bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Enalapril on Urinary Protein Excretion in Patients with Idiopathic Membranous Nephropathy
Authors: Sauter Edward R. , Bakris George L.
Published: March 2013

High doses of the angiotensin converting enzyme inhibitor, captopril, is known to cause significant increases in urinary protein excretion in patients with idiopathic membranous nephropathy. To find whether other angiotensin converting enzyme inhibitors yield similar results, we prospectively examined the effect of enalapril in five consecutive patients with idiopathic membranous nephropathy, elevated arterial pressure, and proteinuria and compared them to age‐matched controls receiving clonidine. Glomerular filtration rate, 24‐hour urinary protein excretion, and arterial pressure were measured. All patients served as their own controls. Those who received enalapril demonstrated an initial increase in proteinuria (−0.3 ± 0.7 Δ gm/day, clonidine vs 3.9 ± 0.9 Δ gm/day, enalapril: P < .05) despite similar decreases in arterial pressure (−18 ± 6 Δ mm Hg, clonidine vs −22 ± 6 Δ mm Hg, enalapril: NS) and glomerular filtration rate (−1.1 ± 0.8 Δ mL/min, clonidine vs −1.9 ± 1.2 Δ mL/min, enalapril: NS) when compared to the clonidine group. This increase in proteinuria, however, did not occur when these patients were rechallenged with enalapril. To our knowledge, this is the first report to document a significant increase in preexisting nephrotic range proteinuria following administration of nonsulfhydryl ACE inhibitor. This increase, however, appears to be unique to the initial treatment phase of the disease and does not affect long‐term management.
Longitudinal Study of Cyclosporine and Lipids in Patients Undergoing Bone Marrow Transplantation
Authors: Luke David R. , Beck Jeanne E. , Vadiei Kiumars , Yousefpour Mehdi , LeMaistre Charles F. , Yau Jonathan C.
Published: March 2013

The metabolic effects of intravenous cyclosporine on lipids and lipoproteins were studied in 29 allogeneic bone marrow recipients compared with 13 autologous bone marrow patients not requiring cyclosporine therapy. Patients were monitored continuously from 5 days prior to 27 days following transplantation; cyclosporine treatment was initiated 4 days before transplantation. Fasting lipid and lipoprotein levels were measured in serial blood samples throughout the study period. Nutritional supplementation, conditioning regimens and concomitant medications were not significantly different between groups. Furthermore, no significant differences in age, weight, lipid, or lipoprotein levels were found at baseline between the patient groups. Cholesterol, triglyceride, low‐density lipoprotein cholesterol, and very low‐density lipoprotein cholesterol levels remained unchanged in autologous patients. As compared with baseline values, plasma total cholesterol increased by an average of 26 percent in allogeneic transplantation patients receiving cyclosporine. Similarly, the ratio of low‐density lipoprotein to high‐density lipoprotein cholesterol was fourfold greater in those patients treated with cyclosporine compared to the autologous group. We conclude that cyclosporine appears to elevate cholesterol levels. Neither acute graft vs host disease nor changes in hepatic function could explain the differences in plasma cholesterol levels between groups.
The Effect of Dilevalol on Cardiac Autonomic Neural Discharge, Plasma Catecholamines, and Myocardial Beta Receptor Density Associated with Coronary Occlusion
Authors: Lathers Claire M. , Spivey William H. , Levin Robert M. , Turner Nihal
Published: March 2013

Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10‐minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 ± 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.3 ± 0.8 (N = 5) and 75.9 ± 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty‐five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion‐induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.
Antihypertensive and Metabolic Effects of Tiapamil
Authors: Ding Yu‐An , Shieh Shyh‐Ming
Published: March 2013

Tiapamil, a new calcium antagonist, was evaluated for its antihypertensive and metabolic effects in a long‐term (58 weeks) drug trial in 20 adult outpatient mild to moderately hypertensive subjects. Baseline systolic and diastolic blood pressure dropped after initiation of treatment and was significantly reduced after 4 weeks of treatment, further improving until the termination of the study. There was no impairment of renal and hepatic functions. Electrolytes, plasma aldosterone, plasma renin activity, as well as plasma lipids were not significantly altered during the course of therapy. Fasting blood sugar determinations and oral glucose tolerance test showed significant reductions from the baseline level as a result of the drug treatment. In conclusion, tiapamil is a metabolically safe and effective antihypertensive drug for long‐term use.
Quinidine Does Not Alter Antipyrine Metabolism
Authors: Bowles Susan K. , Cardozo Lavoisier , Edwards David J.
Published: March 2013

