bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Estimation of Unbound Lidocaine Clearance in Cardiac Patients: Implications for Reducing Toxicity
Authors: Denson Donald D. , Toltzis Robert J. , Ernst Teresa F. , Youngs Charles H. , Thomas Robert L. , Grummich Karl W.
Published: March 2013

The clearance (CL), volume of distribution (Vd) and elimination half‐life (t1/2), based on unbound and total concentration‐time data, were estimated using two serum lidocaine concentrations drawn approximately 6 and 12 hours after the initiation of continuous intravenous lidocaine therapy in nine patients with myocardial infarction (MI) (in the immediate postinfarct period) and in 12 patients with ventricular arrhythmias. No significant intergroup differences were found for any of the parameters based on unbound or total lidocaine concentration‐time data. A significant (P < .01) correlation was found between measured unbound lidocaine and unbound lidocaine concentrations predicted using alpha‐1‐acid glycoprotein (AAGP) and total serum lidocaine concentrations. However, the predicted values were significantly lower than the measured values for both groups (P < .001). Significant correlations were found between total and unbound volumes of distribution and between total and unbound clearances. Coefficients of determination (r2) for these correlations were 0.6906 and 0.9178 respectively. The relationship between total and unbound clearance allows rapid estimation of unbound clearance from two total serum lidocaine concentrations. Unbound clearance can then be used to determine patient‐specific maximum infusion rates and reduce the risk of central nervous system toxicity from lidocaine.
The Effect of Methotrimeprazine on Arterial Blood Gases in Human Volunteers
Authors: Zsigmond Elemer K. , Flynn Kathleen
Published: March 2013

Since methotrimeprazine proved to be both an effective tranquilizer and analgesic, its effect in a tranquilizing dose of 0.15 mg/kg on the arterial blood gases was determined in human volunteers. Because of the known potentiating effect of some phenothiazines on the narcotic‐analgesic induced respiratory depression and analgesia, the effect of methotrimeprazine on the meperidine‐induced respiratory depression was also studied. Before, and at five minute intervals after the administration of the test drugs, PaO2, PaCO2 and pH were determined by a Radiometer Copenhagen Blood Gas Analyzer (Radiometer Copenhagen, 72 Endruvej, Denmark) through a Riley‐needle. Continuous ECG lead II tracings were taken during the experiment. No significant decrease in PaO2 or increase in PaCO2 (P < 0.01) was observed in 6 healthy volunteers (mean age = 25 yrs) after 0.15 mg/kg i.v. methotrimeprazine. In 19 volunteers (mean age = 32 yrs), the intravenous infusion of 1.5 mg/kg meperidine caused significant decrease in PaO2 and increase in PaCO2 five minutes after its administration. The combined administration of both drugs to 6 volunteers (mean age = 23 yr) caused initially the same decrease in PaO2 as after meperidine alone with subsequent increase in PaO2 over normal levels, however, the PaCO2 significantly increased both as compared to baseline values and as compared with meperidine alone. The pH reductions after the combination of both drugs were greater than after meperidine alone, which in combination with the PaCO2 values confirms the potentiation of meperidine‐induced respiratory depression by methotrimeprazine. The results indicate the methotrimeprazine alone causes no significant respiratory depression, but it potentiates the respiratory depression caused by meperidine.
Clinical Pharmacokinetics of Carboplatin
Authors: Oguri Shigeyuki , Sakakibara Tohru , Mase Hideshi , Shimizu Takayoshi , Ishikawa Kiyoyasu , Kimura Kiyoji , Smyth Robert D.
Published: March 2013

The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high‐performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein‐bound platinum and metabolites, declined triexponentially; plasma half‐lives (t1/2Λ1, 0.2 to 0.4 hr, t1/2Λ2, 1–3 to 1.7 hr; t1/2Λ3, 22 to 40 hr) and total body clearance (CLTB 2.8 ± 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterahle platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2Λ1, 0.50 hr; t1/2Λ2 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (U1/2–26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half‐life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first‐generation analog cisplatin.
Metronidazole Impairs Clearance of Phenytoin but Not of Alprazolam or Lorazepam
Authors: Blyden Gershwin T. , Scavone Joseph M. , Greenblatt David J.
Published: March 2013

Healthy volunteers received single doses of either phenytoin (300 mg IV), alprazolam (1 mg orally) or lorazepam (2 mg IV) on two occasions in random sequence. One of the two trials was a control; for the other trial, subjects ingested metronidazole, 250 mg three times daily beginning 4 days prior to and continuing for the duration of each kinetic study. Compared with control, metronidazole significantly prolonged phenytoin half‐life (23 versus 16 hours, P < .02) and reduced its clearance (.28 versus .33 mL/min/kg, P < .005), known to depend on aromatic hydroxylation. However, metronidazole did not significantly alter kinetic variables for either alprazolam (metabolized by aliphatic hydroxylation) or lorazepam (metabolized by glucuronide conjugation). Thus, metronidazole has the capacity to impair the clearance of certain oxidatively metabolized drugs, but there is no apparent way to predict which drugs will be so influenced.
Epoprostenol (Prostacyclin) in Unstable Angina
Authors: Lichstein Edgar , Mendizabal Rolando , Theroux Pierre , Muller Otto , Willerson James T. , Rapaport Elliot , Molk Barry L. , Linet Otto I.
Published: March 2013

