Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

Cyclosporine-drug interactions and the influence of patient age.

Cyclosporine-drug interactions in adult transplant patients and the impact of age were studied. The medical records of transplant patients receiving cyclosporine therapy were identified. Data on patient demographics, cyclosporine dosages, dosage form, blood trough concentrations, clinical laboratory test values, and concurrent medications were collected. One-compartment models for oral and i.v. administration were used to fit cyclosporine concentration data to population pharmacokinetic and statistical models. Nonlinear mixed-effect modeling (NONMEM) software was used. The influence of covariates, including but not limited to concomitant medications and age, on cyclosporine pharmacokinetics was evaluated. The records of 100 patients (36 women and 64 men) were reviewed. A mean +/- S.D. of 9 +/- 2 and 9 +/- 1 medications per day were consumed by patients < 60 and > or = 60 years old, respectively. Mean population pharmacokinetic values of 0.407 L/hr/kg for clearance, 4.0 L/kg for volume of distribution, 31% for bioavailability, and 10.6 hours for half-life were determined on the basis of 569 blood cyclosporine levels. Twelve medications (sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone) with previously unconfirmed pharmacokinetic interactions with cyclosporine were identified as interacting. There was no correlation between age and interactions. Patients taking cyclosporine were at risk for pharmacokinetic drug interactions when cyclosporine was used in combination with sertraline, losartan, valsartan, quinine, atorvastatin, simvastatin, pravastatin, fluvastatin, alendronate, digoxin, acyclovir, and oxycodone. Transplant patients 60-75 years of age had cyclosporine-drug interactions similar to those in younger patients.

Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition.

Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function.

AIMS: To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone. METHODS: Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled into an open-label, multicentre, multiple-dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine. RESULTS: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml(-1) h vs. 467 ng ml(-1) h, P = 0. 042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone lambda(z) in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P<0.001). There was no correlation between antipyrine lambda(z) and ziprasidone lambda(z) in the subjects with normal hepatic function or in those with hepatic impairment. CONCLUSIONS: The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis.

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.

Vancomycin dosing in morbidly obese patients.

OBJECTIVES AND METHODS: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population. RESULTS: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg x kg(-1) x d(-1) TBW or 81.9 mg x kg(-1) x d(-1) IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg x kg(-1) x d(-1) to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2 = 3.3 h, V = 52 L, CL = 197 ml x min(-1); normal: t1/2=7.2 h, V=46 L, CL=77 ml x min(-1), 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. CONCLUSION: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg x kg(-1) x d(-1)). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 microg x ml(-1) in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study.

Mixed-effect modeling for detection and evaluation of drug interactions: digoxin-quinidine and digoxin-verapamil combinations.

Mixed-effect modeling has been suggested as a possible tool to detect and describe drug interactions in patient populations receiving drug combinations for the treatment of disease states. The mixed-effect modeling program, NONMEM, was used to measure the effects of the well-known digoxin-quinidine and digoxin-verapamil drug interactions in 294 patients receiving oral digoxin as hospital inpatients. Fourteen percent of the population took either quinidine or verapamil concurrently with digoxin (mean quinidine dose = 857 +/- 397 mg/day, verapamil = 261 +/- 110 mg/day). Two regression models for digoxin oral clearance were used. Model 1 used the knowledge that digoxin is eliminated by both renal and nonrenal routes (TVCL = ClNR+m.CrCl, where TVCL is the population digoxin oral clearance, ClNR is the nonrenal clearance, and m is the slope of the line that relates creatinine clearance (CrCl) to digoxin clearance); model 2 used a more conventional regression approach with a simple series of multipliers. For both models, quinidine administration decreased population digoxin oral clearance by approximately 45% and verapamil therapy decreased population digoxin oral clearance by approximately 30%. These values are similar to those found by traditional drug interaction studies conducted in small patient or normal subject populations. Mixed-effect modeling can detect clinically relevant drug interactions and produce information similar to that found in traditional pharmacokinetic crossover study designs.

Acute effects of sublingual nitroglycerin on hepatic blood flow in healthy volunteers.

