bluuebunny/crossref_metadata_2025 huggingface dataset:
Diltiazem in the Treatment of Mild or Moderate Essential Hypertension. Comparison with Metoprolol in a Crossover Double‐Blind Trial
Authors: TRIMARCO BRUNO , DeLUCA NICOLA , RICCIARDELLI BRUNO , VOLPE MASSIMO , VENIERO ANNAMARIA , CUOCOLO ALBERTO , CICALA MARCO
Published: March 2013

Abstract: The antihypertensive efficacy and tolerability of a calcium antagonist drug, dilitiazem (60 mg q.i.d. per os), was compared with that of metoprolol (100 mg b.i.d. per os) in a crossover, double‐blind randomized trial in 20 patients with mild or moderate essential hypertension. Blood pressure and heart rate were assessed at rest and during bicycle exercise before and after four‐week periods of treatment. Both metoprolol and diltiazem reduced significantly systolic and diastolic blood pressure, while heart rate decreased only after metoprolol therapy. The reduction in blood pressure and the percentage of patients who responded favorably were similar with the two drugs. Furthermore, the overall levels of blood pressure during exercise were significantly reduced by both treatments, while only metoprolol was able to reduce the maximum increase in systolic blood pressure and heart rate induced by exercise. These results suggest that the use of diltiazem may be appropriate to the treatment of patients with mild or moderate essential hypertension.
A Double‐Blind Parallel Comparison of Ketoprofen, Codeine, and Placebo in Patients with Moderate to Severe Postpartum Pain
Authors: KANTOR T. , CAVALIERE M. B. , HOPPER M. , ROEPKE S.
Published: March 2013

Abstract: A total of 152 patients were treated at a single center in a single‐dose, double‐blind parallel study designed to compare the safety and efficacy of 25, 50, and 100 mg ketoprofen to 90 mg codeine and placebo in patients with moderate to severe postpartum pain (i.e., postepisiotomy, uterine cramping, or cesarean section pain). The analgesic responses to all three doses of ketoprofen and 90 mg codeine were superior to placebo and were not significantly different from each other. No dose‐related response was observed with ketoprofen. The number of side effects was significantly greater (P = 0.001) among patients receiving codeine (six patients) than among those receiving ketoprofen (three patients).
The Effects of Five Potassium Chloride Preparations on the Upper Gastrointestinal Mucosa in Healthy Subjects Receiving Glycopyrrolate
Authors: ALSOP WILLIAM R. , MOORE JOHN G. , ROLLINS DOUGLAS E. , TOLMAN KEITH G.
Published: March 2013

Abstract: The effects on the upper gastrointestinal tract of five different preparations of KCl were compared in 90 healthy subjects treated with glycopyrrolate. The KCl preparations studied were (1) wax‐matrix KCI, (2) microencapsulated KCI, (3) liquid KCI, (4) experimental extended‐release capsules, (5) experimental extended‐release tablets, and (6) placebo. The subjects were endoscoped prior to and after seven days of dosing. Upper gastrointestinal mucosal pathology was seen with all of the potassium preparations as well as with placebo. No statistically significant differences between the various KCI groups or between KCI groups and placebo were seen. All of the lesions were superficial, except for one ulcer seen with the microencapsulated KCI. None of the subjects developed occult gastrointestinal bleeding. There were no differences in the incidence of abdominal symptoms.
Gastrointestinal Microbleeding Associated with the Use of Etodolac, Ibuprofen, Indomethacin, and Naproxen in Normal Males
Authors: SALOM IRA L. , JACOB GINETTE , JALLAD NADER , PERDOMO CARLOS A. , MULLANE JOHN F. , WEIDLER DONALD
Published: March 2013

Abstract: Etodolac, a nonsteroidal antiinflammatory and analgesic drug, was used in a randomized, parallel group, open‐label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400 mg (N = 11) and 600 mg (N = 12) b.i.d. on gastrointestinal microbleeding with that of 600 mg ibuprofen, q.i.d. (N = 12), 50 mg indomethacin in the morning, 50 mg at noon, and 100 mg h.s. (N = 9), and 375 mg naproxen b.i.d. (N = 9). Etodolac was given at about 2 1/2 and 3 1/2 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers' maximum recommended doses. Lead‐in placebo was given for one week, active drug for one week, and washout placebo for one week. Fecal blood loss was measured by the 51Cr‐tagged red cell method, and was averaged over days 4–7 (baseline), 11–14 (treatment period), and 17–20 (washout). The mean increase in blood loss for the treatment period for the 400 mg etodolac b.i.d. group (0.13 ml) and 600 mg etodolac b.i.d. group (0.10 ml) was significantly less (P = 0.001) than the corresponding values for ibuprofen (1.14 ml), indomethacin (1.20 ml), and naproxen (0.87 ml). There was no tendency for greater blood loss at higher doses of etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the seven‐day treatment period than the other drugs tested, and not clinically more than that occurring during baseline placebo.
Amikacin Levels in the Human Biliary Tract
Authors: LEFROCK JACK L. , SCHELL RONALD F. , SISKIND STUART , CARR BERNICE B.
Published: March 2013