The purpose of this randomized, double‐blind multicenter trial was to investigate the potential therapeutic effect of epoprostenol (prostacyclin, PGI2) in patients with unstable angina, as compared with placebo, and to investigate the safety of this agent. Of the 184 patients enrolled, 28 did not fit the study criteria; of the remaining 156 patients, 30 received prostacyclin in an open‐label fashion. In the double‐blind portion of the study, 63 patients each received prostacyclin or placebo. The drug or its vehicle was infused intravenously up to 5 ng/kg/min dose for 72 hours with a tapering off period for the last 12 hours. Both treatment groups from the double‐blind portion were comparable in regard to the demographic data, length of infusion, and total dose received. There were no significant differences between the placebo and prostacyclin group in the following clinical endpoints: levels of cardiac enzymes throughout hospitalization period (with the exception of lower SGOT level in the prostacyclin group at day 2), and severity of angina (throughout the study), and at the end of the study (day 30). The number of patients who had congestive heart failure, new myocardial infarction, balloon pump insertion, coronary artery bypass grafting, or percutaneous coronary angioplasty was similar in both groups. Similar results in regard to the efficacy endpoints were also apparent in the prostacyclin group that was treated under open‐label fashion. There was also no difference in the New York Heart Association (NYHA) functional status at the end of the double‐blind study. The overall incidence of adverse drug reactions was insignificantly higher in the prostacyclin patients as compared with the placebo ones. However, the portion of patients reporting headache, flushing, nausea, and vomiting was significantly higher in the drug group. There were no clinically significant differences between the treatment groups in safety laboratory evaluations (beginning to end of study). The lack of clinical benefit of prostacyclin may be explained by heterogeneous mechanisms of unstable angina, by multiple standard medications patients were exposed to, by PGl2 inability to prevent or lyse coronary thrombus at advanced stages of unstable angina, or simply by its pharmacologic ineffectiveness in this disease.
Interindividual and Intraindividual Variability in Labetalol Pharmacokinetics
Authors: Awni W. M. , Skaar D. J. , Schwenk M. H. , Sirgo M. A. , Plachetka J. R. , Matzke G. R.
Published: March 2013

The between‐subject and within‐subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7‐day washout separated each administration phase. Plasma concentration‐time data for labetalol were obtained over the 24‐hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high‐performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean Vβ/F, Vdss/F, TBC/F, t1/2β, and AUC0r for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 μg ṁ hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect “significant” differences in the disposition of labetalol.
Clinical Pharmacology of NSAIDs
Authors: Brater D. Craig
Published: March 2013

All nonsteroidal anti inflammatory drugs (NSAIDs) are characterized by a high degree of protein binding and small volumes of distribution. Differences in clearance account for the variability in half‐life among these drugs. The majority are metabolized by the liver through a variety of pathways. These drugs are subject to drug interactions of several mechanisms, including protein‐binding‐displacement interactions, induction or inhibition of hepatic drug metabolism, and competition for active renal tubular secretion with other organic acids. NSAIDs are also subject to special pharmacokinetic considerations about which a great deal has been learned recently. These include data demonstrating that assessment of disposition of these drugs using only total drug concentrations can be misleading and that one must instead assess the disposition of unbound, pharmacologically active drug. Second, it appears that only one enantiomer of the propionic acid NSAIDs is active; studies of the pharmacokinetics of this class of NSAID should include assessment of the active stereoisomer. Finally, the propionic acid NSAIDs are metabolized to acyl‐glucuronide conjugates, which are unstable and can cleave back to the parent drug. This feature allows the paradox of a drug that is metabolized by the liver being able to accumulate in patients who have renal insufficiency. Because of these newer pharmacokinetic considerations, much of the old data concerning the clinical pharmacology of NSAIDs are obsolete. More precise new information is needed in this area.
Effects of Tromethamine and Sodium Bicarbonate Buffers During Cardiac Resuscitation
Authors: von Planta Martin , Gudipati Chalipathirao , Weil Max Harry , Kraus Louis J. , Rackow Eric C.
Published: March 2013

The effects on cardiac resuscitability of iso‐osmolal solutions of tris‐hydroxymethyl‐aminomethane (tromethamine), sodium bicarbonate (NaHCO3) and sodium chloride placebo were compared in 30 domestic pigs using a well‐established model of electrically induced cardiac arrest and resuscitation. We hypothesized that a carbon dioxide (CO2) consuming buffer like tromethamine would reduce and sodium bicarbonate would increase the respiratory acidosis of mixed venous blood, which had recently been demonstrated in our laboratory. Tromethamine did decrease and sodium bicarbonate did increase both arterial and mixed venous CO2 during cardiopulmonary resuscitation (CPR). Both concentrations of end‐tidal CO2 and coronary venous Pco2 were significantly lower after tromethamine than after bicarbonate. However, tromethamine produced an unexpected vasodilator effect with reduction of mean aortic and coronary perfusion pressures to levels that are known to reduce resuscitability and survival independently of its buffer action. Neither resuscitability nor survival was altered by bicarbonate therapy in comparison with sodium chloride placebo.
Flunarizine‐Induced Parkinsonism in the Elderly
Authors: Benvenuti Francesco , Baroni Alberto , Bandinelli Stefania , Ferrucci Luigi , Corradetti Renato , Pantaleo Tito
Published: March 2013

