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1.  Full-dose intra-operative radiotherapy with electrons (ELIOT) during breast-conserving surgery: experience with 1246 cases 
Background:
Previous studies showed that after breast-conserving surgery for breast cancer, radiotherapy may be applied to the portion of the breast where the primary tumour was removed (partial breast irradiation (PBI), avoiding the irradiation of the whole breast. We developed a procedure of PBI consisting of a single high dose of radiotherapy of 21 Gy with electrons equivalent to 58–60 Gy in fractionated doses, delivered during the surgical session by a mobile linear accelerator, positioned close to the operating table.
Patients and methods:
From July 1999 to December 2006, 1246 patients with primary carcinoma of less than 2.5-cm maximum diameter, mostly over 48 years, were treated with electron intra-operative radiotherapy (ELIOT) at a single dose of 21 Gy.
Results:
After a follow-up from 0.3 to 94.7 months (median 26), 24 (1.9%) patients showed a local recurrence and 22 developed distant metastases. Sixteen patients died, seven from breast carcinoma and nine from others causes. The five-year crude survival was 96.5%. Six (0.5%) developed severe breast fibrosis, which resolved in 2–3 years. An additional 40 patients suffered for mild fibrosis. Cosmetic results were good.
Conclusions:
Electron intra-operative radiotherapy is a safe method for treating conservatively operated breasts and avoids the long period of post-operative radiotherapy, greatly improving the quality of life and reduces the cost of radiotherapy. ELIOT markedly reduces the radiation to normal surrounding tissues and deep organs. Results on short- and medium-term toxicity are good. Data on local control are encouraging.
doi:10.3332/eCMS.2008.65
PMCID: PMC3234040  PMID: 22275962
2.  Pharmacokinetics of rifabutin in HIV-infected patients with or without wasting syndrome 
Aims
The purpose of the study was to compare the pharmacokinetic parameters of rifabutin obtained in a group of patients without wasting syndrome (NWS) with those obtained in a group with wasting syndrome (WS).
Methods
A single dose of 300 mg rifabutin was administered in the fasting state to the patients in both study groups and blood samples were scheduled to be collected at the following times: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h following administration. Data were analysed using noncompartmental methods. The pharmacokinetic parameters of rifabutin in patients with and without wasting syndrome were compared using the Mann–Whitney U-test.
Results
Cmax was 0.34±0.14 mg l−1 in NWS patients and 0.55±0.16 mg l−1 (P = 0.01) in patients with WS. tmax was 4.2±1.5 and 3.3±2.3 h (P = 0.17) in NWS and WS patients, respectively. The AUCs were similar in the two study groups. V/F was 2905±1646 l in NWS patients and 1701±492 l (P = 0.07) for the WS group. These differences are less pronounced following normalization of V/F to patients body weight (43.7±20.1 vs 35.4±10.3 l kg−1). t1/2,λz tended to be shorter in patients with WS (31.4±12.9 vs 46.0±23.5 h, P = 0.12).
Conclusions
Our study suggests that the pharmacokinetics of rifabutin in patients with wasting syndrome are not altered to a degree that is clinically important.
doi:10.1046/j.1365-2125.1999.00069.x
PMCID: PMC2014354  PMID: 10594472
HIV infection; rifabutin; wasting syndrome
3.  Possible enhancement of the first-pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects 
Aims
This serendipitous study revealed an unexpected effect of Jufeng grape juice on the CYP1A2-mediated metabolism of phenacetin. Investigation of the inhibition of CYP1A2 by grapefruit juice was involved but a translation error led to the grape juice substitution.
Methods
Twelve healthy subjects took a single oral dose of phenacetin (900 mg) on two randomized occasions together with 200 ml water or grape juice. Plasma phenacetin and paracetamol concentrations were assessed by h.p.l.c.
Results
Ingestion of grape juice was associated with reduced plasma phenacetin concentrations, while paracetamol levels were unaffected. Paracetamol to phenacetin AUC ratios increased from 13.9±3.1 to 24.3±3.8 after ingestion of grape juice.
Conclusions
These findings suggest enhanced first-pass metabolism of phenacetin, due to CYP1A2 activation by grape juice or to desaturation of CYP1A2 isoenzymes secondary to a slower rate of phenacetin absorption.
doi:10.1046/j.1365-2125.1999.00065.x
PMCID: PMC2014370  PMID: 10583039
cytochrome CYP1A2; drug metabolism; grape juice; paracetamol; phenacetin
4.  Erythromycin resistance in Streptococcus pyogenes in Italy. 
Emerging Infectious Diseases  2000;6(2):180-183.
