Pharmacokinetics of a single dose of teicoplanin in burn patients.

Patients with severe burns are susceptible to infection with Gram-positive organisms including methicillin-resistant Staphylococcus aureus, and often require higher antibiotic dosages compared with other patients. This study examined the pharmacokinetics of a single iv dose of teicoplanin (12 mg/kg) in 15 adults and five children with severe burns. Adults were aged 21-82 years with a median total body surface area (TBSA) burn of 30% (range 15-60%). Children were aged 10 months-l0 years with median TBSA burn of 15% (10-30%). At 12 h, the median serum teicoplanin concentration was 12.8 mg/L (9.027.1 mg/L) in adults and 7.6 mg/L (6.6-l0.8 mg/L) in children, (P < 0.01); at 24 h, the corresponding values were 8.3 mg/L (4.6-l2.9 mg/L) and 5.2 mg/L (4.2-6.0 mg/L). Using a three-compartment model, the median terminal half life in adults was 114 h (47-278 h). Children fitted a two-compartment model with a terminal half-life of 38 h (2l-41 h). The median concentration of teicoplanin in fluid from the burn wound was 60% of the serum antibiotic concentration. A single iv dose of 12 mg/kg of teicoplanin was sufficient to produce therapeutic serum concentrations in burn patients for 24 h, but monitoring of antibiotic levels in serum may be advisable in those with high total clearance, especially children.

Clearance of gentamicin during cardiac surgery.

Treatment with an aminoglycoside plus flucloxacillin is commonly used to prevent wound infection and endocarditis after cardiac surgery. Cardiopulmonary bypass, blood transfusion and the lack of a steady state greatly affect handling of gentamicin. Urinary gentamicin excretion is not predictable in terms of preoperative risk factors possibly because there is no clear relationship between serum levels and gentamicin clearance. A study was performed to determine whether the existing prophylactic regimen gave adequate serum levels during surgery and to compare renal excretion of gentamicin and the trough serum levels. Ten patients received gentamicin (1.5 mg/kg at the start of surgery followed by 80 mg tds for 2 days) and flucloxacillin 500 mg qds for 2 days. Serum and urinary concentrations of gentamicin were assayed during surgery and in the early postoperative period. The median apparent serum half-life during the first 8 h was 2.5 h (95%CI 1.7-3.2 h). The median gentamicin clearance was 37 mL/min(95%CI 23-64 mL/min) and the creatinine clearance 85 mL/min (95%CI 72-210 mL/min). Serum levels remained above 1 mg/L during surgery but urinary concentrations varied between 0.4 and 364 mg/L (median 70 mg/L). At 24 h (but not 8 or 16 h), trough serum levels appeared to be related to the amount of gentamicin excreted but the relationship was not quite statistically significant (P = 0.057). Despite the effects of cardiopulmonary bypass, therapeutic serum gentamicin levels were maintained during surgery and reduced renal excretion in the postoperative period was associated with raised levels.

Antibiotic prophylaxis in cardiac surgery: factors associated with potentially toxic serum concentrations of gentamicin.

Aminoglycosides are commonly used with flucloxacillin in the prevention of wound infection and endocarditis after cardiac surgery. Earlier studies suggested that the use of aminoglycosides is associated with a small but significant rise in serum creatinine. A regression analysis was performed to identify the preoperative and postoperative factors of importance in determining serum gentamicin concentrations. Serum assays might then be confined to those at particular risk of elevated serum levels. Patients received gentamicin 1.5 mg/kg at the start of surgery followed by 80 mg tds for two days in addition to flucloxacillin. Trough and peak serum gentamicin concentrations were assayed on the first and second days after surgery and urine concentrations were measured with each full catheter bag. Patient characteristics, drug therapy, operation, fluid balance and routine investigations were recorded. A total of 95 of 104 patients were evaluable. Linear discriminant analysis of factors selected by forward stepwise regression identified ten of the 15 patients with subsequent elevated gentamicin concentrations, by using age, and preoperative serum creatinine, systolic blood pressure and serum aspartate transaminase. After operation, factors such as serum creatinine, the quantity of frusemide administered in 24 h, and the integral of the systolic blood pressure over 24 h identified 12 of the 15 patients. However, no satisfactory model could predict urinary concentrations. The discriminant function using preoperative factors prospectively identified 11 of 12 patients with elevated trough levels from a total of 101 further patients. Postoperative gentamicin concentrations cannot reliably be predicted from patient characteristics. Trough assays should be performed or prophylactic courses limited to 24 h.