Twenty‐seven patients (19 women and 8 men, ages 63 to 88 years; mean, 74 years) displayed mild to moderate parkinsonism and altered ballistic motor performances during long‐term flunarizine treatment. One month after, flunarizine withdrawal, 20 patients showed clear‐cut improvements in both clinical features and ballistic motor performances; a complete recovery within 6 months was observed in all these patients but one, who still showed very mild slowness of movement. On the other hand, seven patients showed little clinical improvement and still maintained markedly altered ballistic motor performances 1 month after drug withdrawal. At the 2‐month follow‐up assessments, either they did not improve further or they deteriorated; they were successfully treated with l‐dopa and, despite the ameliorations, after 12 to 24 months they still have definite parkinsonian syndrome. The authors conclude that (1) flunarizine, even at the recommended dose (10 mg daily), can induce reversible parkinsonism, at least in subjects older than 60; (2) the persistence of a marked symptomatology 2 months after flunarizine withdrawal should lead to starting treatment with antiparkinsoniam drugs; (3) the study of ballistic movements is proposed as a useful tool for objective quantisation and early detection of bradykinesia.
A Comparison of Carteolol and Nadolol in the Treatment of Stable Angina Pectoris
Authors: Luther Robert R. , Glassman Harriet N. , Jordan David C.
Published: March 2013

In a multicenter, dose‐ranging, double‐blind study, 63 patients diagnosed as having stable angina pectoris were randomly assigned to treatment with carteolol (33 patients) or nadolol (30 patients). Following a 2 to 4‐week dose‐ranging period, an optimal dose was determined for each patient and treatment with that dose continued for 6 weeks. Data from all 63 patients were analyzed for drug safety; data for 52 patients (27 carteolol and 25 nadolol) were analyzed for drug efficacy. The most commonly chosen dosage levels were 20 mg of carteolol and 80 mg of nadolol. There were no statistically significant differences between the carteolol and nadolol groups in changes in exercise tolerance as reflected by time to onset of angina, end‐point of exercise, and onset of 1 mm ST segment change on ECG. Both drugs significantly suppressed tachycardia and double product during treadmill exercise. The nadolol‐treated group demonstrated a significantly greater reduction in resting heart rate (18.7 bpm) as compared with the carteolol‐treated group (3.1 bpm). Carteolol possesses intrinsic sympathomimetic activity (ISA), which may account for the fact that carteolol effectively reduces exercise‐induced tachycardia while producing relatively little effect on resting heart rate. The frequency of anginal attacks and the use of sublingual nitroglycerin were reduced to a similar extent in both treatment groups. The most commonly reported side effect in both treatment groups was asthenia. Bradycardia occurring for the first time during double‐blind treatment was observed in 70% of the nadolol‐treated patients versus only 3% of the carteolol‐treated patients.
Absolute Bioavailability of Cefixime in Man
Authors: Faulkner R. D. , Fernandez P. , Lawrence G. , Sia L. L. , Falkowski A. J. , Weiss A. I. , Yacobi A. , Silber B. M.
Published: March 2013

In a four‐way cross‐over study, the absolute bioavailability of cefixime was determined in 16 healthy volunteers. Each subject received a single 200‐mg dose as an intravenous (IV) and oral solution, and 200‐mg and 400‐mg capsule doses of the drug. Blood and urine samples were collected for 24 hours after each dose. Cefixime was well tolerated after IV and oral doses of the drug and no serious drug‐related adverse effects were observed. The maximal serum concentration (Cmax) of cefixime following the 200‐mg oral solution and 200‐mg and 400‐mg capsule doses were 3.22, 2.92, and 4.84 μg/mL, respectively. Mean area under the serum concentration time curves (AUC) following the IV, 200‐mg oral solution, and 200‐mg and 400‐mg capsule doses were 47.0, 26.0, 23.6, and 39.4 μg'hr/mL, respectively. Mean elimination half‐life values of the drug were comparable after oral and IV doses, ranging from 3.2 to 3.5 hours. Based on serum AUC values, the absolute bioavailability of cefixime was 52.3%, 47.9%, and 40.2% after the 200‐mg oral solution, 200‐mg capsule and 400‐mg capsule doses, respectively. Respective ratios based on 24‐hour urinary recovery data were 44.7%, 41.7%, and 40.5%. Therefore, the results show that the percent of cefixime adsorbed after 200‐mg and 400‐mg oral doses was similar.
Potassium Homeostasis During Angiotensin‐Converting Enzyme Inhibition with Enalapril
Authors: Scandling John D. , Izzo Joseph L. , Pabico Rufino C. , McKenna Barbara A. , Radke Karen J. , Ornt Daniel B.
Published: March 2013

