bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐Dose Safety and Pharmacokinetics of a Potential Cognition‐Enhancing Compound, CL 275,838, in Healthy Volunteers
Authors: Caccia Silvio , Confalonieri Sergio , Guiso Giovanna , Lucca Ugo , Parma Edoardo , Guido Massimo , Tettamanti Mauro , Tiraboschi Pietro , Spagnoli Alberto
Published: March 2013

The pharmacokinetics and safety of CL 275,838, a potential cognition‐enhancing compound, were studied after single escalating oral doses first in young healthy male volunteers and then in old (60–74 years) and very old (over 75 years) volunteers of both sexes. In all age groups absorption of CL 275,838 was rapid as assessed by the mean time to reach maximum plasma concentrations (Cmax) which averaged 1–2 hr, regardless of the dose administered. In young male volunteers both Cmax and area under the curve (AUC) increased proportionally with dose from 10 to 100 mg. Mean elimination half‐lives (t1/2) of the parent compound (18–21 hr) and of its circulating metabolites II (20–22 hr) and IV (27–30 hr) were well comparable for the doses tested (50 and 100 mg). Age did not appreciably affect plasma Cmax of CL 275,838 or its two metabolites. Mean AUC and elimination half‐life did not appreciably differ between old and very old subjects given 50 mg CL 275,838, with the limitations dictated by the small number of elderly subjects examined. Compared with younger volunteers receiving comparable doses, however, the elderly had higher mean plasma AUC of the unchanged compound and its two metabolites, although the parameter varied widely between subjects. The mean elimination t1/2 (± SD) was longer in the elderly (38.8 ± 19.6, 50.5 ± 24.5 and 41.7 ± 12.1 hr, respectively, for the parent compound and its metabolites II and IV) than in the young subjects. The cause(s) of these variations and the possible clinical implications remain to be established. These preliminary findings showed that, after single oral doses, 1) CL 275,838 is rapidly absorbed, undergoes extensive biotransformation and forms active metabolites, as many lipophilic centrally acting drugs do; 2) it has linear kinetics, at least in young male volunteers in the range of oral aoses tested (10–100 mg) and 3) there may be some differences between its disposition in young and elderly subjects. No major side effects were detected up to doses of 50 mg in subjects aged 19 to 85 years, and up to 100 mg in young volunteers. Mild headache occurred in 13% and 5% after active treatment and placebo, respectively. A slight increase of alanine aminotransferase serum levels was reached in one subject given 50 mg of the test compound.
Steady‐State Pharmacokinetics of Theophylline in COPD Patients Treated With Dirithromycin
Authors: Bachmann Kenneth , Jauregui Luis , Sides Gregory , Sullivan Timothy J.
Published: March 2013

Steady‐state theophylline pharmacokinetic parameters were studied in a panel of 14 patients with chronic obstructive pulmonary disease (COPD). Pharmacokinetic parameters were evaluated before, during, and after a 10‐day regimen of the macrolide antibiotic, dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 am) to a sustained‐release theophylline dosing regimen (every 12 hours) elicited small changes in the steady‐state pharmacokinetics of theophylline, which were not statistically significant. Mean steady‐state plasma theophylline trough concentrations (Css,min) were invariant before, during, and after dirithromycin treatment. Mean average steady‐state plasma theophylline concentrations (Cav) declined by 7% during dirithromycin treatment (NS), and mean peak plasma concentrations (Css,max) declined by 12% (NS). Theophylline clearance (CL/F) also remained relatively unchanged during dirithromycin treatment exhibiting an increase of only 11% (NS). Dirithromycin treatment does not significantly affect the steady‐state pharmacokinetics of theophylline, and its use in COPD patients is not likely to modify treatment outcomes with theophylline.
Twenty‐four‐Hour Control of Gastric Acidity by Twice‐Daily Doses of Placebo, Nizatidine 150 mg, Nizatidine 300 mg, and Ranitidine 300 mg
Authors: Savarino Vincenzo , Mela Giuseppe Sandro , Zentilin Patrizia , Cutela Patrizia , Mele Raffaella , Celle Guido
Published: March 2013

