Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations

Our objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.     

Effects of gender,AIDS, and acetylator status on intrapulmonary concentrations of isoniazid

The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.     

Effect of clarithromycin on steady-state digoxin concentrations

OBJECTIVE: To evaluate the magnitude and dose-relatedness of the effect of clarithromycin on the pharmacokinetics of digoxin, and to compare the effects of clarithromycin with those of P-glycoprotein inhibitors. METHODS: Eight Japanese inpatients with congestive heart failure participated in this study. Each patient received oral digoxin therapy for at least 7 days and were coadministered oral clarithromycin to prevent or treat pneumonia. To evaluate the effects of clarithromycin on the pharmacokinetics of digoxin, digoxin concentrations were compared before and after coadministration of clarithromycin. RESULTS: Digoxin concentrations were higher after coadministration of clarithromycin in all patients (before, 0.838 +/- 0.329 ng/mL; after, 1.36 +/- 0.619 ng/mL); (p < 0.005). A significant correlation was observed between the dose of clarithromycin and the percentage of increase in the digoxin concentration. CONCLUSIONS: Digoxin concentrations increased during concomitant administration of clarithromycin, and this effect was dose-dependent on clarithromycin. The percentage increase in digoxin concentrations after the usual oral dose of clarithromycin (400 mg/d) is approximately 70%. Therefore, digoxin concentrations must be monitored carefully after coadministration of clarithromycin, and the doses of digoxin may need readjustment in patients who are concomitantly receiving clarithromycin.     

Relationship between steady-state plasma nizatidine concentrations and inhibition of basal and stimulated gastric acid secretion

Steady-state plasma nizatidine concentrations were related in a linear fashion to nizatidine infusion rate. Infusion rates of 2.5, 10, and 20 mg/hr resulted in mean plasma nizatidine concentrations of 69, 247, and 575 ng/ml. Basal acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 60 and 430 ng/ml. Protein-stimulated acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 75 and 490 ng/ml. The mean pH of basal gastric secretions was 1.6 during placebo infusion and 4.6 when the mean plasma nizatidine concentration was 575 ng/ml.     

Steady-state plasma and intrapulmonary pharmacokinetics and pharmacodynamics of cethromycin

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C(max)/90% minimum inhibitory concentration (MIC(90)) ratios, area under the concentration-time curve (AUC)/MIC(90) ratios, intrapulmonary drug exposure ratios, and percent time above MIC(90) during the dosing interval (%T > MIC(90)) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C(max) (mean +/- standard deviations), AUC(0-24), and half-life for plasma were 0.181 +/- 0.084 microg/ml, 0.902 +/- 0.469 microg. h/ml, and 4.85 +/- 1.10 h, respectively; for ELF the values were 0.9 +/- 0.2 microg/ml, 11.4 microg. h/ml, and 6.43 h, respectively; for AC the values were 12.7 +/- 6.4 microg/ml, 160.8 microg. h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C(max) (mean +/- standard deviations), AUC(0-24), and half-life for plasma were 0.500 +/- 0.168 microg/ml, 3.067 +/- 1.205 microg. h/ml, and 4.94 +/- 0.66 h, respectively; for ELF the values were 2.7 +/- 2.0 microg/ml, 24.15 microg. h/ml, and 5.26 h, respectively; for AC the values were 55.4 +/- 38.7 microg/ml, 636.2 microg. h/ml, and 11.6 h, respectively. We concluded that the C(max)/MIC(90) ratios, AUC/MIC(90) ratios, %T > MIC(90) values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.     

Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia

BACKGROUND: The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol. METHODS: The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty-four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC. RESULTS: The mean +/- SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8+/-11.0, 30.1+/-10.6, and 31.2+/-21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1+/-2.9, 9.5+/-3.7, and 9.9+/-6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P < .05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P < .05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles. CONCLUSION: This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects.     