The effect of angiotensin‐converting enzyme (ACE) inhibition on renal and extrarenal potassium (K) regulation was examined. Six healthy men were studied in double‐blinded crossover fashion on placebo or enalapril, 80 mg/day. On day 4, the subjects were given an intravenous infusion of KCI and on day 5 an oral dose of 10% NH4Cl. Treatment with enalapril decreased plasma aldosterone and increased plasma renin activity (PRA), epinephrine and norepinephrine, but did not affect serum glucose, plasma insulin or basal plasma K. Maximal increases in plasma K during K infusion or NH4Cl ingestion were similar during enalapril and placebo treatment. With enalapril treatment urinary K excretion was unchanged following K loading but moderately reduced following NH4Cl loading. We conclude that ACE inhibition does not acutely impair K homeostasis in men with normal renal function.
Meptazinol and Morphine in Postoperative Pain Assessed with a New Method for Onset and Duration
Authors: Siegel C. , Sunshine A. , Richman H. , Olson N. Z. , Robissa N. , Cordone R. , Estrada N. , Laska E.
Published: March 2013

Meptazinol, m‐(3‐ethyl‐1‐methyl‐hexahydro‐1‐H‐azepin‐3‐yl) phenol hydrochloride is a centrally active opioid analgesic with a specificity for the mu‐1 receptor. It has been reported to lack many of the side effects commonly observed with morphine and morphinelike drugs in man. The objective of this study was to assess the analgesic efficacy and safety of meptazinol (50 mg and 100 mg) relative to morphine (5 mg and 10 mg) when administered intramuscularly for the treatment of postoperative pain, in addition, a new clinical method for measuring onset and duration and a statistical technique for evaluating the study data are presented. One hundred and seventeen patients were evaluated for 6 hours in G randomized double blind, single dose, parallel‐groups trial. Estimates of relative potency for hourly pain and relief parameters, and the summary variables sum of pain intensity differences (SPID) and total pain relief (TOTPAB) were performed. The estimate of relative potency of meptazinol to morphine for pain relief was 0.19 at ½ hour (i.e. 100 mg of meptazinol was approximately equivalent to 20 mg of morphine). Thereafter, there was a rapid decline of efficacy for meptazinol, with a relative potency estimate of 0.12 at 1 hour and 0.06 at 2 hours. The distribution functions for several time related events were estimated including time to onset, duration and time to remedication. The two drugs had approximately equal onset, but meptazinol had significantly shorter duration. More patients on meptazinol required remedication with a rescue analgesic and at an earlier time than patients on morphine. The incidence of adverse effects was highest for meptazinol 100 mg. In summary, the study showed that intramuscular meptazinol is an analgesic with onset of relief as rapid as that of morphine but with much shorter duration. Because of its short duration of effect, meptazinol at 50 mg may be considered a candidate for use in ambulatory surgical procedures if further studies show the drug is well tolerated at this dose.
Sulindac Kinetics and Effects on Renal Function and Prostaglandin Excretion in Renal Insufficiency
Authors: Klassen David K. , Stout Robert L. , Spilman Patricia S. , Whelton Andrew
Published: March 2013

The purpose of this study was to evaluate the pharmacokinetics of sulindac, a purported “renal sparing” nonsteroidal anti‐inflammatory drug, and its effects on renal function and prostaglandin excretion in patients with reduced glomerular filtration rate.

Twelve female patients (glomerular filtration rate 37 ± 4 mL/min) were treated with sulindac 200 mg bid for 11 days. Urinary PGE2, 6‐keto‐PGF1α and serum thromboxane (TxB2) generation were measured by radioimmunoassay (BIA) following extraction on C‐18 columns. Glomerular filtration rate and effective renal plasma flow were measured by 99TC‐DPTA and 131I‐para‐aminohippuric acid clearance. In six patients serum and urine levels of sulindac and its metabolites were measured by high‐pressure liquid chromatography (HPhC).

Sulindac was rapidly absorbed and converted to sulindac sulfide with peak levels 2 hours after a single dose, but steady state levels were not reached prior to drug discontinuation. Sulindac sulfide AUC (0–5 hours μg min/mL) progressively increased from 382 to 3,030 on day 11. It did not appear in the urine. Baseline urinary PGE2 and 6‐keto‐PGF1α excretion were 23.8 ± 5.6 and 18.9 ± 2.7 ng/hr respectively and were reduced by 68% and 47% by day 4 of therapy. TxB2 generation fell by 34% after one dose and by 67% by day 11. There was a significant increase in serum creatinine from 1.88 ± 0.13 mg/dl before treatment to 2.16 ± 0.15 mg/dL (P <.05) after eleven days. There was a significant (P < .001) decrease in effective renal plasma flow, 184.9 ± 16.3 mh/min before therapy vs 164.1 ± 17.0 mh/min on day 11 of therapy. Glomerular filtration rate (GFR) was significantly reduced following 4 days of therapy (P < .05: day 1 vs day 4) but by day 11 had returned to baseline.

