The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0-infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for short- time sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided.     

The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone

OBJECTIVE: The effects of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor antidepressant, on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled, two-phase cross-over study, ten healthy volunteers took either 100 mg fluvoxamine or matched placebo orally once daily for 5 days. On day 6, 10 mg buspirone was taken orally. Plasma concentrations of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), were measured up to 18 h and the pharmacodynamic effects of buspirone up to 8 h. RESULTS: The total area under the plasma buspirone concentration-time curve was increased 2.4-fold (P < 0.05) and the peak plasma buspirone concentration 2.0-fold (P < 0.05) by fluvoxamine, compared with placebo. The half-life of buspirone was not affected. The ratio of the total area under the plasma concentration-time curve of 1-PP to that of buspirone was decreased from 7.4 [6.3 (SD)] to 4.4 (3.6) by fluvoxamine (P < 0.05). The results of the six pharmacodynamic tests remained unchanged. CONCLUSION: Fluvoxamine moderately increased plasma buspirone concentrations and decreased the production of the active 1-PP metabolite of buspirone. The mechanism of this interaction is probably inhibition of the CYP3A4-mediated first-pass metabolism of buspirone by fluvoxamine. However, this pharmacokinetic interaction was not associated with impairment of psychomotor performance and it is probably of limited clinical significance.     

The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam

The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double-blind, randomized, cross-over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration-time curve and the elimination half-life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first-pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.     

Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir

The effects of fluconazole on the pharmacokinetics of the HIV protease inhibitor ritonavir were investigated after multiple dosing in an open-label study. In this randomized, two-period crossover study, eight healthy subjects received ritonavir alone (200 mg every 6 hr for 4 days) and ritonavir with fluconazole (400 mg on day 1, 200 mg every day on days 2-5) with a 2-week washout period. Ritonavir plasma concentrations were measured during the final four ritonavir dosing intervals (24 hr) and a 12-hr washout period. There were statistically significant increases in ritonavir C(max) and AUC0-24 (p < 0.02), with concurrent administration of fluconazole compared with administration of ritonavir alone. The difference between regimens in C(min) was marginally statistically significant (p = 0.089), and t(max) and beta were not statistically significantly different. Although some ritonavir parameters were affected by fluconazole, mean increases in C(max) and AUC were < or = 15% for the 24-hr period, and only 7-19% for individual dose intervals. Thus, the pharmacokinetics of ritonavir may be influenced only to a small extent when administered with fluconazole. These changes are probably of limited clinical significance and do not necessitate dosage adjustment of ritonavir when fluconazole is added to the regimen.     

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients

Unlike most secretory cells, high extra cellular calcium inhibits rather than stimulates hormonal secretion in several cells such as parathyroid cells, Juxtaglomerular cells and osteoclast. To gain further insight into the common but unique stimulus-secretion coupling mechanism in these cells, bovine parathyroid slices were incubated in various conditions of Krebs-Ringer (KR) solution containing essential amino acids. Parathyroid cells showed the inverse dependency of secretion on extra cellular calcium concentration as we expected. Ammonium acetate overcame the inhibitory effect of 2.5 mM of calcium and the maximum effect was as much as the five times of the basal value, while there was a little additive effect under 0 mM CaCl2. PTH secretion was biphasic according to the change of extra cellular osmolarity and the lowest response was observed at 300 mOsm/l. In Na-rich KR solution, high concentration of nigericin (> 10(-4)M) completely overcame the inhibitory effect of 2.5 mM CaCl2 and the maximum stimulatory effect was 8 times greater whereas it was only 2 times greater without CaCl2. In K-rich KR solution that abolished the K-gradient between the extra cellular solution and the cytoplasm, the rate of PTH secretion increased, and furthermore the addition of nigericin increased the rate of secretion significantly. The results above suggested that the osmotic swelling of the secretory vesicle in parathyroid cells might promote exocytosis as in Juxtaglomerular cells. We propose that the swelling of the vesicle is also prerequisite for secretion in several cells inhibited paradoxically by Ca++, whatever the signal transduction pathway for swelling of the secretory granules induced by the lowering of Ca++ in cytoplasm are.     

Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous azosemide

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of azosemide were evaluated using rabbit as the animal model. Each rabbit received a 4h constant intravenous infusion of 1 mg kg-1 azosemide with 0% replacement (treatment I, n = 4), 50% replacement (treatment II, n = 5), and 100% replacement (treatment III, n = 5) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (D-5-W, treatment IV; n = 5). Renal clearance and urinary excretion rate of the drug in treatment III were considerably higher than those in treatments I, II, and IV. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects of azosemide were markedly different among the four treatments. For example, the mean 8 h urine output values were 98.2, 178, 733, and 237 mL for treatments I-IV, respectively, and the corresponding values for sodium excretion were 11.1, 19.4, 76.4, and 14.2 mmol, and for chloride 13.4, 23.8, 78.9, and 17.1 mmol. Except for treatment III, diuresis and/or natriuresis were found to be time dependent, generally decreasing with time until reaching a low plateau during the later hours of infusion. The present findings also show that (i) no fluid replacement and 100% replacement with D-5-W both produce the same degree (not significantly different) of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (ii) in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis can mainly be attributed to negative water balance under this special condition; and (iii) at steady state the hourly diuresis and natriuresis can differ up to about 6.87- and 5.21-fold between treatments. Some implications for the bioequivalence evaluation of dosage forms of azosemide are discussed.     

Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs

Remifentanil is an esterase-metabolized opioid developed for use in anesthesia. The principal metabolite of remifentanil, GR90291, is considered to be less potent. This study determined the relative potency of GR90291 and alfentanil, compared with remifentanil, in anesthetized dogs. Male dogs received thiamylal sodium, and anesthesia was maintained using isoflurane and N2O in oxygen. Each dog received a 5-min infusion of 0.5 microg/kg/min remifentanil, 500 microg/kg/min GR90291 and 1.6 mg/kg/min alfentanil in random order, separated by 1 week. Serial blood samples were collected during and after the infusion. The electroencephalogram was evaluated using aperiodic analysis. The pharmacokinetics and pharmacodynamics of remifentanil, GR90291 and alfentanil were determined using nonlinear least-squares regression analysis. Remifentanil was rapidly eliminated, with a terminal half-life of 6 min, compared with 19 min for GR90291 and alfentanil. Using the estimated concentration that elicits 50% of the maximum response (EC50) for delta EEG activity and spectral edge95, remifentanil was 4213 to 4637 times more potent than GR90291 and 7.7 to 8.5 times more potent than alfentanil. The blood-brain equilibration half-life was 2.3 to 5.2 min for remifentanil, 0.39 to 0.41 min for GR90291 and 3.1 to 3.7 min for alfentanil.     

The use of microdialysis in pharmacokinetics and pharmacodynamics

Microdialysis is a new in vivo sampling technology applied to the study of pharmacokinetics and drug metabolism in the blood and soft tissues of living systems. A small-diameter probe containing a dialysis membrane is implanted into tissue and perfused with a suitable fluid. Low-molecular-weight substances passively diffuse through the semipermeable membrane along a concentration gradient, resulting in the collection of purified dialysate samples. The advantage of this approach over blood sampling and dissection of tissues is the ability to sample blood and extracellular fluid with minimal tissue damage or alteration of fluid balance. Sampling several tissues simultaneously and continuously in animal models allows data to be obtained that more directly reflect interactions of drugs at their sites of activity and detoxification. Techniques such as this will have a tremendous impact on preclinical and clinical pharmacologic research.     

Relevance of pharmacokinetics and pharmacodynamics

This ex post facto study investigated the relationship of social support from two workplace sources, unit managers and registered nurse (RNs) coworkers, to work-related stress among staff nurses. Sample participants included 51 full-time RNs from a variety of clinical specialties in one nursing organization. The three theoretical components--affect, affirmation, and aid--were measured by the Norbeck Social Support Questionnaire. The Nursing Stress Scale was used to quantify the levels of perceived work-related stress. Statistically significant negative correlations were found between affect from unit managers (r = -299; P = 0.15) and aid from coworkers (r = -.294; P = .036) on levels of perceived work-related stress. Additionally, the increased age of the subjects (r = -.342; P = .007), years of nursing experience (r = -252; P = .037), and length of employment (r = -329; P = .009) had a negative relationship with work stress. The results of this research demonstrated that two components of social support--affect (emotional support) from unit managers and aid (services, information, materials) from coworkers--were linked to lower stress scores in this sample of staff nurses.     