Duplex sonography was used to assess the effects on hepatic blood flow after administering 0.6 mg nitroglycerin (NTG) sublingually to ten healthy volunteers. The study was a randomized, placebo-controlled, cross-over study in which subjects were studied on three separate occasions. Each visit involved administering either placebo or NTG followed by estimation of blood flow through a particular branch of the hepatic artery, portal vein, and hepatic vein every minute for 15 minutes after NTG and placebo administration. Two hours later, subjects were crossed over to the other treatment and the same vessel branch was again examined for 15 minutes. Total blood flow increased 7% in the portal vein and 27% in the hepatic vein during NTG treatment, but did not change significantly in the hepatic artery. Vascular resistance was increased in the hepatic artery and decreased in the portal and hepatic veins after NTG. Qualitatively, flow changed dramatically in the hepatic vein after NTG with the disappearance of normal retrograde flow. The results indicate that nitroglycerin effects hepatic blood flow through the portal and hepatic veins with a decrease in vascular resistance in the portal and hepatic veins and an increase in resistance in the hepatic artery.

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (-76%, P < 0.05). This was due primarily to a lower portal vein blood flow (-36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean +/- s.d.-healthy controls: t1/2 = 13.7 +/- 3.0 h, CL = 30.0 +/- 8.6 ml h-1 kg-1, AUC = 549 +/- 139 mg l-1 h; cirrhotic patients: t1/2 = 32.4 +/- 1.7 h, CL = 12.3 +/- 2.1 ml h-1 kg-1, AUC = 1061 +/- 218 mg l-1 h; P < 0.008). Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: t1/2 = 14.3 +/- 3.7 h, CL = 29.3 +/- 8.5 ml h-1 kg-1, AUC = 498 +/- 142 mg l-1 h). The volume of distribution of antipyrine was similar in all three groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Accuracy of duplex scanning for measurement of arterial volume flow.

This study examined the accuracy of duplex ultrasound measurements of volume flow in a baboon model. Volume flow (Vf) through the external iliac artery was calculated from measurements of blood velocity averaged over several cardiac cycles (time-averaged velocity [TAV]) and vessel cross-sectional area (A) measured from the B-mode image: Vf = TAV x A. Fourteen anesthetized baboons were studied with a duplex scanner with a 7 MHz imaging transducer and 5 MHz pulsed Doppler. B-mode ultrasound measurements of external iliac artery diameters (2.5 +/- 0.2 mm) were used for calculation of cross-sectional area. Timed blood collections obtained through a cannula inserted into the common femoral artery and TAV measurements were obtained simultaneously during 6 to 15-second intervals. These measurements were repeated three to five times per animal with different flow rates each time. Flow rates ranged from 56 to 280 ml/min (170 +/- 54 ml/min). Average velocity was 55 +/- 17 cm/sec. There was no significant difference between the two methods of volume flow measurement (Student t test). Linear regression analysis revealed a high degree of correlation (r = 0.90, slope 0.95, and p = 0.0001). The absolute percentage error was 13% +/- 8%. Volume flow measured by duplex scanning correlates highly with timed blood collections. This method has potential application for the evaluation of diseased arteries and bypass grafts whose rates of flow and waveform patterns are similar to those of this experiment.

Verapamil inhibits ethanol elimination and prolongs the perception of intoxication.

Ten young healthy men received verapamil (80 mg every 8 hours for 6 days) or placebo in a blinded, randomized, crossover design. On the sixth day, ethanol was administered as a single oral dose (0.8 gm/kg), and blood samples were collected over the following 12 hours for determination of verapamil, norverapamil, and ethanol concentrations. Compared with placebo, verapamil increased the peak blood ethanol concentration (106.45 +/- 21.40 to 124.24 +/- 24.74 mg/dl, p less than 0.05) and area under the ethanol concentration versus time curve (365.67 +/- 93.52 to 475.07 +/- 97.24 mg.hr/dl, p less than 0.005). Verapamil areas under the concentration versus time curves (AUC) were positively correlated (r = 0.71, p less than 0.05) to increased ethanol blood AUC values. Each subject's perception of ethanol intoxication was measured by use of a simple visual analog scale. Compared with placebo, verapamil significantly increased area under the effect versus time curve (10.19 +/- 7.6 to 13.83 +/- 7.81 cm.hr, p less than 0.002) but did not change the peak effect or time to peak effect. Ethanol effect versus concentration plots were not significantly different between verapamil and placebo treatment phases when increased ethanol concentrations during verapamil therapy were taken into account. The findings of our study suggest that verapamil significantly inhibits ethanol elimination, resulting in elevated blood ethanol concentrations that prolong the intoxicating effects of alcohol.