We concluded that in this population the active sulindac sulfide metabolite accumulates systemically and can significantly inhibit renal prostaglandin metabolism as well as peripheral TxB2 generation and may effect renal function.
Chronopharmacokinetic Study of Valproic Acid in Man: Comparison of Oral and Rectal Administration
Authors: Yoshiyama Yuji , Nakano Shigeyuki , Ogawa Nobuya
Published: March 2013

Circadian stage‐dependent changes of valproic acid (VPA) kinetics was examined after rectal administration comparing after oral dosing. Eight healthy volunteers took a single oral or rectal dose of VPA 400 mg, in a form of sodium valproate, on two occasions, at 8:30 A.M. or 8:30 P.M. Subjects were synchronized with diurnal activity and nocturnal rest as their usual life under standardized meal conditions. After oral administration, mean total VPA concentrations in plasma were significantly higher in the morning than in the evening during the absorption phase. Cmax tended to be higher, tmax was shorter (P < 0.05) and absorption rate constant (ka) tended to be larger (0.05 < P < 0.1) for VPA in the morning than in the evening, although no difference was demonstrated in other pharmacokinetic values between morning and evening trials. After rectal administration, no significant difference was demonstrated in VPA kinetics between morning and evening trials. The rectal administration might have an advantage to eliminate the time‐dependent changes of VPA kinetics. Thus the current practice of giving a rectal dose seems to be justified because the time‐dependent changes in VPA kinetics observed after oral administration may be reduced without compromising therapeutic efficacy.
Sustained High‐Dose Nitroglycerin Transcutaneous Patch Therapy in Angina Pectoris: Evidence for Attenuation of Effect Over Time
Authors: Frishman William H. , Giles Thomas , Greenberg Steven , Heiman Mark , Raffidal Louise , Soberman Judith , Laifer Larry , Nadelmann Jeremy , Lazar Eliot , Strom Joel
Published: March 2013

The safety and efficacy of using continuous high‐dose transcutaneous nitroglycerin in doses up to 100 mg/24 hours in chronic stable angina was assessed in 20 patients using serial treadmill testing. Patients had first to show a response to sublingual nitroglycerin with a 20% improvement in exercise time. All patients were then titrated with 20 mg (40 cm2), 60 mg (120 cm2), 80 mg (160 cm2) or 100 mg (200 cm2) patches, until intolerable headache in association with a 10 mmHg reduction in blood pressure and a ten‐beat increment in heart rate. Drug was then discontinued for 2 days and patients underwent three repeat stress tests to reestablish a consistent drug‐free baseline. Patients were then randomized in double‐blind fashion to receive either active patch (N = 11) in previous titration dose or placebo patch (N = 9), with treadmill tests performed at 0 (1 hour after previous patch removal), 4, and 24 hours after patch application at baseline and at weeks 1 and 2. Venous blood was obtained for measurement of plasma nitroglycerin levels. After the first 24 hours of active patch therapy, there was a significant reduction in systolic blood pressure (P = .05), a significant increase in heart rate (P = .01), and a minor increase in exercise tolerance (P = .06) compared to placebo. At weeks 1 and 2, there was an attenuation of drug effect in all of these parameters. Plasma nitroglycerin levels demonstrated consistently high plasma levels over each 24‐hour dosing interval, on day 1, week 1, and week 2. Headache was the most common side effect, and with the 1‐hour treatment withdrawal there was no evidence of angina rebound. High‐dose continuous nitroglycerin patch therapy is well tolerated in patients, and there is some evidence of antianginal efficacy during the first 24 hours of therapy. However, despite the high plasma nitroglycerin drug levels seen with continued use of high‐dose therapy, there is an attenuation of hemodynamic and antianginal effects, suggesting the development of pharmacological tolerance.
Preliminary Observations of the Acute Effects of Selective Serum Thromboxane Inhibition and Angiotensin Converting Enzyme Inhibition on Blood Pressure and Renal Hemodynamics in Hypertensive Humans
Authors: Weir Matthew R. , Klassen David K. , Hoover Nancy , Douglas Frank L.
Published: March 2013

CGS 13080, a selective thromboxane synthetase inhibitor, was given intravenously (0.6 mg/kg over 6 hours) to eight hypertensive (diastolic 95–115 mm Hg) euvolemic caucasian females on their customary salt intake (24 hour urine Na: 142.9 ± 14.8 meq). No change occurred in blood pressure or glomerular filtration rate (GFR): 95.2 ± 7.2, control versus 95.0 ± 9.0, CGS 13080 (ml/min); or renal plasma flow (RPF): 363.2 ± 34.2, control, versus 373.2 ± 31.2, CGS 13080, (ml/min). Prostaglandin production was altered: platelet generation of thromboxane B2 83.3 ± 10.9, control, versus 5.4 ± 1.8, CGS 13080 (ng/hr) (P < .001); urinary prostaglandin E (PGE) 249.0 ± 56.3, control, versus 443.9 ± 79.8, CGS 13080 (ng/6 hr) (P = .06); urinary 6‐ketoprostaglandin F1a (6‐ketoPGF1a) 188.6 ± 23.4, control, versus 287.9 ± 21.8, CGS 13080 (ng/6 hr) (P = .01); urinary thromboxane B2 54.8 ± 12.9, control, versus 58.6 ± 20.3 CGS 13080 (ng/6 hr) (P = NS). Serum levels of renin, angiotensin II and aldosterone were not altered by CGS 13080. Captopril when dosed to lower diastolic blood pressure 5–7 mm Hg did not significantly affect GFR, RPF or RVR. Nor did it affect platelet generation of thromboxane B2 or urine concentrations of PGE, 6‐keto‐PGF1a or thromboxane B2. Captopril did increase renin levels 1.2 ± 0.2, control, versus 2.9 ± 1.1, captopril (ng/ml/hr) (P = NS), but did not statistically change angiotensin II, or aldosterone levels. To see if the angiotensin converting enzyme inhibitor, captopril, would unmask a hypotensive effect of CGS 13080, the same experiments were repeated with captopril being dosed for 2 weeks prior to treatment with CGS 13080. The blood pressure decrease seen with captopril was not augmented by CGS 13080. The two drugs when dosed together did not affect GFR or RPF, nor did they significantly affect urinary prostaglandin excretion. Our preliminary observations suggest that CGS 13080 as acutely dosed in this study inhibited serum thromboxane A2 production and increased vasodilator prostaglandins breakdown products in the urine (PGE, 6‐ketoPGF1a), yet did not augment the hypotensive effect of captopril.
Bronchial and Cardiovascular Effects of Ocular Topical B‐antagonists in Asthmatic Subjects: Comparison of Timolol, Carteolol, and Metipranolol
Authors: Jeunne C. L. Le , Hugues F. C. , Dufier J. L. , Munera Y. , Bringer L.
Published: March 2013