Abstract: The concentrations of amikacin in serum, gallbladder, and common duct bile, and gallbladder tissue in patients undergoing surgery of the biliary tract were investigated. Patients received 500 mg amikacin intravenously or intramuscularly from 1 to 11 hours before surgery. Another group had T‐tubes inserted and blood and bile levels were studied serially postoperatively. One half hour after 500 mg amikacin, serum levels were high and bile levels were 30 per cent of the serum levels, with tissue levels less than 19 per cent of the serum levels. At 6 hours, serum levels were 37 per cent of the 1‐hour levels; however, bile levels were 34 per cent of the simultaneous serum levels. At 11 hours, both postdose serum and bile amikacin levels were low. However, simultaneous bile levels were higher than serum levels. No patient suffered from any side effects from amikacin.
Absolute Bioavailability and Effect of Food and Antacid on Diazepam Absorption from a Slow‐Release Preparation
Authors: LOCNISKAR ANN , GREENBLATT DAVID J. , ZINNY MIGUEL A. , HARMATZ JEROLD S. , SHADER RICHARD I.
Published: March 2013

Abstract: A series of healthy volunteers received a single 7.5‐mg intravenous dose of diazepam on one occasion and a single 15‐mg oral dose of slow‐release diazepam (DZ‐SR) on another occasion. Diazepam concentrations were measured by gas chromatography in multiple plasma samples drawn during seven days after each dose. Absorption of diazepam from DZ‐SR was slow, with mean ± S.E. peak concentrations attained at 3.8 ± 0.5 hours after dosage. Absolute bioavailability of DZ‐SR averaged 0.98 ± 0.06. In two other studies, diazepam absorption from DZ‐SR was evaluated when coadministered with a standard breakfast or with an antacid preparation (Maalox). Neither food nor antacid altered the rate of diazepam absorption and did not impair the completeness of absorption. Higher peak total plasma diazepam concentrations occurred in the postprandial as opposed to the fasting state, but this was an artifact of reduced protein binding (increased free fraction) due to fasting. Thus, diazepam absorption from DZ‐SR is slow and essentially complete.
Pilot Study of the Effects of the Angiotensin‐Converting Enzyme Inhibitor CI‐906 on Patients with Essential Hypertension
Authors: GAVRAS I. , VLAHAKOS D. , MELBY J. C. , GAVRAS H.
Published: March 2013

Abstract: The effects of two single doses of the new oral nonsulfhydryl angiotensin‐converting enzyme (ACE) inhibitor CI‐906 on blood pressure and hormone levels are described in eight subjects with essential hypertension. Starting at 0.625 mg, doses were separated by a placebo day and doubled in consecutive patients until the full effect (obtained with 5 and 10 mg) was reached, at which point the remaining patients received the same dosage. All doses, including the smallest, caused ACE suppression to less than 1 per cent of baseline lasting for least 12 hours and remaining below 30 per cent at 48 hours, accompanied by a rise in plasma renin activity (by 10.9 ± 2.1 ng/ml/hr) and fall in aldosterone (by −12.6 ± 2.5 ng/100 ml). However, a clinically significant, though partial and short‐lived, effect on blood pressure was observed at 2.5 mg. The two highest doses produced similar effects in terms of magnitude of mean blood pressure lowering (by 26 ± 5 and 25 ± 2 mm Hg, respectively) and duration (varying from 12 to over 24 hours) regardless of pretreatment renin levels. There was no orthostatic hypotension, tachycardia, or other adverse reaction.
The Effect of Captopril on Renal Hemodynamics in Hypertensive Patients
Authors: DUCHIN K. L. , WILLARD D. A.
Published: March 2013

Abstract: The effects of captopril (50 or 100 mg t.i.d.) with and without hydrochlorothiazide (25 or 50 mg/day) on renal blood flow, glomerular filtration rate, and the renin‐angiotensin system were determined in 20 patients with mild to moderate essential hypertension. Normalization of blood pressure (supine diastolic blood pressure<90 mm Hg) was achieved in 12 patients after four or six weeks of captopril alone (147 ± 3/100 ± 3 mm Hg after a two‐week placebo lead‐in vs. 135 ± 4/83 ± 1 mm Hg after captopril, P < 0.01/P < 0.001). In these 12 patients, no significant alterations in renal blood flow or glomerular filtration rate were observed. Plasma renin activity increased two‐ to threefold above baseline levels, whereas serum and urinary aldosterone decreased by 23 and 35 per cent, respectively. Eight other patients remained hypertensive after four weeks of captopril alone (165 ± 6/110 ± 3 vs. 156 ± 8/102 ± 4 mm Hg, P > 0.05/P < 0.05). With addition of hydrochlorothiazide, blood pressure fell (P < 0.001) to 129 ± 7/84 ± 3 mm Hg. Captopril alone or in combination with diuretic had no significant effect on renal hemodynamics. In the eight patients requiring diuretic, plasma renin activity remained constant after catopril monotherapy, but rose threefold after hydrochlorothiazide was added. The combination of these two antihypertensive agents significantly lowered serum aldosterone levels and urinary aldosterone excretion by 53 and 50 per cent, respectively. In summary, captopril with and without a thiazide diuretic reduced blood pressure without altering renal hemodynamics.
Lack of Effect of Histamine H2‐Receptor Antagonists on Indocyanine Green Disposition Measured by Two Methods
Authors: DONN KARL H. , POWELL J. ROBERT , ROGERS JOHN F. , PLACHETKA JOHN R.
Published: March 2013