In a prospective study of acute pharyngitis in Italian children, 69 (38.3%) of 180 isolates of Streptococcus pyogenes were resistant to macrolides. S. pyogenes was eradicated in 12 (63.1%) of 19 patients with erythromycin-resistant S. pyogenes treated with clarithromycin and in 22 (88%) of 25 patients with erythromycin-susceptible strains. The constitutive-resistant phenotype was correlated with failure of macrolide treatment.
PMCID: PMC2640849  PMID: 10756153
6.  Penetration of dapsone into pulmonary lining fluid of human immunodeficiency virus type 1-infected patients. 
We studied the penetration of dapsone into the epithelial lining fluid (ELF) of sixteen human immunodeficiency virus type 1-infected patients who had received the drug at a dose of 100 mg twice weekly as primary prophylaxis for Pneumocystis carinii pneumonia. Bronchoscopy, bronchoalveolar lavage (BAL), and venipuncture were performed for each patient at a specific time after administration of the last dose of dapsone. Dapsone concentrations in plasma and BAL were determined by high-performance liquid chromatography. The apparent volume of ELF recovered by BAL was determined by using urea as an endogenous marker. The mean concentrations of dapsone in ELF at 2 h (five patients), 4 h (three patients), 12 h (two patients), 24 h (three patients), and 48 h (three patients) were 0.95, 0.70, 1.55, 0.23, and 0.45 mg/liter, respectively, while concentrations in plasma were 1.23, 0.79, 1.31, 0.83, and 0.18 mg/liter, respectively. Dapsone concentrations in ELF were 76, 79, 115, 65, and 291% of those observed in plasma at the same times, respectively. These data show that dapsone is well distributed into ELF and that a twice-weekly 100-mg prophylactic regimen results in sustained concentrations in this compartment.
PMCID: PMC163854  PMID: 9145873
7.  Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients  
1To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500 mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine.
2Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3 h, means±s.d., P<0.001) and higher apparent oral clearance (CL/ F) values (15.3±3.8 vs 9.2±1.9 ml kg−1 h−1, P<0.001). The apparent volume of distribution ( V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1 l kg−1, P<0.05).
3These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity.
4The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.
doi:10.1046/j.1365-2125.1996.03601.x
PMCID: PMC2042613  PMID: 8799524
ethosuximide; carbamazepine; phenobarbitone; enzyme induction; drug interaction
8.  Population pharmacokinetics of dapsone administered biweekly to human immunodeficiency virus-infected patients. 
Antimicrobial Agents and Chemotherapy  1996;40(12):2743-2748.
The population pharmacokinetics of dapsone were examined in human immunodeficiency virus-infected patients receiving dapsone at a dosage of 100 mg twice weekly for the prevention of Pneumocystis carinii pneumonia. Nonlinear mixed-effect modeling was used to determine the best pharmacostatistical model for the data. A one-compartment open model with first-order absorption and elimination was used as the structural pharmacokinetic model. Several covariates were tested for their influence on pharmacokinetic parameters. Rifampin was found to increase the values of clearance/bioavailability (CL/F) and volume of distribution/ bioavailability (V/F) by approximately 70%. CL/F and V/F were 1.83 liters/h and 69.6 liters, respectively, for patients not taking rifampin. The effect of rifampin on the pharmacokinetic parameters of dapsone was appreciably less than expected on the basis of studies with healthy volunteers. Increased bilirubin levels were associated with a significant decrease in the absorption rate constant (Ka). However, this finding may be considered clinically irrelevant because the post hoc Bayesian estimates of Ka for patients with high bilirubin levels ( > 1.2 mg/dl) were at the lower bound of the values for patients with normal bilirubin levels. The value of Ka was 0.957 h-1 for a patient with a bilirubin level of 0.7 mg/dl. After inclusion of covariates in the model, the interpatient variability was 35% for CL/F, not significant for V/F, and 85% for Ka. Simulation of plasma concentration-versus-time curves indicated that the administration of 100 mg of dapsone biweekly is associated with sustained dapsone levels in the plasma of the majority of the patients. Dosage adjustments for patients concomitantly treated with rifampin may be necessary.