Steady-state plasma and intrapulmonary concentrations of cefepime administered in continuous infusion in critically ill patients with severe nosocomial pneumonia

OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid concentrations of cefepime administered in continuous infusion in critically ill patients with severe bacterial pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Twenty adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled. INTERVENTIONS: All subjects received a 30-min intravenous infusion of cefepime 2 g followed by a continuous infusion of 4 g over 24 hrs. The concentrations of cefepime in plasma and epithelial lining fluid were determined at steady state after 48 hrs of therapy with high performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean +/- sd steady-state plasma and epithelial lining fluid concentrations of cefepime 4 g in continuous infusion were 13.5 +/- 3.3 microg/mL and 14.1 +/- 2.8 microg/mL, respectively, with a mean percentage penetration of cefepime into epithelial lining fluid of about 100%. CONCLUSIONS: The administration of 4 g of cefepime in continuous infusion in critically ill patients with severe nosocomial pneumonia appears to optimize the pharmacodynamic profile of this beta-lactam by constantly providing concentrations in excess of minimal inhibitory concentration of most of susceptible organisms over the course of therapy in both serum and epithelial lining fluid.     

Effects of heat treatment on selected plasma therapeutic drug concentrations.

OBJECTIVE: We investigated the heat stability of six common therapeutic drugs routinely assayed in pharmacokinetic and clinical laboratories. DESIGN: Serum samples were spiked at three concentrations (subtherapeutic, therapeutic, and potentially toxic) with amikacin, gentamicin, tobramycin, phenytoin, theophylline, and phenobarbital. The samples were then heated at 56 degrees C and assayed by fluorescence polarization immunoassay at 15-minute intervals for one hour. SETTING: The study was conducted at a clinical research laboratory using standard laboratory methods. MAIN OUTCOME MEASURES: Drug concentrations of heated samples were compared with unheated controls using ANOVA to determine if degradation occurred over time with heating. RESULTS: Analysis of data revealed no degradation of any of the samples. CONCLUSIONS: Heat treatment of samples from high-risk individuals may be a mechanism to protect healthcare workers from exposure to the human immunodeficiency virus.     

The confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide concentrations in critically ill patients

OBJECTIVE: To investigate the confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide (BNP) concentrations in critically ill patients. DESIGN: A prospective cross-sectional study. SETTING: A 20-bed general intensive care unit of a tertiary referral hospital. PATIENTS: Patients were 121 patients admitted to the intensive care unit over a period of 9 wks. INTERVENTIONS: Intravenous blood was collected for BNP measurements, and cardiac investigations including echocardiography were carried out for every patient on admission. MEASUREMENTS AND MAIN RESULTS: The mean BNP concentration was 201 +/- 317 pg/mL (n = 121). Thirty-five patients (28.9%), identified to have cardiac abnormalities, exhibited higher BNP concentrations than those without cardiac abnormalities (518 +/- 394 vs. 60 +/- 98 pg/mL, p <.001). The females exhibited higher concentrations of BNP than males in the noncardiac abnormality group (96 +/- 132 pg/mL, n = 39 vs. 31 +/- 38 pg/mL, n = 47, p =.016). BNP correlated significantly with age (r2 =.19) and creatinine (r2 =.084). The latter correlation became insignificant when patients with cardiac abnormality were excluded. No correlation was found between serum Na+ and K+ concentrations with BNP. Multivariate analyses demonstrated that the presence of cardiac abnormalities accounted for nearly 50% of the BNP variation. Addition of age and gender improved R2 to 60%. The contribution of creatinine was found to be insignificant. There was no association between BNP concentrations and serum Na+ and K+ concentrations. Logistic analysis confirmed that BNP is the strongest predictor for cardiac abnormalities in the critically ill patients. CONCLUSION: The current study demonstrated that plasma BNP concentrations increased with age and were higher in females than in males. Although the presence of cardiac disease was the most important determinant for BNP variations, age and gender also contributed significantly. The results suggest that age and gender need to be taken into account in the interpretation of BNP concentrations in critically ill patients.     