Abstract: Eleven healthy male volunteers were treated according to a randomized, crossover design with ranitidine (300 mg/day), cimetidine (1200 mg/day), or nothing for 48 hours. Ninety minutes after the 48‐hour dose, each volunteer was given 0.5 mg/kg indocyanine green by iv bolus. Indocyanine green plasma concentrations were measured by the traditional spectrophotometric method at 800 nm and by HPLC simultaneously monitored at 214 and 656 nm. Neither histamine H2‐receptor antagonist altered the disposition of indocyanine green. The mean (± S.D.) plasma clearance by the spectrophotometric method was 7.48 ± 2.07 (control), 7.15 ± 3.07 (ranitidine), and 6.88 ± 1.35 ml/min/kg (cimetidine). The power to detect a 20 per cent change is 0.87. The spectrophotometric method generally produced a biexponential plasma concentration decay, whereas the HPLC method resulted in a monoexponential decay. Analysis of the 5‐ to 15‐minute data by the conventional technique showed that although indocyanine green total plasma clearance was not significantly different for the two methods (P > 0.10), the volume of distribution was significantly greater (P < 0.001) and the elimination rate constant was significantly smaller (P < 0.001) for the spectrophotometric than the HPLC method. Although neither ranitidine nor cimetidine chronic administration alters indocyanine green disposition by either method, the absolute values of the pharmacokinetic parameters are dependent upon the analytical technique employed.
Zomepirac‐Aspirin Interactions in Man
Authors: DESIRAJU RAVI K. , NAYAK RAMCHANDRA K. , PRITCHARD J. FREDERICK
Published: March 2013

Abstract: The pharmacokinetic interaction between zomepirac and aspirin was studied in 12 healthy males who received a single dose of 100 mg zomepirac sodium on days 1 and 5 and 975 mg aspirin every 6 hours on days 2 to 5. The results indicated that in the presence of salicylate, the peak concentration of zomepirac was depressed; peak time, AUC(0–24 hr), and clearance of total drug remained unchanged. Percentage unbound zomepirac was increased twofold. In the presence of zomepirac, the peak concentration and AUC of salicylate were increased and clearance decreased. The data suggest that zomepirac and salicylate compete with each other for the enzymes and/or cofactors involved in glucuronidation. This competition for metabolic clearance offsets the consequences of the zomepirac‐salicylate interactions at the plasma protein binding sites. However, in light of increased unbound zomepirac as well as decreased clearance of unbound drug, concomitant therapy of zomepirac and aspirin is not advised.
Effects of Food on Oxaprozin Bioavailability
Authors: CHIANG SOONG T. , KNOWLES JOHN A. , HUBSHER JEROME A. , RUELIUS HANS W. , WALKER BARRY R.
Published: March 2013

Abstract: Twelve healthy volunteers received single 1200‐mg oral doses of oxaprozin while fasting and immediately after a standard breakfast in a two‐period crossover design with three weeks between administrations. Oxaprozin plasma concentrations were monitored during a 10‐day period after each dose. No statistically significant differences were noted between kinetic parameters obtained in the fasting and postprandial states for mean peak plasma concentrations (Cmax, 103 vs, 109 μg/mI), absorption rate constants (ka, 1.1 vs. 0.8 h−1), or total AUC (7042 vs. 7066 μg/ml · hr). Compared with doses administered during fasting, postprandial doses led to a delay in the onset of absorption in the gastrointestinal tract (lag time t0, 24 vs. 9 min), but not in the peak time (tmax ∼5 hours). Oxaprozin's mean residence time t̄ was slightly shorter for subjects in the postprandial state (72 hours) than for those in fasting state (73 hours), probably because of the intrasubject variability in half‐life (48 vs. 50 hours). The results of this study indicate that the ingestion of food has no effect on the bioavailability of oxaprozin.
Methyldopa Does Not Alter the Disposition of Digoxin
Authors: MAY CAROL A. , VLASSES PETER H. , ROCCI MARIO L. , ROTMENSCH HESCHI H. , SWANSON BRIAN N. , TANNENBAUM RENEE P. , FERGUSON ROGER K. , ABRAMS WILLIAM B.
Published: March 2013

Recent reports have documented interactions between digoxin and agents with dissimilar chemical structures, including quinidine,1–3 nifedipine,4 verapamil,5,6 and amiodarone.7,8 Concomitant use of these agents with digoxin has resulted in increased serum concentrations and, in some cases, clinical signs and symptoms of digoxin toxicity. On this basis, the Food and Drug Administration has proposed that future New Drug Applications for drugs that have projected use in the elderly should contain evaluations of digoxin interactions.

Methyldopa (Aldomet, Merck Sharp & Dohme) is a commonly prescribed antihypertensive agent which is frequently administered concomitantly with digoxin. The purpose of this study was to evaluate whether methyldopa alters the disposition of digoxin in normal volunteers.
Antihypertensive Action of Nifedipine: Effects on Arteries and Veins
Authors: Masotti Giulio , Morettini Alessandro , Galanti Giorgio , Paoli Giovanni , Poggesi Loredana
Published: March 2013

Nifedipine is a calcium‐channel antagonist with effective antihypertensive activity and has been suggested for the treatment of high blood pressure as an alternative to vasodilators. The aim of this study was to define the acute effect of nifedipine and in particular the dose‐effect relationship, effects on veins, influence on adrenergic reflexes, and effectiveness on hypertension according to severity and etiologic type. The effects of nifedipine on blood pressure, heart rate, forearm blood flow, peripheral vascular resistance, orthostatic and cold reflexes, and venous tone were examined in 45 patients with hypertension of different etiologies (essential, renovascular, and renal parenchymal) and different World Health Organization grades. The antihypertensive effect was dose dependent, but a dose of 20 mg has nearly maximal activity with acceptable side effects. The drug acts by lowering peripheral vascular resistance, and this lowering is directly related to baseline values; therefore, the antihypertensive effect increases with severity of the hypertension. Nifedipine had the same effect in all three etiologic groups of hypertension studied. The drug seems to increase venous tone, since it caused venoconstriction when locally injected in hand veins. Nifedipine did not alter adrenergic reflexes induced by both cold application and standing and was well tolerated. In conclusion, the calcium antagonist nifedipine for its characteristics of action, at least in acute administration, seems to be a useful alternative in the treatment of various forms of hypertension.
Bioinequivalence of Erythromycin Ethylsuccinate and Enteric‐Coated Erythromycin Pellets Following Multiple Oral Doses
Authors: Yakatan Gerald J. , Rasmussen Clayton E. , Feis Patricia J. , Wallen Stanley
Published: March 2013