Quinidine has been reported to be a potent inhibitor of a specific isozyme of cytochrome P‐450 (P‐450db 1) that is responsible for the metabolism of a select group of drugs. In order to investigate the potential for quinidine to inhibit other isozymes of cytochrome P‐450 and to assess whether or not P‐450db 1 plays any role in antipyrine metabolism, we studied the effects of quinidine pretreatment on the pharmacokinetics and metabolism of antipyrine in six healthy, male volunteers. Using a randomized, crossover study design with a 2‐week washout period between treatments, subjects received a single 1 gram antipyrine dose alone or with quinidine sulfate 200 mg orally every 8 hours for 24 hours prior to the dose of antipyrine and over the 48 hours following antipyrine administration. Mean serum concentrations, apparent oral clearance (1.93 ± 0.86 vs 2.06 ± 1.06 L/hr with quinidine) and half‐life (13.5 ± 3.3 vs 12.4 ± 3.6 hr with quinidine) were not significantly different between the two treatments. The fraction of the administered dose recovered as antipyrine and measured metabolites (56.7% vs 59% with quinidine) as well as the recovery of each individual metabolite was not altered with quinidine pretreatment. In addition, the mean formation clearances for norantipyrine, 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine exhibited no change between treatment phases. These results suggest that the effects of quinidine on the cytochrome P‐450 system are highly specific for particular isozymes, that the isozymes involved in metabolism of antipyrine to its major metabolites are not affected and that P‐450db 1 is not involved in the formation of any of the major metabolites of antipyrine.
Disposition Kinetics of Moclobemide, a New Mao‐A Inhibitor, in Subjects with Impaired Renal Function
Authors: Schoerlin Marie‐Paule , Horber Fritz F. , Frey Felix J. , Mayersohn Michael
Published: March 2013

A single intravenous and oral dose of moclobemide (Ro 11–1163) was administered to 13 subjects with varying degrees of renal impairment (creatinine clearances ranging from 0 to 40 mL/min). The resulting disposition and absorption parameters of moclobemide were more variable than but, with the exception of mean absorption time, were not significantly different from values obtained in another study conducted in 12 normal healthy subjects. There were no relationships between any of the disposition parameters and renal function as measured by creatinine clearance. The disposition of two metabolites of moclobemide were partially characterized from plasma data. One of these (Ro 12–8095) appears to be formation rate‐limited and, from available data, behaves in a manner similar to what has been observed in normals. The other metabolite (Ro 12–5637) has a long apparent disposition half‐life and is present in greater concentrations in the renally impaired compared to the normal subjects. The latter observation may reflect reduced elimination clearance in the renally impaired subjects. Based upon the results of this study there does not appear to be any need to alter the normal dosing regimen of moclobemide in subjects with renal impairment in order to achieve drug concentrations similar to those in healthy subjects.
Transcranial Doppler Studies of Flow Velocity in Middle Cerebral Artery in Weightlessness
Authors: Bondar Roberta L. , Stein Flo , Vaitkus Peter J. , Johnston K. Wayne , Chadwick Lorraine C. , Norris John W.
Published: March 2013

Physiological adaptation to weightlessness requires changes in cardiovascular system parameters to maintain homeostasis in the presence of cephalic fluid shifts. The cerebral circulation must respond immediately to these systemic changes or impairment of cerebral function will occur. Blood flow velocities of the middle cerebral artery were measured by transcranial Doppler (TCD) ultrasound in NASA's KC‐135 aircraft from four healthy subjects in the supine position. Transcranial Doppler data with accompanying acceleration information were analyzed in three segments in each parabola. Cardiac cycles for each segment of all 20 parabolas were pooled for individual subjects. A Student's t test on the data revealed statistically significant differences in the mean and peak frequencies, systolic/diastolic ratios and Doppler power between positive 2 gz and microgravity (10−2 gz) as well as between positive 2 gz and negative 2 gz. Velocity waveform profiles differed for the first one third of each segment, with a more resistive waveform developing during the last two thirds. Changes in systemic arterial resistance and/or raised intracranial pressure may contribute to these TCD waveform changes.
Penbutolol and Carteolol: Two New Beta‐Adrenergic Blockers with Partial Agonism
Authors: Frishman William H. , Covey Steven
Published: March 2013

Penbutolol and carteolol are two new long acting, nonselective beta‐adrenergic blockers which have been approved for the treatment of systemic hypertension. Both drugs have intrinsic sympathomimetic activity (partial agonist activity), however, less than that seen with pindolol. They appear to cause less resting bradycardia than propranolol, have no effect on lipids and lipoproteins, and have favorable side effect profiles.
ACE Inhibition and Pressor Responsiveness to Norepinephrine in Hypertensive Patients
Authors: Malini Pier L. , Strocchi Enrico , Valtancoli Giampaolo , Ambrosioni Ettore
Published: March 2013

The pressor response to norepinephrine (NE) was assessed in normal renin essential hypertensive patients before and after they were randomly assigned to receive in parallel groups of treatment a single dose of an angiotensin converting enzyme (ACE) inhibitor (captopril or lisinopril) or a prolonged therapy with lisinopril (30–45 days) or with hydrochlorothiazide (9 days). Blood pressure was significantly reduced by all treatments. The pressor response to NE was unchanged after the single administration of the ACE inhibitors, while it was blunted after chronic administration of lisinopril and after the diuretic. On the basis of these results, it is suggested that the attenuation of the sympathetically mediated vasoconstriction may represent an additional mechanism contributing to the antihypertensive effect of ACE inhibitors administered chronically.
Effects of Ketanserin on Lipids, Lipoproteins, and Plasma Atrial Natriuretic Factor in Patients with Essential Hypertension
Authors: Bielmann P. , Leduc G. , Gutkowska J. , Davignon J.
Published: March 2013