A comparison of absorption rate models in the prediction of steady-state plasma concentrations during oral theophylline administration

During therapy with oral controlled released theophylline/aminophylline, steady-state plasma drug concentrations may be predicted by fitting estimates of patient pharmacokinetic parameters to a pharmacokinetic model. The choice of model requires an assumption about the type of rate reaction of the drug absorption process (zero order or first order). In 10 subjects, plasma theophylline concentrations after a single intravenous dose of aminophylline were used to make individual estimates of drug clearance and volume of distribution. Each subject then received oral controlled release theophylline ('Theo-Dur', Fisons Pharmaceuticals plc) and steady-state pre-dose and post-dose plasma concentrations were determined. Predictions of steady-state plasma theophylline concentrations using pharmacokinetic models based on first-order (Model A) and zero order (Model 01) drug absorption were compared. Model A and Model 01 each underestimated the pre- and post-dose steady-state plasma drug concentrations. However, Model 01 was more accurate in predicting post-dose drug concentrations, whilst Model A demonstrated better precision in the prediction of pre-dose drug concentrations at steady-state (P less than 0.05).     

Impact of ciprofloxacin on theophylline clearance and steady-state concentrations in serum.

The effect of a multiple-dose regimen of oral ciprofloxacin (750 mg every 12 h for 11 doses) on the clearance and steady-state concentrations of theophylline in trough (predose) serum was evaluated in nine healthy male subjects, each serving as his own control. Theophylline was taken as a sustained release tablet per os in a dose of 200 mg every 12 h for 19 doses. Theophylline concentrations in serum were measured immediately before each theophylline dose. Ciprofloxacin was administered on study day 4 through the first dose of study day 8. Theophylline concentrations in serum were also measured on study days 3, 6, 8, and 10 at the following times after the first dose of each day: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 10, and 12 h. Steady-state theophylline concentrations in trough serum were significantly higher during ciprofloxacin treatment (day 8) than before (day 3) or after (day 10) ciprofloxacin administration (P less than 0.01). Likewise, theophylline clearance was significantly slower (P less than 0.01) during ciprofloxacin treatment (day 8) than before it (day 3) or after it (day 10). The magnitude of ciprofloxacin-induced changes was approximately 30%. These results suggest that a multidose regimen of ciprofloxacin significantly slows the clearance of theophylline and elevates theophylline concentrations in serum.     

Effects of sample preparation on concentrations of cyclosporin A measured in plasma

Because cyclosporin A rapidly changes its distribution in blood with changes in temperature, sample preparation affects results for it as measured in plasma. If whole blood is stored at either 4 degrees C or room temperature, results for cyclosporin A in the plasma are lower than in whole blood stored at 37 degrees C and centrifuged at this temperature. Re-equilibration of the former to 37 degrees C before cells are removed increases the analytical recovery of cyclosporin A in plasma; the optimal equilibration interval is 30 min. Use of such re-equilibration, followed by immediate centrifugation at room temperature, increases values obtained for cyclosporin in plasma by 60 to 65% over those determined after non-temperature-standardized collection procedures, but does not significantly improve the correlation between values for plasma and whole blood. Hematocrit and concentrations of cyclosporin A in plasma are inversely related. Correction for hematocrit improves the correlation between results for plasma and whole blood.     

Relation between age and gender differences in plasma triglyceride concentrations and coronary artery disease in Southern Turkey

BACKGROUND: Coronary artery disease (CAD) is still a leading cause of morbidity and mortality in both genders in Turkey as well as other countries. The role of plasma triglycerides (TG) as a CAD risk factor has been controversial. We investigated the relation between age and gender differences in plasma TG and CAD in patients with angiographically proven CAD. METHODS: The study population consisted of 937 patients (605 males and 332 females, aged between 32 and 82 years). The patients were divided into three age groups as < 45, 45-59 and > or = 60 years. Risk factors were considered as hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking and family history. Hypertriglyceridemia was defined as TG concentration > 150 mg/dl (> 1.69 mmol/l). RESULTS: Of the total, 608 had CAD. TG was an independent risk factor for CAD only in women (p < 0.05). There was also a positive correlation between TG concentrations and number of the diseased vessels only in women (p = 0.001, r = 0.2). CONCLUSION: High TG concentrations increase CAD risk more in women than in men in Southern Turkey. Triglycerides should be taken into consideration as an important risk factor especially in women > 45 years of age.     