PMCID: PMC163614  PMID: 9124833
9.  Protein binding of clindamycin in sera of patients with AIDS. 
Patients with AIDS have altered pharmacokinetics of clindamycin compared with those of healthy control subjects. In an attempt to better understand these differences, we undertook a study of protein binding of clindamycin in sera of patients with AIDS. Fifteen patients with AIDS and 15 healthy volunteers were given a single 600-mg dose of clindamycin orally and intravenously, and serum samples were collected at three time points corresponding to high, midpoint, and low clindamycin concentrations. Protein binding was determined by ultrafiltration, and total and unbound clindamycin concentrations were measured with a gas chromatography assay. AIDS patients had alpha 1-acid glycoprotein values approximately twice those of healthy volunteers (mean +/- standard deviation, 103 +/- 27 versus 61 +/- 11 mg/dl; P = 0.001). Overall, serum protein binding levels were higher in AIDS patients (mean +/- standard deviation, 83 +/- 7 versus 78% +/- 8%; P = 0.0001), which is likely the result of increased alpha 1-acid glycoprotein levels in these patients. Total concentrations of clindamycin in plasma were significantly higher in AIDS patients at most time points studied, while unbound serum clindamycin concentrations did not differ among the groups at each sampling time after both oral and intravenous dosing. Increased protein binding may partly explain the altered pharmacokinetic disposition of clindamycin in AIDS patients; however, other factors cannot be excluded.
PMCID: PMC163278  PMID: 8723453
10.  Pharmacokinetics of dapsone in human immunodeficiency virus-infected children. 
Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means +/- standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 +/- 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 +/- 1.3 (2 to 6) h; half-life at elimination phase, 24.2 +/- 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 +/- 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 +/- 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r = 0.614 and P = 0.034), as did V (r = 0.631 and P = 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r = 0.765 and P = 0.004, and for V/F to height, r = 0.748 and P = 0.005). Since oral CL from plasma and V were positively and highly correlated (r = 0.898 and P = 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.
PMCID: PMC162691  PMID: 7625796
11.  Effect of inflammation on intraocular penetration of intravenous ofloxacin in albino rabbits. 
The effect of inflammation on the intraocular penetration of ofloxacin was studied in 20 albino rabbits (New Zealand White). Inflammation was induced in the left eye by inoculation of a suspension of 10(9) CFU of heat-killed Staphyloccus epidermidis per 0.1 ml of saline solution (0.9%) in the midvitreous cavity. The other eye was kept as a control. Twenty-four hours following inoculation, ofloxacin was administered in the marginal ear vein at a dose of 15 mg/kg over 20 min with an infusion pump. Animals were sacrificed at different times up to 24 h following drug administration. Ofloxacin levels were determined in aqueous humor, vitreous humor, and serum by a bioassay. Inflammation was scored on the basis of perilimbal and corneal reactions and vitreoretinal statuses. Inflammation had a relevant effect on intraocular penetration of ofloxacin, with levels in the ocular fluids of the inflamed eye markedly exceeding the ones of the control eye. In the uninflamed eye, the levels were rapidly decaying below assay sensitivity and were no longer detectable at approximately 5 h following drug administration while they were still detectable in both ocular fluids of the inflamed eye at 24 h. Ofloxacin levels in the ocular fluids of the inflamed eye were superior to the MIC for several of the bacteria which commonly cause endophthalmitis, including Staphylococcus epidermidis, Staphylococcus aureus, most members of the family Enterobacteriaceae, Haemophilus influenzae, and strains of Pseudomonas aeruginosa.
PMCID: PMC162578  PMID: 7726531
12.  Vigabatrin-induced decrease in serum phenytoin concentration does not involve a change in phenytoin bioavailability. 
The possibility that vigabatrin (VGB) decreases serum phenytoin (PHT) concentration by lowering the oral bioavailability of PHT was investigated in 21 patients with epilepsy. Each patient was switched from oral to intravenous PHT for 5 days before and after combined treatment with VGB. After VGB (2-3.5 g day(-1) for at least 5 weeks), serum PHT concentrations decreased slightly from 87 +/- 25 to 76 +/- 31 micromol l(-1) (means +/- s.d., P < 0.05), but in a subgroup of seven patients the decrease was more prominent (from 72 +/- 22 to 49 +/- 17 micromol l(-1), P < 0.005). At baseline (before VGB), serum PHT remained unaffected (85 +/- 30 micromol l(-1)) after switching PHT dosage to the intravenous route, indicating that the oral availability of the drug was virtually complete. During VGB treatment, serum PHT was also unchanged (74 +/- 34 micromol l(-1)) after switching from oral to intravenous therapy, and this was also true for the subgroup of patients showing a prominent interaction (48 +/- 18 micromol l(-1)). The urinary recoveries of PHT and its metabolites pHPPH and mHPPH remained constant throughout the study. It is concluded that the oral availability of PHT is unaffected by VGB and that the VBG-induced decrease in serum PHT is mediated by alternative mechanisms.
