intravenous milrinone administration were assessed in 13 patients with severe congestive heart failure. Serial hemodynamics were measured and blood samples were obtained to determine plasma milrinone concentration and calculation of pharmacokinetic variables after administration of milrinone at 12.5, 25, 50 and 75 micrograms/kg, allowing at least 6 hours to elapse between consecutive milrinone doses. At each dose milrinone effected prompt but very short-lived increases in cardiac output and left ventricular stroke work and decreases in pulmonary artery pressure, right atrial pressure and systemic and pulmonary vascular resistance in a non-dose-dependent fashion. Pulmonary artery wedge pressure decreased in a dose-related manner. Heart rate increased significantly after the 75-micrograms/kg dose and mean arterial pressure decreased significantly only after the 50- and 75-micrograms/kg milrinone dose. The time-dependent decline in plasma milrinone concentration was biexponential and log linear, conforming to an open 2-compartment model of drug distribution and elimination. Mean plasma milrinone clearance (+/- standard error) was 0.15 +/- 0.03 liters/min/kg, volume of distribution was 0.35 +/- 0.02 liters/kg and mean elimination half-life was 1.7 hours.     

Effects of ranitidine on plasma clearance of indocyanine green in patients with liver cirrhosis

The effects of ranitidine on plasma clearance of ICG were investigated in 68 cirrhotic patients (9 were positive for HBsAg, 33 were alcoholics and 26 had cryptogenic cirrhosis). The ICG clearance test was performed before and after ranitidine administration. In 31 patients treated with ranitidine (150 mg perorally), the plasma ICG clearance were 233.6 +/- 20.4 ml/min (mean +/- S.E.) and 239.2 +/- 20.5 ml/min before and after ranitidine, respectively. In the 37 treated with intravenous ranitidine 50 mg, the corresponding values were 205.4 +/- 17.7 ml/min and 206.4 +/- 17.9 ml/min. There was no significant change in the plasma clearance of ICG or the elimination rate constant after ranitidine administration. Even in patients with decompensated liver cirrhosis, no significant change was demonstrated in the plasma ICG clearance after ranitidine. These results led to the conclusions that ranitidine does not reduce the hepatic blood flow and that it is a safe and useful drug for the treatment of gastrointestinal tract bleeding in patients with liver cirrhosis.     

Serum concentrations of lignocaine before, during and after fiberoptic bronchoscopy

BACKGROUND: Lignocaine is commonly used for local anesthesia during fiberoptic bronchoscopy (FOB). Several studies have reported the peak serum concentration of lignocaine in relation to time, but most of them did not specify the administered dose of lignocaine gel and its possible correlation with peak serum concentration. OBJECTIVE: The aim of our study was to record the plasma concentrations of lignocaine before, during and after FOB and to evaluate whether the doses for nasal and tracheobronchial anesthesia have any correlation with the peak serum concentrations of the drug. METHODS: Twelve patients with no comorbid conditions undergoing FOB were studied. Lignocaine was administered as a 2% solution using a larynx syringe, 2% gel (mean dose 182.5 +/- 15 mg) and finally 2% solution through the bronchoscope (mean dose 339 +/- 12 mg). Total dose was 622 +/- 20 mg. Venous blood samples were taken before the beginning of local anesthesia and then at 5, 10, 20, 60, 90 and 120 min thereafter. RESULTS: Our results showed that peak plasma concentrations of lignocaine were observed in 8 patients 20 min after the beginning of local anesthesia, in 3 patients 30 min afterwards and in 1 patient 60 min afterwards (2.15 +/- 0.4 microg/ml, 1.9 +/- 0.3 microg/ml, 1. 81 microg/ml, respectively). None of our patients exceeded the critical level of toxicity (5 microg/ml). Both the total and tracheobronchial doses of lignocaine were significantly correlated with peak serum concentration (r = 0.63, p = 0.05 and r = 0.64, p = 0.02, respectively). No correlation was found between the dose for nasal anesthesia and peak serum concentration. No adverse reactions were observed. CONCLUSIONS: In conclusion our data show that although the amount of lignocaine used in this study exceeded the recommended highest dose (400 mg) in all patients, no toxic levels were observed. Peak plasma concentrations were found within 20-30 min from the beginning of local anesthesia. The dose for the anesthesia of nasal mucosa represented a significant percentage of the total dose, but did not correlate with the peak serum concentration of the drug.     

Evaluation of a new antianginal agent, nipradilol, in effort angina using holter monitoring

The purpose of this study was to investigate the efficacy, effective dose, administration frequency and antianginal effect of a new antianginal agent, nipradilol, in 12 patients with stable effort angina. A single blind design was employed; the test consisted of an observation period (1 week) and a treatment period (1-2 weeks). Twenty four hour Holter monitoring was performed on the penultimate day of each period. Nipradilol was administered twice a day at a daily dose of 3-12 mg (mean 7.9 +/- 3.3 mg). The mean frequency of ST-segment depression was 7.1 +/- 6.7 times per day at baseline and 3.1 +/- 2.7 after drug administration, showing a significant reduction (p less than 0.05). The suppression of ST-segment depression and decrease in heart rate due to this drug persisted for 12 hours following administration. The plasma drug concentration at a daily dose of 12 mg peaked at 9.5 +/- 2.4 ng/ml 1 hour after administration and the 12 hour value was 2.3 +/- 1.2 ng/ml. No side effects were observed. Therefore, it seems that, when administered twice a day (total daily dose 6 mg) this drug is effective in effort angina and that the antianginal effect is mainly attributable to beta-adrenoceptor blockade.