The effects of ketanserin, 40 mg/day (KE40) and 80 mg/day (KE80) on mean arterial pressure, lipids, lipoproteins, and circulating atrial natriuretic factor (ANF) were investigated in a 24‐week controlled study in 29 patients suffering from mild to moderate hypertension. A significant decrease in mean arterial pressure (MAP) was observed after 18 weeks of therapy, accompanied by a 64% (P < .05) and 80% (P < .02) increase in circulating ANF levels with KE40 and KE80, respectively. There were no significant changes in mean total cholesterol, triglycerides, or cholesterol of the high density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL) fractions. There was a significant increase in the mean apo B levels and consequently a slight hut statistically significant decrease in the ratio of LDL C/B. It is concluded that both doses of KE are effective for monotherapy of mild to moderate essential hypertension. The drug sharply increases circulating ANF levels without significantly altering the plasma lipids. In contrast, by increasing the apolipoprotein B content of the LDL fraction, the beneficial cardiovascular effect of a lowered blood pressure may be partly blunted.
Failure of Ceftibuten to Alter Single Dose Theophylline Clearance
Authors: Bachmann K. , Schwartz J. , MPH  , Martin M. , Nunlee M.
Published: March 2013

Twelve volunteers participated in a two‐way crossover trial in which the effects of ceftibuten on the pharmacokinetics of theophylline were evaluated. Subjects were given single intravenous doses of theophylline (4 mg/kg) with no ceftibuten treatment and on the sixth day of ceftibuten treatment. Ceftibuten 200 mg was taken orally twice daily (7:00 AM and 7:00 PM). A total of 13 blood samples per subject were collected over 48 hours following theophylline administration. Ceftibuten failed to alter either the systemic clearance of theophylline (CL), its volume of distribution (Vss), or its elimination half‐life (t1/2). The 24‐hour plasma theophylline concentration measured both by high performance liquid chromatography (HPLC) or fluorescence polarization immunoassay (FPIA) was used for a single sample estimate of theophylline clearance (CL), and it was found to provide a suitable estimate of the multisample value for CL.
Lack of Probenecid Effect on Nonrenal Excretion of Ceftriaxone in Anephric Patients
Authors: Patel Indravadan H. , Soni Peter P. , Carbone John J. , Audet Patricia R. , Morrison Gail , Gibson Gene A.
Published: March 2013

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h × 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model‐independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.
Effects of a Week's Beta‐Adrenoceptor Blockade with Atenolol and Metoprolol CR/ZOK on the Response to Exercise in Healthy Women Aged 50 to 70 Years
Authors: Patrick John , Bassey Joan , Morrant John , Macdonald Ian
Published: March 2013

12 healthy women with a mean age of 60 years (range 50–70 years) were treated with 50 mg atenolol or 100 mg metoprolol CR/ZOK or placebo for 1 week in a double‐blind, randomized, cross‐over study. Laboratory measurements of the cardiovascular responses to exercise were made 2–4 hours after and again 24 hours after the last tablet. Blood pressure and heart rate at rest were reduced equally by the two beta‐adrenoceptor antagonists. The reductions in blood pressure and heart rate during graded exercise and then during prolonged steady treadmill exercise 3–4 hours after the tablet were greater for atenolol than metoprolol CR/ZOK. The reductions in cardiac output showed a similar pattern. Lactate concentrations and ratings of perceived exertion tended to be highest on metoprolol CR/ZOK, but these differences were inconsistent. We conclude that despite the changes in the cardiovascular system in these 50–70 year‐old women, exercise tolerance was not greatly affected by beta‐adrenoceptor blockade.
Effect of Short‐Term Beta Blockade on Serum Lipid Levels and on the Interaction of LDL with Human Arterial Proteoglycans
Authors: Lindén Tomas , Camejo Germán , Wiklund Olov , Warnold Ingrid , Olofsson Sven‐Olof , Bondjers Göran
Published: March 2013

In view of conflicting evidence suggesting that beta‐blockers have an anti‐atherogenic effect as well as induce a potentially atherogenic lipoprotein profile, the effects of a short term beta‐blockade on serum lipoproteins were studied in 39 healthy volunteers. Because the interaction of LDL with arterial proteoglycans appears to play a role in lipoprotein accumulation during atherogenesis, the effects of metoprolol and atenolol on low density lipoprotein interaction with human aortic proteoglycans were included in the study. We could confirm that the beta‐blockers caused a decrease in HDL cholesterol and an increase in triglycerides, both potentially undesirable effects. In addition, however they induced a significant decrease in the in vitro LDL affinity for arterial proteoglycans. Since there appears to be a strong association between LDL reactivity with proteoglycans and risk for myocardial infarction, this effect of the beta‐blockers may be an antiatherogenic effect which overrides other effects on the lipoprotein pattern.
The Long‐Term Treatment of Stable Angina Pectoris with Verapamil
Authors: Miller Albert J. , Grais I. Martin , Kaminsky Leonard A.
Published: March 2013

In a double‐blind 16‐week crossover study, the effectiveness of verapamil therapy for chronic stable angina was evaluated in 19 patients (Phase I). Twelve of these patients were then followed for 38 to 58 months of open‐label treatment (Phase II). Clinical responses were assessed with traditional indices, treadmill exercise tests, and a newly developed Performance Index (PI).

During Phase I, verapamil resulted in a 50% mean reduction in the number of patients developing effort angina on treadmill exercise, a 15% mean increase in treadmill exercise time, and an 18% mean improvement in the PI. In eight of ten patients, diastolic blood pressure rises during exercise were significantly lowered during verapamil treatment in Phase I.