PMCID: PMC1364668  PMID: 12959280
13.  The pharmacokinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid. 
The kinetics of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-carbazepine (10-OH-CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10-OH-CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10-OH-CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10-OH-CZ were lower than in controls (2.9 +/- 0.4 vs 5.1 +/- 0.7 microg ml(-1) h and 89 +/- 7 vs 119 +/- 10 microg ml(-1) h respectively, means +/- s.e. mean, P < 0.05), whereas 10-OH-CZ half-lives were only marginally shorter (17 +/- 1 h vs 20 +/- 2 h, NS). These data indicate that the biotransformation of OXC and 10-OH-CZ may be accelerated by concomitant treatment with phenobarbitone but that the magnitude of this effect is unlikely to be of great clinical significance.
PMCID: PMC1364692  PMID: 12959317
14.  Safety, activity, and pharmacokinetics of GLQ223 in patients with AIDS and AIDS-related complex. 
GLQ223 is a highly purified single-chain ribosome-inactivating protein with selective effects against a variety of cells, including macrophages infected with human immunodeficiency virus. We evaluated the safety, pharmacokinetics, and immunologic effects of multiple doses of GLQ223 in 22 patients with AIDS or AIDS-related complex; CD4+ T-cell counts were between 100 and 350/mm3. GLQ223 was administered intravenously at doses of 8, 16, 24, 36, and 50 micrograms/kg of body weight; the drug was administered by constant infusion over 3 h to achieve a concentration in serum of 50 ng/ml; this concentration is known to be associated with anti-HIV effects in vitro. All patients reported a flu-like syndrome characterized by muscle and joint aches and an increase in creatinine kinase levels; symptoms were controlled easily. For patients who received 36 and 50 micrograms/kg, target concentrations in serum were achieved and an increase in CD4+ and CD8+ T cells was sustained; this sustained increase persisted for at least 28 days after the last infusion. beta 2-Microglobulin levels increased during the infusions and then declined when the infusions ended. Repeat infusions of GLQ223 were safe and relatively well tolerated. The target concentration of GLQ223 in serum was achieved and sustained. Our results suggest that GLQ223 may have activity in treating patients with human immunodeficiency virus infection.
PMCID: PMC284438  PMID: 7910722
15.  Comparative study of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS. 
The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 +/- 0.06 liter/h/kg in healthy volunteers and 0.21 +/- 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 +/- 0.13 and 0.66 +/- 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 +/- 0.14 versus 0.75 +/- 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 +/- 2.5 versus 5.3 +/- 1.0 mg/liter; P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particularly for orally administered drugs.
PMCID: PMC187917  PMID: 8517703
16.  Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients 
1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively.
2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P < 0.01) in patients taking enzyme-inducing anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate.
3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls.
PMCID: PMC1368527  PMID: 1777370
nimodipine; dihydropyridine; calcium channel blockers; pharmacokinetics; anticonvulsants; epilepsy; drug interaction
17.  Pharmacokinetics of GLQ223 in rats, monkeys, and patients with AIDS or AIDS-related complex. 
Antimicrobial Agents and Chemotherapy  1991;35(12):2531-2537.
The pharmacokinetics of GLQ223 administered as a single short intravenous infusion to rats, monkeys, and patients with AIDS or AIDS-related complex (ARC) are presented. GLQ223 was given at a dose of 3,500 micrograms/kg of body weight to five Sprague-Dawley rats; a dose of 300 micrograms/kg was given to three cynomolgus monkeys; and doses of 1, 8, 16, 24, and 36 micrograms/kg were given to 10 patients with AIDS and 8 patients with ARC in an escalating dose design. Plasma clearance was 0.85 +/- 0.24 liter/h/kg in rats, 0.16 +/- 0.08 liter/h/kg in monkeys, and 0.13 +/- 0.07 liter/h/kg in patients with AIDS or ARC. The volume of distribution at steady state was 0.42 +/- 0.12, 0.21 +/- 0.20, and 0.18 +/- 0.50 liter/kg in rats, monkeys, and patients, respectively. The elimination half-life was 1.3 +/- 0.4, 3.7 +/- 1.5, and 3.2 +/- 1.0 h in rats, monkeys, and patients, respectively. The disposition of GLQ223 was not dose dependent within the dose range tested in patients with AIDS or ARC. Interspecies pharmacokinetic scaling resulted in a good linear correlation for plasma clearance and the volume of distribution at steady state plotted versus species body weight on a log-log scale, indicating the predictability of elimination and distribution of GLQ223 among species. Allometric equations derived may be useful for the prediction of doses and dosage regimens to be used in animal models.