Bioavailability and pharmacokinetics of beta-methyldigoxin after multiple oral and intravenous doses

To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of beta-methyldigoxin 0.3 mg. After oral or intravenous administration of beta-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.     

Topiramate: pharmacokinetics and pharmacodynamics

Topiramate is a structurally novel anti-epileptic drug with at least 3 postulated mechanisms of action including: 1) potentiation of GABA responses, 2) impairment of AMPA/kainate glutamate receptors and 3) suppression of high frequency action potential firing. It has a favourable pharmacokinetic profile with rapid absorption, good bio-availability, linear pharmacokinetics, relatively long half-life and limited pharmacokinetic drug interactions. However, topiramate can reduce the estrogen component of oral contraceptive medications. Women may require birth control preparations containing 50 micrograms of estrogen. Topiramate clearance is reduced in severe renal failure and increased by enzyme-inducing anti-epileptic drugs. The dose of topiramate may have to be reduced in renal failure or when withdrawing enzyme inducers.     

Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

Historically, women, the elderly, and minorities were underrepresented in clinical drug trials. Information on possible gender-related differences in the pharmacokinetics of drugs is often lacking, although for some drugs significant differences could be demonstrated. In women, absorption, protein binding, volume of distribution, and metabolism of drugs may differ due to hormonal influences on physiological functions. Sex-related differences could be shown for phase I (cytochrome P450) as well as phase II (especially glucuronidation) reactions. Since many women world-wide take oral contraceptives, data should be provided to determine to what extent other drugs are influenced by estrogens and progestogens or to what extent the other drugs may attenuate the contraceptive efficacy. Moreover, estrogens interact with various enzymes and receptors, e.g. at the endothelial function as well as dopaminergic receptor sites, and may therefore attenuate or enhance drug effects or even drug side-effects. For a number of drugs it is well recognized, that women suffer more frequently from side-effects, however, it is often not clear, if this is due to gender differences in the pharmacokinetics or pharmacodynamics of the responsible drug. Very little is known about these gender-related differences and the possibility that women may show a different pattern of treatment response than men. As a result, drug approval authorities now require more data on the pharmacokinetics of novel drugs in women as well as a sufficient accrual of women in efficacy and outcome trials.     

Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium

OBJECTIVE: Different sets of diagnostic criteria have been proposed for Sj?gren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. METHODS: The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study included 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. RESULTS: The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. CONCLUSION: Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.     

Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam

The pharmacokinetic-pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double-blind, placebo-controlled crossover study. Sixteen healthy male volunteers enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12-day period. In both periods, lorazepam (1 mg every 12 hours) was administered on days 6 through 9 and on the morning of day 10. Concomitant administration of divalproex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady-state maximum plasma concentration, area under the concentration-time curve, and trough plasma concentrations of lorazepam, respectively. The apparent clearance of lorazepam through the formation of lorazepam glucuronide was reduced by 31% during coadministration of divalproex sodium. Pharmacokinetic properties of valproate did not change significantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant differences in sedation between the two regimens. It is concluded that valproate increases plasma concentrations and reduces clearance of lorazepam, most likely by impairing hepatic glucuronidation, and that coadministration of lorazepam does not affect the steady-state pharmacokinetic properties of valproate.     

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels

Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.     

Within-subject variability in cocaine pharmacokinetics and pharmacodynamics after intraperitoneal compared with intravenous cocaine administration.

Performance in rats (Rattus norvegicus) was measured on a differential reinforcement of low-rate schedule (DRL 45-s) in 1.5-hr sessions after 2 mg/kg intravenous (IV) or 10–20 mg/kg intraperitoneal (IP) cocaine administration, with each dose given twice and separated by 3–5 days. For successive IV doses, cocaine effects were similar, with minimal within-subject variability. For IP cocaine, the effects were not always similar; performance was variable and sometimes remained at baseline level. These diminished effects occurred following either the 1st or 2nd IP injection. A parallel pharmacokinetic study of cocaine confirmed that within-subject variability existed in cocaine concentration-time profiles after IP cocaine, and that a low serum cocaine concentration-time profile could account for the diminished effects. The IP route for cocaine administration should be used with caution. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metocurine pharmacokinetics and pharmacodynamics in goats