In a limited population of patients followed for long periods of time, our data show that verapamil remains acceptably effective in the treatment of angina pectoris. Though diastolic blood pressure rises were decreased during Phase I, we could not confirm that effect over longer periods of time. Functional capacity as determined by the PI was sustained in Phase II.
Unaltered Drug Metabolizing Enzyme Systems in Type II Diabetes Mellitus Before and During Glyburide Therapy
Authors: Juan David , Molitch Mark E. , Johnson Mariana K. , Carlson Rodney F. , Antal Edward J.
Published: March 2013

Diabetes mellitus is associated with alterations in hepatic drug metabolizing enzyme activities in experimental animals. To determine whether Type II diabetes or glyburide affect hepatic drug metabolism, the authors used 13C‐labeled aminopyrine and caffeine breath tests as in vivo probes of the hepatic cytochrome P450 and P1450 enzyme activities respectively in six subjects with Type II diabetes (4 women, 2 men). These subjects had been treated previously with diet, had an age range of 41–63 years, had a body mass index range of 24.1–43.3 kg/m2 and had a mean fasting plasma glucose of 14.6 ± 1.2 mM and a mean hemoglobin A1c of 12.2 ± 0.7%. These subjects did not drink alcohol or take drugs known to affect hepatic drug metabolism. The caffeine and aminopyrine breath tests (CBT, ABT) were performed sequentially while fasting before the start of glyburide treatment (5 mg daily) and at weekly intervals for 4 weeks. ABT and CBT values are expressed as cumulative percentage of dose exhaled through 2 hours. Before beginning glyburide, the mean ABT and CBT results were 10.2 ± 0.7% and 4.2 ± 0.7% respectively, well within the normal ranges for these tests (ABT 6.5–15%; CBT 2.5–10%). The ABT and CBT values remained unaltered during 4 weeks of glyburide therapy. However, FBS decreased to 10.2 ± 1.1 mM and HbA1C to 10.1 ± 0.8% by the end of drug treatment.

Type II diabetes that is poorly controlled by diet alone is not associated with alterations of the hepatic drug metabolizing enzymes as judged by the caffeine and aminopyrine breath tests. Furthermore, glyburide does not induce or inhibit the drug metabolizing enzyme systems in the liver, thereby precluding drug‐drug interactions of this type.
Multiple Dose Pharmacokinetics, Safety, and Tolerance of Velnacrine (HP 029) in Healthy Elderly Subjects: A Potential Therapeutic Agent for Alzheimer's Disease
Authors: Puri Surendra K. , Ho Irwin , Hsu Robert , Lassman Howard B.
Published: March 2013

The pharmacokinetics, safety, and tolerance of 1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐ol‐ maleate (HP 029) a potential therapeutic agent for Alzheimer's disease, were assessed after multiple oral doses in a randomized double‐blind, placebo controlled, ascending dose study in 56 healthy elderly men (14 per dose group). The subjects in the first three groups received 25, 50, or 100 mg two times a day and a fourth group was administered 100 mg velnacrine tid for 28 days. All subjects received a final dose on day 29. Subjects were confined for continuous observation during the 36‐day study period. Blood and urine samples were collected for the pharmacokinetic assessment. There were no clinically important changes in the safety variables in both age groups after any dose. There was no evidence of hepatotoxicity when elderly men were given 100 mg tid for 28 days. Nine subjects reported one or two episodes of gastrointestinal (diarrhea) side effects (6 in the 100 mg bid group and 3 in the 100 mg tid dose group) during a 29‐day trial. None required treatment or were discontinued from study. These results indicate that the safety and tolerance up to 100 mg tid for 28 days in healthy elderly men are acceptable.

Velnacrine was rapidly absorbed after oral administration. There were dose‐related increases in Cmax, AUCs, and amount of drug excreted in urine. During multiple dosing, the Cmax increased as a function of dose. The tmax and t1/2 were not affected by dosage nor multiple dosing. Steady state levels of velnacrine were reached between days 2 and 3 with no evidence of further accumulation of velnacrine thereafter. Approximately 11–30% of the administered dose was excreted in the urine over the course of the study.

The favorable pharmacokinetic characteristics and acceptable safety and tolerance of multiple dosing oral doses of velnacrine support further testing of this compound for efficacy and safety in Alzheimer's patients.
Intraperitoneal Administration of Acyclovir in Patients Receiving Continuous Ambulatory Peritoneal Dialysis
Authors: Burgess Ms. Ellen D. , Gill M. John
Published: March 2013

In subjects with normal renal function, acyclovir is rapidly removed from the body via the kidneys. In subjects with end‐stage renal disease, the half‐life is significantly prolonged. The half‐life in subjects receiving hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) is similarly prolonged (10.0 ± 2.2 and 13.2 ±4.7 hours, respectively). After intravenous dosage, peritoneal clearance was 3.4 ± 0.2 mL/min. Intraperitoneal dosing in subjects receiving CAPD resulted in a bioavailability of 61 ± 10% and drug levels sufficient to inhibit herpes simplex virus (HSV) and varicella zoster virus (VZV). Intraperitoneal administration is an alternative route of administration in patients with poor vascular access.
Acute and Steady‐State Pharmacokinetics and Antihypertensive Effects of Felodipine in Patients with Normal and Impaired Renal Function
Authors: Larsson Rutger , Karlberg Bengt E. , Gelin Agneta , Åberg Jan , Regårdh Carl‐Gunnar
Published: March 2013