Primary pancreatic tuberculosis.

A 71-year-old man developed weight loss, nausea, and night sweats. A PPD skin test was positive; chest films were normal. Abdominal computerized tomography revealed a mass in the head of the pancreas. Laparotomy revealed a 3 cm by 5 cm multi-loculated abscess cavity. Cultures grew Mycobacterium tuberculum. The diagnostic criteria for abdominal tuberculosis include skin test positivity, localized disease, and culture verification. This is the first reported case that fulfills diagnostic criteria for primary pancreatic tuberculosis.

The effects of oral nifedipine on hepatic blood flow in humans.

Duplex ultrasonography was used to measure changes in hepatic blood flow in 13 healthy volunteers after they received single doses of 10 mg oral nifedipine and placebo. Blood flow was measured in the hepatic artery and branches of the portal and hepatic veins at baseline and 0.3, 0.6, 1, 1.5, 2, 3, 4, and 5 hours after drug administration. Cardiac output was also measured at baseline and 1, 2, and 3 hours after dosing. Blood flow initially increased in all three vessels 0.6 hour after administration of nifedipine (29%, 56%, and 31% in the hepatic artery, hepatic vein, and portal vein, respectively) compared with placebo. Flow rapidly returned to baseline in the hepatic artery and hepatic vein, whereas it appeared to remain elevated through 3 hours in the portal vein. Nifedipine administration resulted in an increase in cardiac output of 26%, 22%, and 14% above placebo at 1, 2, and 3 hours, respectively. No significant differences were detected in the systolic, diastolic, or mean arterial blood pressures after nifedipine or placebo. This study demonstrates that nifedipine increases hepatic blood flow in a transient nature and systemic hemodynamic parameters do not necessarily reflect specific organ responses. The nifedipine-induced change in blood flow should be considered when nifedipine is coadministered with high-clearance drugs, because systemic availability may be increased.

Disposition of drugs in cystic fibrosis. II. Hepatic blood flow.

To determine whether the increased clearance of high extraction-ratio drugs in cystic fibrosis is caused by an increase in hepatic blood flow, the blood flow in main branches of the hepatic vein and portal vein was measured by use of noninvasive duplex ultrasound scanning in 10 adult subjects with cystic fibrosis and in 10 healthy age-, gender-, and height-matched control subjects. No statistically significant differences between subjects with cystic fibrosis and control subjects were detected in either the hepatic vein (217 +/- 103 ml/min for subjects with cystic fibrosis versus 211 +/- 135 ml/min for control subjects) or the portal vein (205 +/- 114 ml/min for subjects with cystic fibrosis versus 190 +/- 101 ml/min for control subjects) blood flows. These data indicate that a large (greater than or equal to 100%) increase in the clearance of high extraction-ratio drugs in patients with cystic fibrosis is unlikely to be primarily caused by an increase in hepatic blood flow. It is probable that alternative mechanisms such as enhanced secretory or metabolic pathways account in large part for increases in clearance of high extraction-ratio drugs.

Estimation of hepatic blood flow in branches of hepatic vessels utilizing a noninvasive, duplex Doppler method.

The measurement of hepatic blood flow by indirect methods such as indocyanine green clearance has several limitations. The duplex Doppler offers the potential for noninvasive, real-time measurement of blood flow and has been employed in the evaluation of arterial disease in a variety of vascular beds. We evaluated Doppler ultrasound estimation of blood flow in branches of the hepatic artery, hepatic vein, and portal vein in 12 healthy subjects on two separate days. In vitro accuracy of the scanner was assessed using phantom targets of known diameter and velocity. Blood velocity and vessel diameter measurements were obtained five times over a period of 2 hours. No significant differences were seen in velocity or blood flow measurements within or between days. The interday coefficients of variation, which include intrasubject variability, were 10-15% and 14-20% for velocity and blood flow measurements, respectively. This study demonstrates the potential utility of Doppler ultrasound to detect intrinsic, drug, or disease-induced changes in hepatic blood flow.

Single and multiple doses of oral cimetidine do not change liver blood flow in humans.