Bioequivalence comparisons between erythromycin ethylsuccinate and an enteric‐coated erythromycin base pellet product were made following multiple‐dose, oral administration. Twenty‐four volunteers participated in a ten‐dose protocol (one dosage unit every six hours) using a complete crossover design. Plasma samples were assayed using a microbiological method specific for erythromycin base in the presence of the ester. Without correcting for the differences in doses administered, the amount of active erythromycin base absorbed from the enteric‐coated pellet (250 mg base) was five to seven times that absorbed from the erythromycin ethylsuccinate product (400 mg base equivalent) at steady state. Erythromycin ethylsuccinate is not bioequivalent to an enteric‐coated erythromycin base pellet product The lower bioavailability of the ethylsuccinate may be due to instability in the acidic medium of the stomach.
Studies With Stable Isotopes I: Changes in Phenytoin Pharmacokinetics and Biotransformation During Monotherapy
Authors: Browne Thomas R. , Evans James E. , Szabo George K. , Evans Barbara A. , Greenblatt David J. , Schumacher Gerald E.
Published: March 2013

Six patients were given tracer doses of 13C15N2‐phenytoin (PHT) before and four and 12 weeks after beginning monotherapy. The following significant (P < .05) changes occurred during monotherapy: (1) Apparent (from tracer doses) PHT total clearance by linear method decreased; (2) apparent PHT elimination half‐life increased; (3) apparent mean PHT serum concentration per unit dose increased; (4) apparent rate of excretion of p‐hydroxyphenyl‐phenylhydantoin (p‐HPPH) decreased; (5) apparent rate of excretion of PHT dihydrodiol increased; and (6) apparent PHT total clearance and elimination half‐life and apparent p‐HPPH rate of excretion were dose dependent. Phenytoin apparent pharmacokinetic and biotransformation values undergo a typical series of changes after beginning monotherapy at typical dosing rates, because PHT's dose‐dependent pharmacokinetics result in differing apparent vaiues as the serum concentration rises to steady state. Stable iostope methods are particularly suitable for investigating such phenomena.
Studies With Stable Isotopes II: Phenobarbital Pharmacokinetics During Monotherapy
Authors: Browne Thomas R. , Evans James E. , Szabo George K. , Evans Barbara A. , Greenblatt David J.
Published: March 2013

Six healthy adults receiving no other medications were given tracer doses of 90 mg of stable isotope‐labeled phenobarbital (PB) intravenously before, and four weeks after, and 12 weeks after beginning therapy. Serum samples were collected for 96 hours after each injection, and the concentration of stable isotope‐labeled PB in each sample was determined by gas chromatographic mass spectrometry. The volume of distribution, elimination half‐life, and total clearance of PB did not differ significantly on any of the three occasions measured. Phenobarbital clearance did not correlate significantly with total PB serum concentration. Clearances determined from single‐dose studies before beginning PB therapy accurately predicted steady‐state PB serum concentrations. Therefore, it is not necessary to adjust PB dosage for time‐dependent or dose‐dependent changes in clearance during monotherapy. In addition, clearance or serum concentration determined at one dosing rate directly predicts serum concentration at another dosing rate.
Studies With Stable Isotopes III: Pharmacokinetics of Tracer Doses of Drug
Authors: Browne Thomas R. , Greenblatt David J. , Harmatz Jerold S. , Evans James E. , Szabo George K. , Evans Barbara A. , Schumacher Gerald E.
Published: March 2013

Stable isotope labeled tracer doses of phenytoin (PHT) and phenobarbital (PB) were given intravenously before and four and 12 weeks after beginning monotherapy in two groups of six patients. Phenytoin demonstrated nonlinear pharmacokinetics, while PB demonstrated linear pharmacokinetics. Each of the 36 sets of tracer dose serum concentration versus time data points appeared linear during the elimination phase on semilog plots, and each demonstrated a high degree of linearity using semilog regression analysis (r2 = .977‐.999, P < .001, for PHT; r2 = .791‐.996, P < .005, for PB). We conclude tracer doses administered at steady‐state serum concentration will exhibit linear serum concentration versus time relationships on semilog plots regardless of whether the steady‐state serum concentration is in the linear or the nonlinear portion of a drug's dose versus steady‐state serum concentration relationship. The mechanism and implications of this conclusion are discussed.
Therapeutic Initiatives for the Avoidance of Aminoglycoside Toxicity
Authors: Whelton Andrew
Published: March 2013