Eighteen patients (14 men and 4 women, aged 36–74 years) treated with metoprolol for a month were included in the study. Twelve had impaired renal function (IRF) with a glomerular fitration rate (GFR) of 7.5–77.1 mL/min and six having normal renal function (NRF) with a GFR of 84.9–113.0 mL/min. Plasma and urine concentrations of felodipine and metabolites, heart rate, and blood pressure were recorded over 24 hours on day 1 after an oral dose of 10 mg felodipine and 0.04 mg 3H‐felodipine IV and repeated on day 29 during continuous treatment with felodipine, 10 mg bid.

The bioavailability of the oral dose on day 1 and day 29 was 13% and 12.5%, respectively. The terminal plasma half‐life (t1/2) on day 29 was 22 hours and systemic clearance was 490 mL/min on day 1 and 434 mL/min on day 29 (NS). There were no differences in these parameters between NRF and IRF. The protein binding determined by equilibrium dialysis in the six patients with the lowest GFR was 99.74% on day 1 and 99.73% on day 29 and did not differ significantly from previously reported values in healthy subjects.

The mean supine blood pressure before the acute dose of felodipine was 164/96 mm Hg in the IRF patients and 145/95 mm Hg in the NRF patients. A maximum decrease of 37/22 mm Hg and 32/19 mm Hg, respectively, was seen within 1.5 hours after dose and at 12 hours the reduction was 12/9 and 15/10 mm Hg, respectively, compared to baseline values. At steady state the morning blood pressure before dose was 152/87 mm Hg in the IRF patients and 129/86 mm Hg in the NRF patients. Similar maximum decreases and effects at 12 hours were seen after dose on day 29 as on day 1. Data on the effect on diastolic blood pressure and plasma felodipine concentrations were well fitted to the Emax model. The maximum reduction in diastolic blood pressure using this model was 27% and the plasma concentration leading to 50% of the maximum effect was 6.2 nmol/L. In conclusion, renal disease does not affect the pharmacokinetics of felodipine. The pharmacokinetic and pharmacodynamic effects of felodipine are not altered during steady state. The renal excretion of inactive metabolites is reduced in IRF. However, the accumulation of metabolites in the blood does not affect the protein binding or the clearance of felodipine. No dosage adjustment of felodipine seems to be necessary in patients with hypertension and renal impairment.
Clinical Evaluation of Diphenhydramine Hydrochloride for the Treatment of Insomnia in Psychiatric Patients: A Double‐Blind Study
Authors: Kudo Yoshio , Kurihara Masanao
Published: March 2013

The usefulness of the antihistaminic agent diphenhydramine hydrochloride was evaluated using a double‐blind procedure at sleeping doses of 12.5, 25, and 50 mg in 144 psychiatric patients with insomnia. The general condition of the patients with insomnia was at least “slightly improved” in 62.5% (12.5‐mg group), 60% (25‐mg group), and 67.4% (50‐mg group) after treatment with the test drug for 2 weeks. Side effects were observed in a total of 11 patients (7.6%) but were not severe. No symptoms suggestive of drug dependence were evident. Global improvement was not influenced by patient background factors except for the presence or absence of previous treatment for insomnia. The hypnotic effect of diphenhydramine hydrochloride was significantly greater in patients who had not been treated previously. A dose‐dependent increase in the hypnotic effect was also seen in patients who had not received any previous treatment. Diphenhydramine hydrochloride thus appears to be effective in the treatment of insomnia, but the appropriate dosage will depend on previous medical treatment of insomnia.
The Correlation Between Predicted and Measured Patient Specific Analgesic Concentrations After Intravenous Titration: A Guide for Initial Maintenance Requirements with Methadone
Authors: Denson Donald D. , Concilus Robert R. , Gregg Richard V. , Crews James C.
Published: March 2013

The relationship between the analgesic methadone concentrations measured and those predicted using a pharmacokinetic approach were assessed in 22 patients referred for long‐term management of severe pain with intravenous methadone. Five milligrams of methadone were administered IV every 10 minutes until the patient reported a visual analog scale (VAS) pain score of ≤2. Initial maintenance infusion rates were chosen based on the number of 5 mg doses required to produce satisfactory analgesia. Overall the methadone concentrations predicted using pharmacokinetic modeling were in excellent agreement with those actually measured. Over 95% of the variance in the data was explained using this model (r2 = 0.9704). Using the rapid titration paradigm described here, one can obtain a reasonable estimate of patient specific analgesic (target) concentration as well as initial infusion requirements for methadone.
FDA Audits of Clinical Studies: Policy and Procedure
Authors: Lisook Alan B.
Published: March 2013