Liver blood flow was measured in 10 healthy men for 6 hours after single (300 mg) and multiple (300 mg every 6 hours for 5 days) oral doses of cimetidine. Blood flow measurements were determined in the superior mesenteric and hepatic arteries and in the intrahepatic branches of the portal and hepatic veins by use of a duplex Doppler ultrasound technique. Compared with baseline measurements obtained before drug administration, cimetidine treatment did not change blood flow in any of the four blood vessels. Cimetidine serum concentrations and pharmacokinetic parameters were similar to those reported in other studies conducted in healthy adults. The findings of this study indicate that single and multiple 300 mg doses of oral cimetidine do not change liver blood flow.

Procainamide-cimetidine drug interaction in elderly male patients.

Thirty-six hospitalized male patients receiving oral sustained-release procainamide every six hours for the treatment of ventricular arrhythmias were studied at steady-state before and after oral cimetidine 300 mg every six hours for three days. Average age and weight were 73 +/- 12 (SD) years and 76 +/- 10 kg. Patients did not have a myocardial infarction within the last two years or congestive heart failure and had calculated creatinine clearances (CrCl) between 35 and 75 mL/min/70 kg. Ten patients had urine collections that permitted computation of the ratio between the renal clearance of procainamide and CrCl (PA/CrCl) and the renal clearance of n-acetyl-procainamide (NAPA) and CrCl (NAPA/CrCl). The average steady-state procainamide and NAPA concentrations increased 55% and 36%, respectively, during cimetidine treatment (P less than .01). Twelve patients experienced mild to severe symptoms of what may have been procainamide toxicity. Apparent procainamide oral clearance decreased 41% while patients received cimetidine (P less than .01). PA/CrCl and NAPA/CrCl ratios decreased by 33% and 21%, respectively, during cimetidine therapy (P less than .05). Cimetidine therapy given to older male patients taking procainamide can cause steady-state concentrations of procainamide to rise to toxic levels. Patients prescribed this combination should be monitored carefully for adverse side effects.

Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing.

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0-2.5 hours), Cmax (385-465 micrograms/l), and t1/2 (4.0-4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, Cl, Vss and V area were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55-0.64%), but Cl int did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.

Influence of age, renal function and heart failure on procainamide clearance and n-acetylprocainamide serum concentrations.

Twenty Caucasian adult patients with ventricular tachycardia were treated with intravenous procainamide. Seven patients also had moderate congestive heart failure. Steady-state procainamide (PA) and n-acetylprocainamide (NAPA) concentrations were used to compute procainamide clearance and NAPA/PA concentration ratio. Using stepwise multiple linear regression age, creatinine clearance and congestive heart failure were found to influence procainamide clearance significantly (p less than 0.05). Age and creatinine clearance effected the NAPA/PA concentration ratio (p less than 0.05). Based on this data, age appears to have an independent effect on both procainamide clearance and the NAPA/PA ratio that is separate from the decline in renal function that occurs in elderly patients.

Influence of nifedipine therapy on indocyanine green and oral propranolol pharmacokinetics.

Nine healthy adults were administered indocyanine green (ICG) 0.5 mg.kg-1 IV alone and after the administration of the following oral drugs: nifedipine 10 mg, propranolol 80 mg, propranolol 80 mg and nifedipine 10 mg, and propranolol 80 mg after nifedipine 10 mg every 8 h for 5 days. Heart rate and mean arterial blood pressure (MAP) were also determined. Nifedipine increased ICG clearance by 14% and decreased t1/2 by 26%. Propranolol decreased ICG clearance by 21% and increased t1/2 42%. Nifedipine and propranolol given together increased ICG clearance 63% and decreased t1/2 by 19%. All changes were statistically significant. Propranolol given after multiple doses of nifedipine did not change ICG kinetic parameters. Propranolol Cmax, tmax, oral clearance, and t1/2 did not change after nifedipine therapy. However, partial propranolol AUC values between 0-0.33, 0-0.5, 0-1.0 and 0-1.5 h were significantly larger after single and multiple doses of nifedipine indicating higher propranolol concentrations during the absorption phase. Heart rate and MAP did not change after nifedipine treatment. Similar declines in heart rate and MAP occurred after propranolol alone and propranolol after single and multiple doses of nifedipine.