Determination of MK-383, a non-peptide fibrinogen receptor antagonist, in human plasma and urine by radioimmunoassay.

MK-383 is a novel, non-peptide fibrinogen receptor antagonist. A sensitive and specific radioimmunoassay has been developed for the determination of this drug candidate in plasma and urine. The immunogen was prepared by coupling to albumin via the N-hydroxysuccinimide ester from which the radioligand was also prepared by reaction with [I125]iodotyrosine. The method was specific and no immunoreactive material other than the parent drug was detectable in plasma and urine from dosed volunteers. This direct assay, using 5 microliters of plasma or 0.5 microliter of urine, is sensitive to 1 and 10 ng ml-1, respectively, without matrix interference and has sufficient sensitivity, specificity, accuracy, and precision for the analysis of clinical samples.

Determination of L-691,121, a new class III antiarrhythmic, and its principal metabolite in plasma by differential radioimmunoassay.

A sensitive and specific method based on radioimmunoassay (RIA) has been developed for the analysis of L-691,121, a new antiarrhythmic agent, and its major metabolite, L-692,199, in plasma. Two RIAs using immunogens and radioligands prepared from different derivatives of L-691,121 were used in conjunction to determine both parent compound and metabolite concentrations by solving simultaneous equations, since neither assay alone was adequately specific. Variable cross-reactivity factors were incorporated into the calculations to correct for non-parallel drug and metabolite displacement curves. The direct assay using 30 microliters of plasma is sensitive to 0.1 ng ml-1 and has sufficient precision, accuracy and specificity for the analysis of clinical samples.

Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of MK-852, a new fibrinogen receptor antagonist, in plasma and urine by radioimmunoassay.

MK-852 is a novel fibrinogen receptor antagonist. A sensitive and specific radioimmunoassay has been developed for the determination of this drug candidate in plasma and urine. The immunogen was prepared by coupling to albumin via a dinitrophenylene bridge and the radioligand by reaction of the drug with the 125I-labelled Bolton-Hunter reagent. The method was specific and no immunoreactive material other than parent drug was detectable in plasma from dosed volunteers. The direct assay using 0.05 ml of plasma is sensitive to 0.2 ng ml-1 without matrix interference and has sufficient sensitivity, precision, accuracy, and selectivity for the analysis of clinical samples. The lower quantifiable limit in (diluted) urine is 50 ng ml-1.

In vivo and in vitro metabolism studies on a class III antiarrhythmic agent.

The metabolism of L-691,121 (I), a class III antiarrhythmic agent, was studied in vivo in rats and dogs and in vitro by using liver S9 or slices from these species and humans. After oral doses of [14C]I to rats (5 mg/kg) and dogs (1 mg/kg), urinary recoveries of label were, respectively, 6% and 28%. Biliary excretion (0-24 hr) accounted for 68% of a 5 mg/kg, po dose in rats and 19% of a 10 mg/kg dose, po in dogs. Metabolites were identified by application of FAB/MS, NMR, and diode-array UV spectroscopy. The major dog metabolites were the secondary alcohol (II) produced by carbonyl reduction and its glucuronide conjugate (III). It was estimated that II and III represented 24 and 36%, respectively, of the dog biliary radioactivity. After a 50 mg/kg dose of I, II represented approximately 50% of the dog urinary label. A minor metabolite (IV) in dog urine was produced by reduction and loss of N-substitution. There were species differences in that, relative to dogs, II represented a much smaller fraction of the excreted dose in rats and there was no evidence for excretion of III in rats. N-Dealkylated I (V) was excreted, along with IV in rat bile. Dog liver slices and S9 fractions were most efficient (relative to human and rat liver tissues) at reducing I to II. Metabolic reduction of I to II was highly stereoselective and yielded the (-)-antipode as determined by chiral chromatography.