The Food and Drug Administration has been conducting audits of the work of clinical investigators since 1962, and has done so on a routine basis since 1977. Since 1977 the work of approximately 2,800 drug investigators has been subject to inspection; approximately 500 of these have been “for cause,” including 49 performed outside of the United States. The routine audits are done on studies important to the FDA's approval of therapeutic claims, and are thus not targeted at the investigator, but at the validity of the study. Nevertheless, problems with consent were found in 54%; inadequate drug accountability in 25%; nonadherence to the protocol in 26%; inadequate and inaccurate study records in 21%; problems with institutional review board notification/approval in 13%; nonavailability of study records in 3%; and inappropriate delegation of authority in 4%. Ten percent of routine inspections revealed deficiencies of frequency and/or magnitude sufficient to warrant follow‐up activity. We believe that this figure represents the only available assessment of the incidence of scientific misconduct. Of interest is a decrease to 6% in the past few years. “For cause” inspections may be either investigator‐targeted or study‐targeted. The former have resulted in regulatory action in 100 cases and successful criminal prosecution in 16. The latter have resulted in nonapproval or delay of approval of drugs for marketing. A subset of study‐targeted inspections is the foreign inspections performed on studies important to U.S. approval of claims of efficacy of 24 drugs. Of the 49 such studies evaluated, 23 were judged seriously flawed—15 of 25 in the western hemisphere (Mexico, Canada, and Venezuela) and 8 of 24 in the rest of the world (Europe, Australia, and Japan).
Steady State Pharmacokinetics and Dose‐Proportionality of Phenylpropanolamine in Healthy Subjects
Authors: Scherzinger S. S. , Dowse R. , Kanfer I.
Published: March 2013

The pharmacokinetics of phenylpropanolamine (PPA) were studied in five healthy male volunteers after single oral doses of 25, 50 and 100 mg of the drug as well as at steady state after seven, 4‐hourly doses of PPA. The peak serum concentrations and AUC∞ values increased linearly with an increase in dose, whereas the time to reach peak serum concentrations did not vary significantly between doses. The half‐life remained relatively constant with an increase in dose (t1/2 = 3.8 to 4.3 hours), as did renal clearance (ClR = 0.41 to 0.44 1/kg/h). The percentage of unchanged PPA excreted in the urine over a 14 hour period was 64%, 63% and 73% for the 25, 50 and 100 mg doses, respectively. The pharmacokinetics of PPA were found to be linear in the dosage range 25 to 100 mg. Steady state serum concentrations were significantly higher than single dose concentrations, with the mean peak serum concentration increasing from 113 ng/ml after a single dose to 183 ng/ml at steady state. The time at which these were attained decreased from 1.47 hours after a single dose to 0.73 hours at steady state. Both clearance and volume of distribution were significantly different after a single dose compared to steady state (P <0.05), whereas no significant differences were found between the other parameters.
Comparison of Labetalol and Hydrochlorothiazide in Elderly Patients with Hypertension Using 24‐Hour Ambulatory Blood Pressure Monitoring
Authors: Weidler Donald J. , Vidt Donald G. , Toth Philip D. , Due Deborah L. , Sirgo Mark A.
Published: March 2013

The safety and efficacy of labetalol and hydrochlorothiazide (HCTZ) were compared in a group of 34 patients aged 65 years or older with mild to moderate essential hypertension. After a 4‐week placebo run‐in period, during which all previous antihypertensive medication was discontinued, patients were randomized to receive either labetalol (100 mg bid) or HCTZ (25 mg bid). The patients' blood pressure and heart rate were evaluated biweekly and drug dosage was titrated (up to 400 mg and 50 mg bid of labetalol and HCTZ, respectively) to achieve a standing diastolic blood pressure < 90 mm Hg. Patients underwent 24‐hour ambulatory blood pressure monitoring at the end of the placebo run‐in period and again after the 6‐week titration period. Both labetalol and HCTZ significantly (P< .01) reduced standing systolic (−19.4 vs −27.7 mm Hg) and diastolic (−14.0 vs −15.2 mm Hg) blood pressures following 12 weeks of treatment. Both antihypertensives effectively controlled the 24‐hour ambulatory blood pressure, however, the labetalol group experienced a significantly lower rate of rise in diastolic blood pressure (P= .02) and mean arterial pressure (P= .02) during the acceleration period (400–1200) compared to the HCTZ group. HCTZ caused significant decreases in serum potassium (P< .01) and alkaline phosphatase (P< .05) and increases in uric acid (P< .01) and urea nitrogen (P= .07). These results indicate that labetalol may offer some unique advantages over thiazide diuretics that may be particularly important in the treatment of elderly patients with hypertension.
Ventilatory Response to Single, High Dose Estazolam in Healthy Humans
Authors: Skatrud James B. , Badr Safwan , Begle Robert L. , Juan David
Published: March 2013

The purpose of this study was to determine the effect of oral estazolam at two and three times the usually recommended dosage (2 mg) on ventilation and respiratory drive during wakefulness. Sixty healthy subjects were randomized to receive a single oral dose of either: 1) estazolam 4 mg; 2) estazolam 6 mg; 3) placebo; or 4) morphine 0.15 mg/kg. Predrug and postdrug measurements were obtained for ventilation, respiratory cycle timing, metabolic rate, temperature, and ventilatory and mouth occlusion pressure (P0.1) responses to exogenous CO2. No difference between placebo and the study drugs was noted during eupneic breathing. During administration of exogenous CO2, morphine caused a decrease in the slope of the ventilatory (–0.4 ± 0.1 L/min/mm Hg, P = .008) and P0.1 (–0.22 ± 0.06 cm H2O/mm Hg, P = .015) responses. Estazolam (4 and 6 mg) had no effect on the ventilatory response to exogenous CO2. However, estazolam (6 mg) caused the P0.1 at a PCO2 of 57 mm Hg to decrease (–0.67 ± 0.30 cm H2O, P = .005). The preservation of ventilation with the highest dose of estazolam, despite the decrease in P0.1, indicates that a compensatory strategy independent of respiratory center drive may have been activated. Sedation was a common side effect of estazolam reported in 13% and 53% of subjects at the 4 mg and 6 mg doses, respectively. We conclude that a single, high dose of estazolam does not cause ventilatory depression during wakefulness in healthy subjects.
The Effects of a Single Night's Dosing with Triazolam on Sleep the Following Night
Authors: Mamelak M. , Csima A. , Price V.
Published: March 2013