Aminoglycosides continue to be indispensable in the management of serious and life‐threatening aerobic gram‐negative infections. On an annual basis in the United States, they are used in the management of four million patients. Despite their clinical utility, they continue to manifest a high profile of toxic side effects such as nephrotoxicity and ototoxicity with the rare occurrence of neuromuscular toxicity. Animal experimental models have been invaluable in elucidating the pathophysiologic mechanisms by which aminoglycosides damage the kidney and the inner ear. However, it is from clinical therapeutic experience and prospective clinical trials that we have been able to solidly define the risk factors that accentuate the development of aminoglycoside‐related toxicity. The clinical toxicity of these agents can be kept to a minimum by ensuring the use of an appropriate dose, for periods of time not exceeding nine to ten days, in a well‐hydrated, normokalemic patient. Special subpopulation groups such as the elderly, the obese, those with preexisting renal disease, or patients who need the concurrent use of other nephrotoxins, require special care in the monitoring of their aminoglycoside therapy to ensure a safe and effective clinical outcome.
The Pharmacokinetics and Serum and Urine Bactericidal Activity of Ciprofloxacin
Authors: Brittain David C. , Scully Brian E. , McElrath M. Juliana , Steinman Richard , Labthavikul Pornpen , Neu Harold C.
Published: March 2013

Ciprofloxacin is an investigational quinolone agent possessing an impressive antibacterial spectrum. Its pharmacokinetics were studied in six volunteers after 250‐mg and 500‐mg single oral doses, and its bactericidal activity compared to that of trimethoprim‐sulfamethoxazole given to the same volunteers. Mean peak serum levels were 1.45 μg/mL and 2.46 μg/mL for 250‐mg and 500‐mg doses, and time to peak was 1 and 1.3 hours. The 12‐hour levels were 0.12 μg and 0.22 μg. Half‐life (T1/2)α were 0.32 and 0.43 with T1/2β were 3.97 and 4.15 and volume of distribution (area) were 80L and 90L, respectively. Area under the concentration curve (AUC) was 5.65 h · μg/mL and 10.37h · μg/mL. Serum clearance was 23L for both doses. Approximately 49% of the 250‐mg dose and 43% of the 500‐mg dose was recovered in the urine. Bactericidal levels were determined against clinical isolates. Sera at 1.5 hours after the 500‐mg dose averaged bactericidal levels of 1:20 or better for an Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa,and beta‐lactamase producing Haemophilus influenzae and Branhamella catarrhalis. Urinary bactericidal levels at eight to 12 hours were 1:157 for E coli, K pneumoniae, gentamicin‐piperacillin resistant P aeruginosa, Staphylococcus aureus, and 1:20 for Streptococcus faecalis. Serum bactericidal levels were superior, and urine bactericidal levels were superior or equal to the bactericidal levels obtained with trimethoprim‐sulfamethoxazole. Ciprofloxacin's in vitro activity and human pharmacology should permit a twice or once daily dosing schedule for system 1C infections due to most Enterobacteriaceae, Haemophilus, Branhamella and Pseudomonas, and S aureus, and once daily for urinary gastrointestinal infections.
The Excretion of Rosaramicin in Breast Milk
Authors: Stoehr Gary P. , Juhl Randy P. , Veals J. , Symchowicz Sam Son , Gural Richard , Lin C. , McDonald Robert H.
Published: March 2013

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250‐mg oral dose of rosaramicin. Mean serum half‐life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 μg, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug‐induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.
Tolerance and Percutaneous Absorption of Topically Applied Arildone
Authors: Bosso John A. , Spruance S.L. , Wenerstrom Gay
Published: March 2013

Arildone, an investigational antiviral agent, was compared to both its vanishing cream and 90% dimethyl sulfoxide (DMSO) solution vehicles to determine cutaneous and systemic tolerance as well as percutaneous absorption. In separate studies, immunosuppressed patients randomly received either arildone in vanishing cream (study 1), arildone in DMSO solution (study 2), or the vehicles without arildone. Test formulations were applied to the same area of one forearm four times daily for seven days. Blood, urine, and fecal samples were collected on days 1, 4, and 7, and patients were observed daily. Arildone was sporadically detected in biologic specimens suggesting limited percutaneous absorption. Unexpectedly, DMSO did not appear to enhance absorption of the drug. No clinical or laboratory evidence of systemic intolerance was observed for any preparation. While cutaneous tolerance was excellent for the vanishing cream preparations, the DMSO preparations were associated with a high (90%) incidence of erythematous reactions.
The Effect of Tolmetin on the Chronic Pain and Decreased Functional Capacity Associated With Degenerative Joint Disease
Authors: Amadio P. , Cummings D.M.
Published: March 2013

Degenerative joint disease (DJD) is a common disorder characterized by chronic pain and limitation of activity, for which treatment with a nonsteroidal anti‐inflammatory drug (NSAID) is often useful. The anti‐inflammatory activity of the NSAID tolmetin sodium has been well described, being comparable in efficacy to indomethacin and effective for the relief of the acute and chronic symptoms that accompany DJD. To examine specifically the effect of tolmetin in controlling the pain and functional limitation in DJD of the spine, tolmetin was tested against placebo in a double‐blind, two‐segment, crossover study. Twenty‐six patients (mean age, 62.5 years; range, 42–79 years) received three weeks of tolmetin 1,200 mg/d and three weeks of placebo. The results showed that tolmetin provided significantly greater relief of symptoms than placebo in virtually all measurements of joint pain and stiffness: tenderness, pain at rest, pain on motion, intensity of joint pain (P < 0.001), and duration of morning stiffness (P = 0.002). Statistically significant improvement was noted in two of the three measures of cervical range of motion (P 0.01) and in all assessments of daily living activities (P = 0.001 in four parameters; P = 0.02 in a fifth parameter). Global evaluations of response to treatment by both patients and investigator also demonstrated significant effects (P 0.002). Significantly more placebo patients (13 of 26) than tolmetin patients (two of 26) found the medication ineffective and discontinued treatment prematurely (P = 0.01). No serious or limiting adverse reactions were seen during placebo or tolmetin therapy. The most frequently reported side effects on both therapies were gastrointestinal. Dermal and central nervous system adverse reactions were encountered only rarely. Side effects apparently related to the pharmacologic activity of NSAIDs on renal prostaglandins were seen in some tolmetin patients who experienced mild hypertension, edema, and weight gain. The study was effective in demonstrating a significant difference between active drug and placebo. Tolmetin provided safe and effective relief from the chronic pain and limited functional capacity associated with DJD of the spine.
The Influence of Liver Dysfunction on the Pharmacokinetics of Carprofen
Authors: Holazo Alice A. , Chen Susan S. , McMahon F. Gilbert , Ryan Jerome R. , Konikoff John J. , Brazzell Romulus K.
Published: March 2013