B antagonists eye drops are most effective for the treatment of chronic open angle glaucoma. By this way of administration they have a very good systemic bioavailability.

Bronchial, and cardiovascular effects of three of these topicals: timolol, carteolol and metipranolol have been evaluated in three parallel groups of asthmatic patients. The three topics induce bronchoconstriction without significant difference between them, and lower heart rate (sometimes very intensely) whatever the B antagonist studied.

From these data, it is recommended to practitioners to follow carefully the rules of administration of B blockers, even in eye drops.
Pharmacokinetic Equivalence of 5(ethyl(2H)5)‐ and Unlabelled Phenobarbitone
Authors: Benchekroun Y. , Ribon B. , Falconnet J. B. , Cherrah Y. , Brazier J. L.
Published: March 2013

The present study shows the absence of in vivo pharmacokinetic isotope effect on phenobarbitone (PB) C5‐ethyl deuteration (PBd5) following oral administration to man of equimolar PB/PBd5 mixtures (0.40 mmol each). Plasma PB and PBd5 (17 days) and urine PB, PBd5 and parahydroxy‐metabolites (PBOH, PBHOd5) levels were determined by GC‐MS. Isotope effect research includes comparison of pharmacokinetic parameters, study of time‐dependence of isotope ratios (IRs) in plasma and urine (linearity test), comparison of IRs between samples and administered mixtures (Mann Whitney's test) and comparison of PBOH/PBOHd5 ratios before and after urine enzymatic hydrolysis (Student's two tailed t‐test). No significant isotope effect was observed on pharmacokinetic parameters, PB hydroxylation or PBOH conjugation (x ≤ 5%); which the absence of pentadeuteration‐induced alteration in PB's HSA binding parameters (binding mode, Ka, N) corroborates (x ≤ 5%). These results establish bioequivalence of PB and PBd5; the latter can be used with benefit in stable‐isotope clinical pharmacology (steady state pharmacokinetics, drug interactions …) investigations as well as bioavailability studies of PB preparations.
Correction of Blood Drug Levels for Changes Over the Day
Authors: Swartz Conrad M.
Published: March 2013

A graph‐based method is presented to compensate for the influence of variations in drug dosage schedules and blood sampling times upon the blood concentrations of drugs whose elimination half‐life is between 7 and 48 hours. This method permits the clinician to interpret blood drug levels drawn at nonstandard times, and to correct blood drug levels for how the daily dose was divided. This method is expected to improve the convenience of monitoring blood drug levels.
Acetylator Phenotypes of Saudi Arabians by a Simplified Caffeine Metabolites Test
Authors: El‐Yazigi Adnan , Chaleby Kutaiba , Martin Cazemiro R.
Published: March 2013

The authors examined acetylator phenotypes of 296 Saudi subjects of Arabic origin by measuring the molar concentration ratio of two caffeine metabolites, 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU) and 1‐methylxanthine (1MX), using a simplified version of a previously reported high‐performance liquid chromatographic method. Spot urine samples were collected from the subjects who regularly drink coffee, tea, or other caffeinated beverages. The subjects were originally from different regions of Saudi Arabia but currently live primarily in the capital city of Riyadh. The day‐to‐day reproducibility of the molar concentration ratio of AFMU/1MX was established in 14 randomly selected subjects. These metabolites were stable in urine at 4° and −20°, but AFMU was unstable at room temperature (23°). The frequency distribution data indicate that 72.3% of the subjects are of slow acetylator phenotype.
Doxylamine and Diphenhydramine Pharmacokinetics in Women on Low‐Dose Estrogen Oral Contraceptives
Authors: Luna Becki G. , Scavone Joseph M. , Greenblatt David J.
Published: March 2013

Thirteen women chronically using low‐dose estrogen‐containing oral contraceptives (50 μg or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age‐matched drug‐free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen‐phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half‐life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half‐life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low‐dose estrogen‐containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.
Single‐ and Multiple‐Dose Pharmacokinetics of Ceftazidime in Infected Patients with Varying Degrees of Renal Function
Authors: Lin Min‐Shung , Wang Lee‐Shing , Huang Jin‐ding
Published: March 2013