This study was undertaken to determine whether a single night's use of triazolam by normal healthy sleepers leads to withdrawal insomnia on the subsequent night, and whether there is a dose response relationship to this phenomenon. Thirty normal sleepers of both sexes were randomly assigned to three parallel treatment groups. All subjects were studied for five consecutive nights by means of pre‐ and post‐sleep questionnaires and all night polysomnography. Multiple sleep latency tests were conducted on the days following the second, third, and fourth nights in the laboratory. All subjects received placebo capsules on the first, second, fourth, and fifth nights in the laboratory and either placebo, 0.25 mg triazolam or 0.5 mg triazolam according to their assigned group on the third night. Both doses of the drug increased subjective estimates of sleep duration, but no objective increase was found. Neither dose altered daytime measures of sleepiness. No changes were found in any of the sleep parameters on withdrawal of the 0.25 mg dose of triazolam. However, discontinuation of the 0.5 mg dose did lead to significant objective and subjective withdrawal effects. It was concluded that higher doses of triazolam could lead to withdrawal effects in normal sleepers even when this drug was used for only a single night.
Effects of Subchronic Treatment with Natural Human Interferons on Antipyrine Clearance and Liver Function in Patients with Chronic Hepatitis
Authors: Echizen Hirotoshi , Ohta Yasuo , Shirataki Hiromichi , Tsukamoto Kazuhisa , Umeda Noritsugu , Oda Toshitsugu , Ishizaki Takashi
Published: March 2013

To determine whether natural human interferon administered under the usual therapeutic dosing scheme would inhibit the hepatic drug metabolism, we performed an antipyrine test in eight patients with chronic B or non‐A, non‐B hepatitis before and after a subchronic interferon therapy (6 megaunits/day for 17 ± 4 days, mean ± SD). Six patients received interferon‐β and 2 received interferon‐α. To circumvent a possible influence of interferon‐induced fever on the hepatic drug metabolism, the antipyrine test during the interferon therapy was performed at least 14 days after the interferon‐induced fever disappeared. The kinetic parameters of antipyrine were obtained from seven saliva samples over 32 hours postdose. There were no significant differences in any kinetic parameters of antipyrine observed before and during the interferon therapy. With the sample size of the study, there was only a 20% chance (i.e., β‐power = 0.8 at α = 0.05) that we might have missed a 17% reduction in antipyrine clearance by the interferon therapy (type II error). On the other hand, the subchronic interferon therapy lowered serum aminotransferases and DNA polymerase activity significantly (P < .05) compared with the respective baseline values. Our results suggest that the subchronic therapeutic dosing scheme of interferon as conducted in the present study does not cause the inhibitory effect on the oxidative drug metabolism to a statistically significant or clinically relevant degree in patients with chronic hepatitis, while it improves their liver function. Further studies are required for determining if different types of interferons administered under the different dosing schemes would alter the hepatic drug metabolism and the inhibitory effect would be time‐dependent.
The Influence of Pentoxifylline and Torbafylline on Muscle Blood Flow in Animals With Peripheral Arterial Insufficiency
Authors: Dinn Richard F. , Yang H. T. , Terjung Ronald L.
Published: March 2013

The potential of pentoxifylline to enhance blood flow to relatively ischemic muscle during running was evaluated in rats with peripheral arterial insufficiency. Femoral artery stenosis, sufficient to limit exercise hyperemia but not affect resting blood flow, was surgically induced in adult male rats (∼350 g). Day three after stenosis, rats were assigned to either a control (N = 14) or treatment (N = 14) group and exercised 5 days a week for 3 weeks. Exercise tolerance of rats fed pentoxifylline (34 ± 1.3 mg/kg/day) or an analog (torbafylline; 34 ± 2.3 mg/kg/day) increased more (P < .001) than control rats in the third week of treatment. This was evidenced by a higher treadmill speed and longer duration of running. Blood flows determined with 85Sr and 141Ce labeled 15μ spheres at low (20 m/min) and high (30–35 m/min) treadmill speeds were similar for each group and ∼50% of that found in normal nonstenosed rats. Blood flows to the entire hindlimb, to the proximal and distal hindlimb segments, and to individual muscle fiber sections were not different between control and pentoxifylline groups. Thus, the increase in exercise tolerance could not be attributed to an increase in muscle blood flow. Rather, an enhanced oxygen extraction by the working limb muscles should lead to the increased VO2, required by the faster running speed in the pentoxifylline rats. This suggests that pentoxifylline may act to improve microvascular flow heterogeneity in working muscle. Our findings support clinical evidence that pentoxifylline is effective in managing patients with peripheral arterial insufficiency.
Noninvasive Blood Pressure Monitoring at the Finger for Studying Short Lasting Pressor Responses in Man
Authors: Christen Yves , Waeber Bernard , Nussberger Jürg , Brunner Hans R.
Published: March 2013