The pharmacokinetics of the investigational agent carprofen were examined in 12 patients with liver dysfunction (hepatic cirrhosis) and in six normal volunteers following single 100‐mg oral administration of carprofen. In addition, three patients with acute hepatitis received a single 100‐mg dose during the acute phase of the disease, and two of these patients received the same dose after they had convalesced. The pharmacokinetic parameters and urinary excretion data did not differ significantly (P > 0.05) between patients with hepatic cirrhosis and healthy volunteers. The mean ± SD area under plasma concentration‐time curve and apparent oral plasma clearance values were 57.8 ± 11.7 μg × h/mL and 30.0 ± 6.3 mL/min, respectively, in patients and 52.4 ± 11.3 μg × h/mL and 33.1 ± 7.2 mh/min in normals. The respective harmonic mean elimination half‐lives were 10.5 and 9.4 hours. The 0–24 hour urinary recovery of intact drug and the glucuronide conjugate were 7.0 ± 4.9% and 28.9 ± 11.0%, respectively, in patients compared to 5.5 ± 7.1% and 20.1 ± 12.3% in normal subjects. The results of this study showed that liver dysfunction (hepatic cirrhosis) had no effect on the pharmacokinetic profile of carprofen. In the two patients with acute hepatitis who completed the study, the results suggest that the apparent oral clearance of carprofen may increase during the acute phase of the disease.
Rebound Insomnia and Elimination Half‐Life: Assessment of Individual Subject Response
Authors: Bixler Edward O. , Kales Joyce D. , Kales Anthony , Jacoby Judith A. , Soldatos Constantin R.
Published: March 2013

Following abrupt withdrawal of five benzodiazepine hypnotics, the presence of rebound insomnia on individual subject nights was evaluated in comparison to a placebo group. During the first three nights of withdrawal, the frequency of occurrence of rebound insomnia for drugs with relatively rapid rates of elimination (triazolam, midazolam, and lormetazepam) was significantly higher than that for the placebo control group. In contrast, the frequency of withdrawal sleep difficulty for two slowly eliminated hypnotics (flurazepam and quazepam) was similar to that of the placebo control group during each of five successive three‐night segments of a 15‐night withdrawal period. These findings, based on individual subject‐night data, confirm and extend previous reports using group mean values that demonstrate a frequent, immediate, and intense degree of rebound insomnia following abrupt withdrawal of relatively rapidly eliminated hypnotic drugs and an infrequent, delayed, and milder degree of sleep difficulty following withdrawal of slowly eliminated drugs.
Correlation of Plasma Levels of Nifedipine and Cardiovascular Effects After Sublingual Dosing in Normal Subjects
Authors: Traube Morris , Hongo Michio , McAllister R.G. , McCallum Richard W.
Published: March 2013

Only limited work has been reported about the relationships of cardiovascular effects and plasma concentrations of the calcium‐channel blocker nifedipine. In this study, placebo and nifedipine in 10−, 20−, 30−, and 40−mg doses were administered sublingually to ten normal subjects with at least three days between dosing periods. Blood pressure and heart rate were monitored every 30 minutes for two hours, and blood samples were taken after each measurement for determination of plasma nifedipine concentration by a sensitive and specific gas chromatographic method. Systolic blood pressure fell significantly (P < 0.05) although briefly after 10 mg, but the effect persisted with larger doses. Diastolic blood pressure fell significantly only after 30− or 40‐mg dosing. Heart rate increased significantly after all doses of nifedipine with the effect lasting longer with higher doses. Systolic blood pressure measurements were significantly related to the log of the concurrently measured plasma nifedipine concentrations (r = −.82, P < 0.001). Diastolic blood pressure was also related to log nifedipine concentration (r = −.69, P < 0.01). Heart rate, too, was linearly related to the log of nifedipine plasma levels (r = .75, P < 0.001). These data indicate that the hemodynamic effects observed after acute nifedipine administration may be used to estimate whether or not significant quantities of the drug are being absorbed and that the intensity of the hemodynamic effects may, therefore, serve as a bioassay to evaluate the appearance of drug in plasma in therapeutic quantities.
Comparison of Acebutolol and Propranolol Therapy for Ventricular Arrhythmias
Authors: Platia Edward V. , Berdoff Russell , Stone Gregg , Reid Philip R.
Published: March 2013