To determine the single‐ and multiple‐dose ceftazidime kinetics, we administered ceftazidime, 2 gm intravenous bolus every 12 hours, to 14 infected Chinese patients with various degrees of renal function. Blood samples were drawn in serial after the first and 7th dose and serum ceftazidime concentrations were measured by high pressure liquid chromatography. Ceftazidime concentration‐time data were fitted to a two‐compartment model with a nonlinear regression program. Ceftazidime kinetics was unaltered by repeated dosing. Both total body clearance and elimination rate constant of ceftazidime decrease significantly in proportion to the creatinine clearance estimated by Bjornsson's method. Renal insufficiency did not modify the steady‐state volume of distribution (Vdss) of ceftazidime which, however, appeared to be larger than those reported previously. This larger Vdss may be explained by acute infection process, confinement to bed, and increased extracellular fluid volume as a result of hypoalbuminemia. Our study indicates the estimated creatinine clearance as a useful guide to ceftazidime dosage adjustment and also emphasizes the clinical relevance of conducting kinetic studies of antibiotics in infected patients.
Spironolactone Metabolism: Steady‐State Serum Levels of the Sulfur‐Containing Metabolites
Authors: Gardiner Peter , Schrode Kathy , Quinlan David , Martin Bernard K. , Boreham Donald R. , Rogers Maurice S. , Stubbs Katherine , Smith Margaret , Karim Aziz
Published: March 2013

Metabolism of spironolactone in man is extensive and complex. For many years the dethioacetylated metabolite, canrenone, was assumed to be the major metabolite. However, recent studies using specific high performance liquid chromatography (HPLC) have demonstrated the presence of spironolactone and the sulfur‐containing metabolites 7α‐thiomethylspirolactone (IV) and 6β‐hydroxy‐7α‐thiomethylspirolactone (V), in addition to canrenone, in the serum after a single oral dose of spironolactone. The importance of spironolactone and metabolites IV and V relative to canrenone at steady state remains unknown and was the subject of the present investigation. Twelve healthy males received 100 mg spironolactone, once daily, for 15 days. Repeated blood samples were taken on days 1, 8 and 15 for estimation of spironolactone and its metabolites. Peak serum levels [mean (SD)] of spironolactone, canrenone, and sulfur‐containing metabolites IV and V were 72 (45), 155 (43), 359 (106) and 101 (26) ng/ml, respectively on day 1 and 80 (20), 181 (39), 391 (118) and 125 (24) ng/ml, respectively on day 15. The AUC (0–24) values of these compounds on day 15 were 231 (50), 2173 (312), 2804 (777) and 1727 (367) ng·hr/ml, respectively and the post‐steady state elimination half‐life (t1/2) values were 1.4 (0.5), 16.5 (6.3), 13.8 (6.4), and 15.0 (4.0) hours, respectively. It was concluded that unmetabolized spironolactone is present in the serum and that the sulfur‐containing metabolite IV rather than canrenone is the major metabolite in serum following single or repeated doses of spironolactone.
Long‐term Efficacy and Toxicity of High‐ and Low‐Dose Amiodarone Regimens
Authors: Kerin Nicholas Z. , Aragon Eric , Faitel Kathy , Frumin Howard , Rubernfire Melvyn
Published: March 2013

Amiodarone is an effective antiarrhythmic drug for the control of potentially lethal and lethal ventricular arrhythmias (VA). In the United States, a high‐dose regimen has been used at the expense of a high toxicity profile for the control of lethal VAs. Significant antiarrhythmic efficacy has also been established with low‐dose regimens, which carry a low rate of intolerable side effects (5.4%) when compared with the high‐dose regimen (16.7%). The high incidence of tolerable and intolerable adverse side effects is probably related to high amiodarone loading (31.92 g) and maintenance doses (520 mg/d). In contrast, the low‐dose regimen uses much lower loading (7.2 g) and maintenance (280 mg/d) doses.
Effects of Food and Antacid on Oral Absorption of Misoprostol, A Synthetic Prostaglandin E1 Analog
Authors: Karim A. , Rozek L. F. , Smith M. E. , Kowalski K. G.
Published: March 2013

Misoprostol, a synthetic PGE1 analog with mucosal protective and antisecretory properties, is rapidly and essentially completely metabolized to its active metabolite, misoprostol acid. Relative to fasting conditions administration of misoprostol with antacid resulted in reduced bioavailability, as manifested by lower AUC(0–4) values from (mean ± SD; n = 12) 417 ± 135 to 349 ± 108 pg · hr/ml (P < 0.05), without significant changes in the rate of absorption (tmax = 14 ± 8 [fasting] vs. 20 ± 14 min [with antacid]). The observed Cmax values were also reduced (from 811 ± 317 to 689 ± 315 pg/ml), however, the difference was not statistically significant. Drug administration with a high‐fat content meal resulted in a marked slowing in the absorption rate without a substantial decrease in the extent. Relative to fasting conditions food decreased misoprostol acid Cmax from 811 ± 317 to 303 ± 176 pg/ml (P < 0.05) and increased tmax from 14 ± 8 to 64 ± 79 min (P < 0.05): the AUC changes remained statistically insignificant from 417 ± 135 to 373 ± 111 pg · hr/ml. Administration of misoprostol with food could potentially decrease the incidence of systemic side effects by reducing the early high peak plasma concentrations of misoprostol acid.
Isotretinoin Embryopathy—A Continuing Problem
Authors: Rappaport Elizabeth B. , Knapp Mary
Published: March 2013