Crystalluria is important in the evaluation of patients with urinary stone and is more frequently encountered in elderly than in younger adults. After noting that calcium oxalate monohydrate crystalluria was higher in elderly patients, we undertook a study to determine if oral treatment with naftidrofuryl oxalate, a drug frequently prescribed for elderly patients in France, was associated with crystalluria. The presence of early morning crystalluria was assessed in non-stone-forming patients hospitalized in a geriatric department. We studied 251 patients without a history of nephrolithiasis (mean age; 81.6 +/- 8.5 years) of whom 49 had been treated orally with naftidrofuryl oxalate at a mean dosage of 485 +/- 120 mg/24h. We identified and quantified the crystals in one early morning urine sample kept at room temperature. The frequency of crystalluria in elderly patients without stones who were not taking naftidrofuryl oxalate was 31.7% compared with only 6% in the general adult population. In this group, mainly calcium phosphate crystals were found. In patients who received naftidrofuryl oxalate, the frequency of crystalluria was 51% of which the major component was calcium oxalate monohydrate and not calcium phosphate. Naftidrofuryl oxalate may enhance crystal formation in elderly patients. This should be taken into account, particularly when other predisposing factors for nephrolithiasis are present, and a preventive increase in fluid intake considered.     

The pharmacokinetics and steady state pharmacodynamics of mivacurium in children

BACKGROUND: The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable acute rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival. METHODS: We compare here in a case-control study 24 retransplantations with 47 first transplants in patients matched for date of transplantation. RESULTS: Between 1973 and 1996, 1,063 patients underwent cardiac transplantation in our institution. In this cohort, 22 patients had a total of 24 retransplantations (2 second-time retransplantations). The causes of retransplantations were primary graft failure (n=4), acute rejection (n=7), coronary graft disease (n=11), and miscellaneous (n=2). Survival at 1 and 5 years of patients with retransplantations is 45.5% and 31.2%, and survival of control patients is 59.4% and 38.8% (p=0.07). An interval between first transplantation and retransplantation shorter (n=11) or longer (n=13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively (not significant). Intervals shorter than 1 year between first transplantation and retransplantation were exclusively secondary to primary graft failure or intractable acute rejection. CONCLUSIONS: In the face of lack of donor grafts, these and other data indicate that retransplantation should be considered cautiously, especially when the interval between the first transplantation and retransplantation is short.     

Stereoselective pharmacokinetics of bisoprolol after intravenous and oral administration in beagle dogs

We report 81 of 107 cases of hemolytic uremic syndrome (HUS), admitted between July 1994 and February 1996, following an outbreak of Shigella dysenteriae type 1 dysentery in Kwazulu/Natal. All patients, excluding 1, were black with a mean age of 38 months (range 1-121); 50 (61.7%) were males. The mean duration of dysentery was 11.3 days (range 1-41) and HUS 15 days (range 1-91). Most patients had acute oliguric renal failure (90.1%), 42 (51.6%) required peritoneal dialysis. Complications included encephalopathy 30 (37.0%), convulsions 12 (14.8%) and hemiplegia 2 (2.3%), gastrointestinal perforation 8 (9.9%), protein losing enteropathy 26 (32.1%), toxic megacolon 4 (4.9%), rectal prolapse 5 (6.2%), hepatitis 11 (13.6%), myocarditis 5 (6.2%), congestive cardiac failure 3 (3.7%), cardiomyopathy 3 (3.7%), infective endocarditis 1 (1.2%), septicemia 15 (18.5%), disseminated intravascular coagulation 17 (21%). Leukemoid reactions were found in 74 (91.3%) patients, hyponatremia in 56 (69.1%), and hypoalbuminemia in 67 (82.7%). Stool culture for Shigella dysenteriae type I was positive in only 7 (8.6%) patients; Shiga toxin assays were not performed. Outcome was as follows: recovery 32 (39.5%), impaired renal function 8 (9.9%), chronic renal failure 26 (32.1%), end-stage renal disease 1 (1.2%), and death 14 (17.3%) patients.