The effects of acebutolol, a new investigational cardioselective beta blocker, and propranolol on ventricular arrhythmias were compared in 14 patients with more than 30 premature ventricular contractions (PVCs) per hour. Each patient served as their own control, receiving both drugs and placebo in random sequence and in double‐blind fashion, with an intervening one‐week, drug‐free period. Each drug was given for a two‐month period, the maximum acebutolol dosage reaching 600 mg tid and the maximum propranolol dosage 80 mg tid. Seventy‐two‐hour ambulatory electrocardiographic monitoring assessed arrhythmia frequency for each study period. Mean PVC counts did not significantly differ during the two control periods. Acebutolol decreased mean PVC count by 65% (P < .02), with eight patients exhibiting a 70% or greater decrease. Only three patients exhibited a similar decline with propranolol. The incidence of PVCs was not significantly decreased by propranolol. Acebutolol reduced the number of couplets by 70% (P < .04), whereas propranolol did not significantly affect couplets. At the dosage of 600 mg tid, acebutolol was well tolerated, effectively suppressed total PVCs and couplets, and appeared to be more effective than propranolol administered at 80 mg tid.
Assessment of the Potential Pharmacokinetic Interaction Between Digoxin and Ethmozine
Authors: MacFarland R.T. , Moeller V.R. , Pieniaszek H.J. , Whitney C.C. , Marcus F.I.
Published: March 2013

The potential for a pharmacokinetic interaction between the investigational antiarrhythmic drug ethmozine (moricizine HCl, the generic name that is infrequently used in existing literature) and digoxin was evaluated in nine healthy male adults. Serum and urinary digoxin concentrations were measured by radioimmunoassay following intravenous digoxin administration before and during steady‐state ethmozine dosing. Plasma ethmozine levels following a single oral dose were measured before and after a single intravenous dose of digoxin. A mean elimination half‐life of 45.6 hours was determined for digoxin alone, compared to 43.1 hours in combination with ethmozine. Average values for digoxin systemic clearance, apparent volume of distribution, and renal clearance were 2.87 mL/min/kg, 11.3 L/kg, and 2.44 mL/min/kg, respectively for digoxin alone, compared to 3.01 mL/min/kg, 11.3 L/kg, and 2.64 mL/min/kg, respectively for digoxin with ethmozine. A mean half‐life of 2.0 hours was determined for ethmozine alone, compared with 1.8 hours following a single intravenous dose of digoxin. No change was observed in the oral pharmacokinetics of ethmozine following a single intravenous dose of digoxin, as indicated by the area under the plasma concentration versus time curve, Cmax or Tmax. These findings suggest that no pharmacokinetic interaction occurs when single intravenous doses of digoxin are co‐administered with multiple oral doses of ethmozine.
The Uricosuric Effect of Oxaprozin in Humans
Authors: Goldfarb Stanley , Walker Barry R. , Agus Zalman S.
Published: March 2013

The effects of oxaprozin, a new investigational propionic acid analogue, and indomethacin on uric acid metabolism were compared in 12 healthy volunteers receiving either agent, first as a single dose and then daily for seven days. While indomethacin did not alter either serum or urinary uric acid values, oxaprozin caused a fall in serum uric acid levels from 5.8 ± 0.2 mg/dL to 4.8 ± 0.4 mg/dL (P < 0.01). Urinary uric acid excretion rose from a baseline of 673 ± 47 mg to 825 ± 66 mg/24 h by day 7 of treatment (P < 0.01). Since oxaprozin was associated with no change in glomerular filtration rate in these studies, the hypouricemic effect of oxaprozin is most likely a result of its direct uricosuric action. Because indomethacin and oxaprozin both are inhibitors of urinary prostaglandin E2 excretion, the data suggest that prostaglandin inhibition per se is not associated with changes in uric acid excretion.
A Comparative Study of Captopril and Enalapril in Patients With Severe Hypertension
Authors: Chrysant Steven G. , Bal Iqbal Singh , Johnson Bruce , McPherson Mike
Published: March 2013

Twenty patients with moderate to severe essential hypertension were randomized in a paralleled, double‐blind, 22‐week study of captopril (ten) and enalapril (ten) following four weeks of hydrochlorothiazide (50 mg/d) baseline treatment. The captopril group was administered 25 mg tid and increased to 100 mg tid, while the enalapril group began with 5 mg bid and increased to 20 mg bid, depending on the patient's blood pressure (BP) response. Methyldopa, 250 mg to 500 mg bid and 1,000 mg bid, was administered to patients in both groups if BP was not adequately controlled. Patients were seen every two weeks for BP monitoring and metabolic evaluation. Each group showed a significant and equal decrease in BP, with the effect being the greatest on the diastolic pressure, supine and upright. Of the 20 patients, ten (four whites and six blacks) required methyldopa for adequate BP control. Four patients, two from each group, developed reversible prerenal azotemia (BUN [blood urea nitrogen] ⋍50 mg/dL). No other clinical or metabolic side effects were noted. We concluded that (1) captopril and enalapril were equally effective in lowering BP in the dosages given; (2) no racial differences in BP response were noted, although more black patients required the addition of methyldopa for adequate BP control; and (3) both drugs were safe and well tolerated.
The French Drug Approval Process II: The Clinical Basis for Negative Decisions by the Commission for Authorization of Marketing a Medication
Authors: Weintraub Michael
Published: March 2013

Between 1982 and 1983, the Commission on Approval for Marketing Medications of the French government made 76 negative decisions based on problems with clinical trials. In 21 instances, the reasons for a temporary negative decision could be resolved from data already on hand or readily available. More serious problems resulted in requests for new studies having better controls, better management of ancillary therapy, more participants, or lasting longer. Indications that denial of the application is likely or outright refusals to grant approval were based on failure to demonstrate efficacy and concerns about toxicity. Analysis of the reasons for negative decisions can ameliorate the clinical trials submitted in support of an application for marketing approval. Improving the design and conduct of clinical trials based on correcting the defects discussed here would benefit the sciences of drug development, regulation, and patient care.
Chemoprevention of Cancer: Implications for Clinical Pharmacology
Authors: Micozzi Marc S. , Boone Charles W. , Kelloff Gary J. , Tangrea Joseph A. , Helzlsouer Kathy J. , Taylor Philip R.
Published: March 2013