The treatment of neonatal meningitis due to gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid.

We describe two cases of neonatal meningitis due to Gram-negative bacilli treated successfully with ciprofloxacin. Examination of serial samples of cerebrospinal fluid indicated the effect of meningeal inflammation on penetration of this drug into the CSF.

Renal handling of alendronate in rats. An uncharacterized renal transport system.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone diseases. Earlier studies from this laboratory have demonstrated that systemically administered alendronate is rapidly either taken up by bone tissues or excreted by the kidney, and that renal excretion is the only route of elimination. The purpose of this study is to characterize the renal handling of alendronate in rats by standard clearance procedures with inulin as a marker of glomerular filtration rate. Alendronate is highly bound to rat serum protein. The excretion of alendronate by the kidney is concentration-and dose-dependent, and saturable, indicating that it is secreted by an active transport mechanism. The secretory mechanism exhibits limitation of transport, with an apparent Tm of approximately 25 micrograms/min/kg. However, high doses of cimetidine, quinine, probenecid, and p-aminohippuric acid had no effect on the renal excretion of alendronate, suggesting that alendronate is not secreted by anionic or cationic transport systems. In contrast, alendronate clearance is inhibited by etidronate, another bisphosphonate, in a dose-dependent manner, implying that these two bisphosphonates compete for an as yet uncharacterized renal transport system. As expected, the renal excretion of alendronate is drastically reduced in rats with acute renal failure. As a consequence of renal impairment, alendronate accumulates in plasma, and the concentration of the drug in bone tissues increases significantly.

Dopamine receptor changes in untreated and (+)-PHNO-treated MPTP parkinsonian primates.

Fifteen monkeys (Macaca fascicularis) were utilized in this study. Seven naive animals received no treatment and served as controls. Eight animals were rendered parkinsonian with serial injections of MPTP. Three of the parkinsonian monkeys were treated with (+)-4-propyl-9-hydroxynaphthoxasine [(+)-PHNO], a selective dopamine D2 agonist. (+)-PHNO (2-5 micrograms/kg/h) was administered continuously using subcutaneous osmotic pumps. All animals were given weekly scored neurologic examinations throughout the study. Their movement was quantitated in an activity box. The animals were sacrificed 30-120 days after their last MPTP injection by an overdose of sodium pentobarbital. The brains were removed, frozen and cut into 20-microns sections. The density of D1 and D2 receptors was studied in the basal ganglia of these animals at the level of the anterior commissure. For the D2 assay, total binding was determined using various concentrations of [3H]spiperone in buffer containing 300 nm mianserine. For the D1 assay, total binding was determined using various concentrations of [3H]SCH-23390. Tissue isotope concentration was determined from the autoradiographs. The parkinsonian animals demonstrated 90-97% dopamine depletion in the striatum. There was a 75-90% decrease in free movement in the untreated parkinsonian monkeys and their composite clinical score was 8.9 on a scale of 0-16 (zero being normal). Control monkey scores averaged 0.6. The untreated parkinsonian monkeys demonstrated an increase in the number of D2 sites as compared to controls. This increase was greatest at the lateral putamen. The (+)-PHNO-treated monkeys demonstrated increased activity, a neurologic score of 3.4, and a 40-70% decreased in D2 sites in both caudate and putamen. There was no change in the number of D1 binding sites in both the untreated and the (+)-PHNO-treated parkinsonian monkeys as compared to controls.

Metabolism of antiparkinson agent dopazinol by rat liver microsomes.