First trimester exposure to isotretinoin is associated with an estimated 20% risk of major fetal malformations. Product labeling in force up to August 1988 included a statement that the drug is contraindicated in pregnancy and suggested procedures for prescribing physicians to follow to prevent inadvertent first trimester exposure to the product. This limited educational intervention did not prevent the continued occurrence of isotretinoin‐related birth defects. The effectiveness of recent changes in the package labeling in preventing such birth defects remains to he demonstrated. Two infants with major birth defects associated with first trimester exposure to isotretinoin (Accutane, Roche Laboratories**) were reported to the New Jersey Birth Defects Registry within 6 months. Stimulated by these reports, we sought additional cases in New Jersey and found three. We here describe these five cases of isotretinoin embryopathy, including available information on the circumstances which led to maternal use of isotretinoin during the first trimester of pregnancy. In response to a preliminary report of these cases1 and to investigations by epidemiologists at the U.S. Food and Drug Administration (FDA), the manufacturer altered the package labeling.2 The revised product information includes a more prominent “contraindication and warning” section and a new “patient information/consent” section. The effectiveness of this educational intervention should be evaluated.
New Therapeutic Modalities in Hypertension: Focus on a New Calcium Antagonist—Nicardipine
Authors: Frishman William H.
Published: March 2013

A new generation of dihydropyridine calcium antagonists which are related structurally to nifedipine is undergoing clinical investigation. Among these newer agents, nicardipine and nimodipine have become available for clinical use. In controlled trials, nicardipine is superior to placebo and equal to other antihypertensive agents for the treatment of systemic hypertension. Nicardipine is associated with a low incidence of adverse effects that are related primarily to its peripheral vasodilatory actions. In addition, nicardipine appears to have little if any negative effects on myocardial contractility or conduction.
Long Term Survival of Class IV Heart Failure Patients Treated with Oral Amrinone
Authors: Moran John F. , Rad Nancy , Scanlon Patrick J.
Published: March 2013

The purpose of this study was to evaluate the effect of amrinone on the survival of a group of 51 Class IV congestive heart failure patients as well as changes in exercise capacity, hemodynamics, and clinical status. In those 22 patients able to exercise before treatment with amrinone, exercise duration increased from 4.15 minutes to 6.58 minutes on the treadmill. In those 19 patients first treated with intravenous amrinone, there was an increase in cardiac index from 1.9 to 2.6 L/min/m2. Thirty seven patients (72%) died in the follow‐up period, most in the first four months. In this group of Class IV heart failure patients, there were two subsets of patients: one with a stable course (Group I) and one with a malignant course (Group II). The Group II patients accounted for much of the mortality in the follow‐up. Patients with coronary artery disease did worse than patients with idiopathic dilated cardiomyopathies. There was no evidence that amrinone shortened or prolonged the survival of these Class IV patients.
Interaction Between Propranolol and Propafenone in Healthy Volunteers
Authors: Kowey Peter Russell , Kirsten Edward B. , Fu Chau‐Hwei J. , Mason William D.
Published: March 2013

The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady‐state, were analyzed for propafenone and its two metabolites as well as for propranolol and 4‐hydroxypropranolol. Left ventricular function, exercise performance and electrocardiographic intervals were assessed. Coadministration of propranolol did not produce any significant change in propafenone kinetics including peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination rate constant (t1/2), mean steady‐state plasma concentration (Css), or area under the concentration vs time curves. However, concomitant propafenone administration significantly increased Cmax (83%), Tmax (55%), t1/2 (30%), and Css (213%) which were accompanied by significant decreases in plasma levels of 4‐hydroxy‐propranolol. Propafenone and propranolol significantly reduced supine systolic and diastolic blood pressure by 2.5 to 15.4%. The combination did not reduce diastolic blood pressure further (64.0 ± 2.8 to 59.7 ± 1.7 mmHg) nor did it produce a supplemental reduction in heart rate (12% reduction with propranolol, 10% reduction with concomitant administration). Propranolol, but not propafenone, significantly decreased end‐diastolic volume index (13%), stroke volume index (15%), and velocity of circumferential fiber shortening (19%). The combination did not cause any further changes in echocardiography measurements. Electrocardiographic intervals were not altered by either drug used alone or in combination. We conclude that the concomitant administration of propafenone and propranolol can produce marked increases in propranolol plasma levels with only modest enhancement of beta‐adrenergic blocking effects when administered to patients with preserved left ventricular function, and a normal conduction system.
Single and Multiple Dose Pharmacokinetic Evaluation of Flutamide in Normal Geriatric Volunteers
Authors: Radwanski Elaine , Perentesis George , Symchowicz Samson , Zampaglione Nicola
Published: March 2013

Single dose and steady‐state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady‐state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady‐state gave a distribution and elimination half‐life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half‐lives of HF at steady‐state were 1.9 and 9.6 hours, respectively. The steady‐state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.