The study of vasoactive agents in man often requires accurate measurement of short‐lasting changes in blood pressure. Using a noninvasive photoplethysmographic device (Finapres), the authors investigated in normotensive subjects whether rapid increases in blood pressure can be assessed precisely by monitoring finger blood pressure continuously. Six volunteers were studied on two consecutive days. On the first day, increasing doses of angiotensin I were injected intravenously with the aim to find a test dose which raised systolic blood pressure by 25 to 40 mm Hg. After oral administration of a placebo, the same test dose was injected repeatedly over the next 24 hours. On the second day, the subjects took either 6.25 (n = 3) or 25 mg (n = 3) captopril PO and the serial administration of the test dose of angiotensin I was continued for the next 4 hours. After placebo intake there was a good reproducibility of the blood pressure response to angiotensin I with a coefficient of variation of 15 ± 4.5% (Mean ± SD, n = 6). Captopril caused a dose‐dependent inhibition of the pressor effect of angiotensin I. These data indicate that noninvasive blood pressure monitoring at the finger represents a useful tool to study short‐lasting blood pressure changes produced by vasoactive agents in man.
An Evaluation of the Biological Response to Fraxiparine, (A Low Molecular Weight Heparin) in the Healthy Individual
Authors: Freedman Michael D. , Leese Philip , Prasad Rajani , Hayden Dan
Published: March 2013

The tolerance of a low molecular weight heparin (Fraxiparine®, Choay, Paris, France) in normal individuals was determined using a two part investigation. Study 1 consisted of administering escalating doses of Fraxiparine in a single blinded, placebo controlled, rising dose tolerance evaluation. The daily doses tested were 3750 U AXA IC, 7500 U AXa IC, 11250 U AXa IC, 15000 U AXa IC, and 22500 U AXa IC Fraxiparine subcutaneously for 5 consecutive days. In study 2, we compared the tolerance of unfractionated heparin (UH) administered as 5000 IU every 8 hours, to that of 7500 U AXa IC/day or 15000 U AXa IC/day of Fraxiparine administered once daily. Our results indicated very good tolerance to this low molecular weight heparin (LMWH) at doses up to and including 22500 U AXa IC/day. We observed significantly elevated increases in transaminases following LMWH administration. In our second study we observed that the increase in serum transaminases seen after 15000 U AXa IC/day Fraxiparine was without significant difference from that observed following UH (5000 IU every 8 hours). AXa examination revealed an accumulation of AXa effect after 5 days of administration at doses > 15000 U AXa IC, and there was good correlation between AXa and APTT at Fraxiparine doses > 15000 U AXa IC/day. No thrombocytopenia was associated with Fraxiparine. We conclude that Fraxiparine is relatively well tolerated and shows accumulation after daily dosing with > 15000 U AXa IC.
Norfloxacin Does Not Alter Warfarin's Disposition or Anticoagulant Effect
Authors: Rocci Mario L. , Vlasses Peter H. , Distlerath Linda M. , Gregg M. Hall , Wheeler Sarah C. , Zing Winnie , Bjornsson Thorir D.
Published: March 2013

Drug interactions related to inhibition of hepatic drug metabolism have been identified for some fluoroquinolone antibiotics. This study was designed to investigate whether the fluoroquinolone norfloxacin at the usual clinical dosage interacts with the anticoagulant agent warfarin. Ten healthy male subjects were administered a single oral dose of 30 mg warfarin sodium alone or during multiple‐dose treatment with norfloxacin, 400 mg bid, in a randomized, crossover fashion. Plasma warfarin concentrations and prothrombin times were measured for 6 days after each of the two warfarin doses. The pharmacokinetic parameters of warfarin were comparable in the absence and presence of norfloxacin, including no significant differences in warfarin's elimination half‐life, apparent total clearance, apparent volume of distribution, or peak plasma concentration. Norfloxacin also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction observed in this study suggests that a clinically important interaction of norfloxacin and warfarin is unlikely to occur in patients requiring both drugs.
Lack of Effect of Cefixime on the Metabolism of Vitamin K1
Authors: Trenk D. , Wagner F. , Bechtold H. , Nies B. , Jähnchen E.
Published: March 2013

It seems that cephalosporins bearing a N‐methyl‐thio‐tetrazole or a methyl‐thiadiazole moiety in their molecule can cause hypoprothrombinemia in patients via inhibition of the metabolism of vitamin K1 if they are in addition in a vitamin K1‐deficient state. The authors therefore studied the effects of two different oral doses (200 and 400 mg) of the cephalosporin cefixime on the metabolism of vitamin K1, in healthy volunteers, because the accumulation of vitamin K1‐2,3‐epoxide in plasma is a sensitive marker of coumarin‐like activity of drugs. The results indicate that the development of hypoprothrombinemia due to an impairment of the metabolism of vitamin K1 by cefixime seems unlikely because only trace amounts of vitamin K1‐2,3‐epoxide could be determined in the plasma of the subjects investigated.