Cancer chemoprevention may be defined as the prevention of cancer in human populations by chemical agents that inhibit carcinogenesis. The concept of cancer chemoprevention is based on the cancer inhibitory potential of certain chemical compounds that may be considered as cancer chemopreventive agents. The characteristics of cancer chemopreventive agents that are relevant to human cancer prevention include their mechanisms of action, toxicity, and efficacy. A theoretic approach to selection of cancer chemopreventive agents for human clinical trials is presented. Since cancer chemopreventive agents currently used in clinical trials include micronutrients and their synthetic analogues, the cancer preventive activity of this class of agents is specifically reviewed.
Adverse Drug Reaction Monitoring in Kuwait (1981–1984)
Authors: Moussa Mohamed A. A. , Bayoumi Ahmed , Al‐Khars Abdulla A. , Thulesius Olav
Published: March 2013

The methodologic, operational, and medical aspects of general population spontaneous adverse drug reaction (ADR) monitoring system organized in the State of Kuwait between June 1981 to June 1984 are described. The objectives of the study were to outline the procedures required for the establishment of a national ADR center in addition to studying the pattern of ADRs. Ethnic and sociocultural variables were factors influencing the frequency of adverse effects. A computer data base was created to handle incoming reports. A total of 704 reports were received from 26 hospitals and health clinics; the majority (90.5%) were classified as having a possible positive causal relationship. Anti‐infectives were the most commonly reported drugs (32.2%), and cutaneous reactions were encountered most often (48.6%). Serious drug‐induced reactions have been identified. Intake of nifedipine adversely affected glucose tolerance among diabetic and nondiabetic subjects. Bromocriptine causal sexual dysfunction was reported among women. Cimetidine and ethambutol were associated with optic neuritis and blindness. Metoclopramide and prochlorperazine resulted in dystonic reactions in children. Based on this study, the health authorities in Kuwait indicated their intention to establish a national ADR center.
Plasma Concentration‐Response Relationships of Two Formulations of Propranolol
Authors: DeLeve Laurie D. , Endrenyi Laszlo , Leenen Frans H. H.
Published: March 2013

The time‐course of beta blockade induced by two formulations of propranolol was compared to their plasma concentration‐time curves. Graded infusions of isoproterenol were used to assess the degree of beta blockade at different times after oral administration of 80 mg of propranolol to 11 healthy volunteers. The time‐course of drug effect was measured as the decline of the systolic pressor dose 20 (SPD 20) and the chronotropic dose 20 (CD 20). Variability of plasma propranolol concentration was small, varying within subjects from 27% to 36% and between subjects from 19% to 28% at the various sampling times. Pharmacodynamic effects showed a similar reproducibility: intra‐individual variation was 15% to 28% for CD 20 and 17% to 32% for SPD 20; interindividual variation was 10% to 24% for CD 20 and 13% to 23% for SPD 20. Pooling of the data of all subjects indicated a parallel decline of drug concentration and effect. However, three of the 11 subjects showed drug effects declining at a faster rate than drug levels. This dissociation between serum concentrations and effects points out the clinical relevance of complementing kinetic studies of propranolol with pharmacodynamic studies. The good reproducibility within subjects and the small interindividual variation suggests that isoproterenol dose‐response curves may be a useful tool for such studies.
Cardiovascular Effects of Ketanserin, A New Antiserotonergic Agent in the Treatment of Arterial Hypertension
Authors: Ferrara L.A. , Fasano M.L. , Soro S. , Rubba P. , Iannuzzi A.
Published: March 2013

Ketanserin, an investigational, antiserotonergic agent, at a dose of 40 mg bid was given to 18 patients with mild to moderate primary hypertension in a randomized, double‐blind, crossover study, with 100‐mg metoprolol bid for four weeks each. The following parameters were evaluated: blood pressure, heart rate, cardiac workload (product of systolic blood pressure and heart rate during bicycle exercise), systolic time intervals, and peripheral blood flow (by strain‐gauge plethysmography). Significant reductions in diastolic and concomitant slight decreases in systolic blood pressure without changes in heart rate were observed during ketanserin treatment; cardiac oxygen demands during exercise test did not change, however. Pre‐ejection period and left ventricular ejection time were unchanged, while significant increase in rest flow to the lower limbs and decrease in peripheral resistance were demonstrated by strain‐gauge plethysmography. The results indicate that ketanserin has vasodilating properties and hypotensive activity that may be useful in the management of patients with essential hypertension.
Nifedipine in the Treatment of Hypertension in the Elderly
Authors: Stessman Jochanan , Leibel Bonnie , Yagil Yoram , Eliakim Rami , Ben‐Ishay Ori
Published: March 2013

The effect of nifedipine monotherapy, retard tablets, 20 mg bid, was evaluated in 23 hypertensive patients, mean age, 79 ± 2 years. Twenty‐one patients completed an eight‐week study. Blood pressure (BP) decreased to 160/90 mm Hg in 15 patients; in four additional patients diastolic BP dropped by 15% to 28%. In a subset of five patients with isolated systolic hypertension, a significant reduction in systolic BP was noted. Side effects were relatively mild and only two patients discontinued the study. The results suggest that nifedipine monotherapy offers an alternative, logic, therapeutic approach to hypertension in the elderly.