Effects of subcutaneous sumatriptan on plasma growth hormone concentrations in migraine patients

The purpose of this study was to assess the sensitivity of 5-HT1D receptors in migraine using sumatriptan as a pharmacological probe. The drug stimulates the release of growth hormone (GH) and this effect may be used to explore the function of cerebral serotonergic systems in vivo. We administered sumatriptan and placebo to 15 migraineurs and to 10 controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injection. Placebo had no effect on hormone concentrations. Sumatriptan induced a significant (P<0.01) increase in GH concentrations both in migraine patients and healthy controls. The GH increase was not significantly different in the two groups. Our results suggest that cerebral serotonergic functions mediated by 5-HT1D receptors are not altered in migraine. Sumatriptan overuse could lead to adverse effects mediated by its neuroendocrine activity.     

Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia

OBJECTIVE: To determine the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Sixteen critically ill adult patients with ventilator-associated pneumonia. INTERVENTIONS: All subjects received 1-hr intravenous infusions of linezolid 600 mg twice daily. After 2 days of therapy, the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean +/- sd linezolid peak and trough concentrations were 17.7 +/- 4.0 mg/L and 2.4 +/- 1.2 mg/L in plasma and 14.4 +/- 5.6 mg/L and 2.6 +/- 1.7 mg/L in epithelial lining fluid, respectively, showing a mean linezolid percentage penetration in epithelial lining fluid of approximately 100%. The mean +/- sd area under concentration-time curve during the observational period (AUC0-12) was 77.3 +/- 23.7 mg x hr/L, corresponding to a mean AUC0-24 of 154.6 mg x hr/L. CONCLUSIONS: Our study shows satisfactory results, with linezolid concentrations exceeding the susceptibility breakpoint for Gram-positive bacteria in both plasma and epithelial lining fluid. This suggests that a dosage of 600 mg administered intravenously twice daily to critically ill patients with Gram-positive ventilator-associated pneumonia would achieve success against organisms with minimum inhibitory concentrations as high as 2-4 mg/L in both plasma and epithelial lining fluid.     

Arterial and venous plasma catecholamines during submaximal steady-state exercise

Arterial and venous plasma catecholamine responses to 15 min of cycling at 60% of maximal oxygen uptake were examined 11 times during exercise and recovery in nine young men. Intra-arterial blood pressure, heart rate and oxygen uptake were recorded continuously. All variables increased significantly during the initial 4 min, after which oxygen uptake, diastolic blood pressure and arterial plasma adrenaline showed no further increase. Heart rate and plasma noradrenaline, however, continued to increase, although significantly more slowly, and were closely correlated (r = 0·81, 95% CI 0·71–0·87), as were systolic blood pressure and heart rate (r = 0·78, 95% CI 0·71–0·87). Venous plasma adrenaline showed a steady increase during the whole exercise period and thus a different response pattern from arterial plasma adrenaline. In conclusion, arterial plasma catecholamines respond to steady-state exercise by a two-phase pattern paralleling the changes in arterial blood pressure and heart rate. Venous sampling does not reveal this association.     

Effects of cardiothoracic physiotherapy on intrapulmonary shunt in abdominal surgical patients

This study investigated the provision of additional evening physiotherapy on pulmonary complications and intrapulmonary shunt (Qs/Qt) after abdominal surgery. Thirty-one elderly patients received either daylight only or daylight plus evening physiotherapy for up to 48 hours. Physiotherapy included combinations of positioning, gravity assisted drainage, breathing exercises, manual techniques, coughing and airway suctioning. Measurements included Qs/Qt and post-operative pulmonary complications. While no significant difference in atelectasis was found, the post-operative Qs/Qt data averaged into six-hour time frames demonstrated significantly lower mean Qs/Qt for the daylight plus evening physiotherapy group between 18 and 24 hours post-surgery. Additional evening physiotherapy may reduce post-operative deterioration in gas exchange after major abdominal surgery.