Metabolism of dopazinol (DZ) by liver microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats has been investigated. Liver microsomes from control and treated rats metabolized DZ to N-despropyl-DZ (39-53% of total metabolites); 8-hydroxy-DZ, a catechol metabolite (32-39%); and 5- or 6-hydroxy-DZ (12-20%). The last metabolite was identified as its dehydration product 5,6-dehydro-DZ. N-Dealkylation was favored only slightly over catechol formation (ratio = 1.2) by liver microsomes from control and phenobarbital-treated rats, whereas with liver microsomes from 3-methylcholanthrene-treated rats, N-dealkylation predominated (ratio = 1.7). Liver microsomes from control rats metabolized DZ at a rate of 0.86 nmol/nmol cytochrome P-450/min. Pretreatment of rats with phenobarbital or 3-methylcholanthrene stimulated rates of metabolism by 2.4- and 3-fold, respectively. Metabolism of DZ was inhibited by SKF 525-A, methimazole, and thiobenzamide. SKF 525-A completely inhibited metabolism of DZ, while methimazole and thiobenzamide, two alternate substrates of the microsomal flavin-containing monooxygenase (MFMO) inhibited N-dealkylation only. These results indicated that while the cytochrome P-450-dependent monooxygenase is the primary enzyme system in DZ oxidation, the MFMO also catalyzes the N-dealkylation reaction. The catechol metabolite was converted to isomeric O-methylated derivatives in approximately 1:1 ratio by purified catechol-O-methyl transferase or 105,000g liver cytosol. The late eluting isomer was 8-methoxy-DZ.

A radioimmunoassay for the anticonvulsant and neuroprotective agent, MK-801.

A radioimmunoassay is described for MK-801, a potent anticonvulsant and neuroprotective agent. Two immunogens were prepared from N-glutaryl- and N-carboxyethyl-MK-801 by coupling through their carboxyl groups to bovine serum albumin. Radioligands were I-125-iodotyramine conjugates of the same derivatives. Both types of antisera displayed bridge recognition which could be circumvented. In the first case, specificity for N-acyl derivatives was satisfied by acetylating the analyte prior to measurement. Antisera to the N-alkyl derivative yielded a satisfactory assay for MK-801 when the heterologous radioligand was employed. The first of these strategies was adopted for the routine assay. Specificity relative to hydroxylated metabolites was a function both of antiserum selectivity and sample preparation. High plasma concentrations of drugs concomitantly administered to epileptics posed special analytical problems. Assay sensitivity is 40 pg/ml in plasma and the interassay CV is about 5%.

Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers.

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin-converting enzyme (ACE). The half-life for the terminal phase (approximately 40 h) was not predictive of steady-state parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half-life for accumulation was 12.6 h. The mean accumulation ratio was 1.38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.

Antiparkinsonian efficacy of a novel transdermal delivery system for (+)-PHNO in MPTP-treated squirrel monkeys.

We examined the ability of the antiparkinsonian agent (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) to enter the systemic circulation in therapeutic concentrations after continuous transdermal absorption in squirrel monkeys rendered parkinsonian by MPTP. Direct subcutaneous administration of (+)-PHNO in the dose range of 2.5 to 20 micrograms/kg restored locomotor activity to levels seen in normal monkeys for approximately 1 hour. Application of transdermal patches capable of delivering, into an infinite sink, an estimated 2.6 micrograms/cm2/h of (+)-PHNO over a skin surface area of 4.78 to 19.12 cm2 also restored locomotor activity to the normal range during a 24-hour period. We suggest the use of transdermal application of PHNO as a novel drug delivery system for the improved management of Parkinson's disease.

The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.

The antiparkinsonian actions and pharmacokinetics of transdermal (+)-4-propyl-9-hydroxynaphthoxazine (+PHNO): preliminary results.

(+)-4-Propyl-9-hydroxynaphthoxazine (+PHNO) is a potent dopamine agonist that has been administered transdermally to four patients with Parkinson's disease and "on-off" fluctuations. Skin patches of increasing size were used to treat these patients, who also received infrequent doses of oral levodopa if required. The effect of +PHNO was measured as an increased duration of action of individual levodopa doses. The clinical effect measured in this way was directly proportional to the plasma concentrations of +PHNO achieved. The plasma concentrations of +PHNO began to rise 4-6 h after patch application and reached a steady state by 24 h. The final plasma concentration of +PHNO was proportional to the area of skin covered.