PMCID: PMC245426  PMID: 1810186
18.  The disposition of primidone in elderly patients. 
1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 h and 34.8 +/- 9.0 vs 33.2 +/- 7.2 ml h-1 kg-1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.
PMCID: PMC1368252  PMID: 2291873
19.  Inhibition by erythromycin of the conversion of carbamazepine to its active 10,11-epoxide metabolite. 
The serum levels of carbamazepine (CBZ) and its 10,11-epoxide metabolite (CBZ-E) were determined in seven subjects after a single dose of CBZ (400 mg) in the control state and during co-administration of erythromycin (500 mg three times daily for 10 days). Erythromycin treatment was associated with a decrease in CBZ clearance and a prolongation of CBZ half-life, while CBZ-E levels were markedly reduced. These data provide evidence that erythromycin inhibits the conversion of CBZ to its epoxide metabolite.
PMCID: PMC1386415  PMID: 3440106
20.  Pharmacokinetic and pharmacodynamic studies with a new controlled-release formulation of propranolol in normal volunteers: a comparison with other commercially available formulations. 
The kinetics and dynamics (inhibition of exercise tachycardia) of two controlled-release preparations of propranolol (Elanolol and Inderal LA) were examined in six normal volunteers. Conventional propranolol (Inderal) was also studied for comparison purposes. As compared to conventional propranolol (120 mg), single doses of Elanol (120 mg) and Inderal LA (160 mg) produced a smoother serum level profile, with lower and delayed peak times. Dose-corrected AUC0-24 values were greater after Elanol than after Inderal LA (651 +/- 147 vs 402 +/- 159 ng ml-1 h, means +/- s.e. mean, P greater than 0.05). The profile of inhibition of exercise tachycardia mirrored closely that of the serum levels. At steady state, all regimens studied (Inderal 40 mg three times daily; Elanol 120 mg once daily; Inderal LA 160 mg once daily) ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose-corrected AUC0-24 values were 797 +/- 148 ng ml-1 h after Inderal, 908 +/- 113 ng ml-1 h after Elanol and 602 +/- 122 ng ml-1 after Inderal LA. The bioavailability of Inderal LA was significantly lower than that of the other preparations. These results demonstrate that long-acting formulations of propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first-pass metabolism.
PMCID: PMC1463571  PMID: 6743489
21.  Pharmacokinetics of valproic acid in the elderly. 
The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.
PMCID: PMC1463439  PMID: 6430313
22.  Pharmacokinetics of prednisone and its metabolite prednisolone in children with nephrotic syndrome during the active phase and in remission. 
The kinetics at steady state of prednisone and its metabolite prednisolone were determined in nine nephrotic children during the active phase of the disease and in remission. There were no differences in serum prednisone levels between the two occasions. Prednisone levels were lower than prednisolone levels. Total serum prednisolone levels were significantly lower during the active phase than in remission (AUC: 2452 +/- 207 vs 3392 +/- 293 ng ml-1 h respectively). Half-life values were similar on both occasions. The binding of prednisolone to serum proteins was markedly impaired during the active phase as compared to the remission. Free fraction values correlated positively with total drug concentration. A negative correlation between free fraction and serum albumin level was found during the active phase. Free prednisolone levels during the active phase did not differ significantly from those observed during remission (AUC: 937 +/- 128 vs 847 +/- 81 ng ml-1 h respectively). These data indicate that pharmacokinetic changes are unlikely to be responsible for alterations in steroid responsiveness in nephrotic patients with hypoalbuminaemia.
PMCID: PMC1463411  PMID: 6721988
23.  Modification of phenytoin clearance by valproic acid in normal subjects. 
1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.
PMCID: PMC1429910  PMID: 391257
24.  Disposition of sodium valproate in epileptic patients. 
1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half-lives averaged 9.0 +/- 1.4 h (s.d.). Volumes of distribution were 0.175 +/- 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half-lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5--2 h. Biological availability was 96 +/- 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.
PMCID: PMC1429371  PMID: 350251
25.  Pharmacokinetics of valproic acid after oral and intravenous administration 
1 The kinetics of sodium valproate (di-n-propyl-acetate, Depakine®) have been studied in six healthy volunteers after administration of single oral and intravenous doses (800 mg).
2 Kinetic parameters were similar for both routes of administration. In all subjects absorption was rapid and complete. Half-lives ranged from 11-15 h. Apparent volumes of distribution were relatively low (0.147 ± 0.004 l/kg) and showed little variation amongst individuals.
3 The factors responsible for the poor correlation between dosage and serum levels during chronic treatment and therapeutic implications are discussed.
PMCID: PMC1429296

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