This study was carried out to assess the effects on gastric acidity of placebo twice daily (bid), nizatidine 150 mg bid, nizatidine 300 mg bid, and ranitidine 300 mg bid by means of continuous 24‐hour intragastric pH monitoring. Twelve patients with duodenal ulcer in remission were randomized to receive in single‐blind fashion the above medications on four separate occasions, at least 1 week apart. The three active regimens produced higher pH values (P < .001) and maintained gastric pH above 3.0 units for a longer period (P < .001) than placebo in all time intervals but evening. Nizatidine 150 mg bid caused a lower rise in pH than nizatidine 300 mg bid (P < .01) and ranitidine 300 mg bid (P < .05) during both the daytime and the whole 24 hours. In these time windows also the time spent above 3.0 pH units was significantly shorter for the former regimen than for 300 mg bid of both nizatidine (P < .01) and ranitidine (P < .05). There was no difference between the latter two dosing schedules in terms of both potency and duration of action in all the time intervals considered. It is concluded that twice daily doses of H2 blockers are more effective than placebo in reducing gastric acidity. Three hundred milligrams twice daily of both nizatidine and ranitidine produce a significantly greater and longer‐lasting acid suppression than 150 mg bid of nizatidine. Our study also confirms the greater effectiveness of H2 antagonists during nighttime than during day‐time.
Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: II. Absolute Bioavailability of Intravenous Phenytoin Prodrug at Therapeutic Phenytoin Serum Concentrations Determined by Double‐Stable Isotope Technique
Authors: Browne T. R. , Szabo G. K. , McEntegart C. , Evans J. E. , Evans B. A. , Miceli J. J. , Quon C. , Dougherty C. L. , Kres J. , Davoudi H.
Published: March 2013

Measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of Phenytoin prodrug (PPD) at therapeutic PHT serum concentrations is complicated by two problems: 1) the area under the serum concentration versus time curve (AUC) produced by a given size of test dose will vary directly with background PHT serum concentration due to the nonlinear pharmacokinetic properties of PHT; 2) PPD is more water soluble than PHT, making renal excretion of PPD more likely. The authors describe a double‐stable isotope method that obviates these two problems. Using only six subjects, the authors were able to demonstrate bioequivalence of PHT derived from intravenous PPD with intravenous PHT by current FDA standards for AUC ratio of test/reference formulation (90% confidence intervals between 0.80 and 1.20; ratio ⋝ 0.80 in ⋝ 80% of subjects; statistical power to detect a difference of 0.20 with a probability of 0.80).
Tangential Symbols: Using Visual Symbolization to Teach Pharmacological Principles of Drug Addiction to International Audiences
Authors: Giannini A. James
Published: March 2013

Visual art was used to teach the biopsychiatric model of addiction to audiences in the Caribbean, Europe and Mideast. Art slides were tangentially linked to slides of pharmacological data. Stylistically dense art was processed by the intuitive right brain while spare notational pharmacological data was processed by the intellectual (rationalistic) left brain. Simultaneous presentation of these data enhanced attention and retention. This teaching paradigm was based on the nonliterate methods developed by Medieval architects and refined by Italian Renaissance philosopher, Marsilio Ficino.
Drug Design with a New Type of Molecular Modeling Based on Stereochemical Complementarity to Gene Structure
Authors: Hendry Lawrence B.
Published: March 2013

Why certain chemical structures and not others are present in nature has been a recurring question raised by scientists since the first organic natural products were characterized. Of equal interest has been elucidating what structural features within any given class of organic molecules are responsible for biological activity. Historically, the lack of satisfactory answers to both questions has relegated the development of biologically active molecules either to serendipity or to exhaustive synthesis and biological testing of large numbers of compounds. This frustration is particularly evident in the pharmaceutical industry where the development of drug agonists and antagonists is often time consuming, tedious and expensive. Fortunately, this picture is beginning to change as more information is derived from modern molecular modeling techniques including characterization of the active sites in enzymes and the ligand binding sites in receptors. Over the past 15 years another approach has emerged based upon a series of discoveries made in our laboratories with molecular models. Namely, many biologically active small molecules have been found to possess complementary stereochemical relationships with gene structure. These relationships have proven useful in understanding constraints imposed by nature on the structures of small molecules and in correlating structure with activity among certain classes of compounds. Recently, computer graphics and energy calculations have confirmed salient observations lending credence to what promises to be a powerful and rapidly evolving technology for designing new safe and effective drugs.
A Controlled Comparison of Continuous Ranitidine and Intermittent Famotidine Infusions on Gastric pH
Authors: Bachmann Kenneth , Sullivan Timothy J. , Jauregui Luis
Published: March 2013

Continuous infusions of any given H2‐blocking drug have uniformly been found to be superior to intermittent infusions of the same H2‐blocking drug in sustaining elevations in gastric pH. Comparisons of intermittent and continuous infusions among different H2‐blocking drugs have heretofore not been made. Owing to its greater potency and longer half‐life, the authors were interested in determining whether intermittent infusions of famotidine might be as effective as continuous infusions of ranitidine in sustaining elevations of gastric pH. The effectiveness of a continuous intravenous infusion of ranitidine (6.25 mg/hr) was compared with the effectiveness of intermittent intravenous infusions of famotidine (20 mg every 12 hours) in sustaining gastric pH above 4.0 in 18 young, healthy adult male subjects using a randomized two‐way cross‐over design. Gastric pH was continuously monitored for 24 hours. The intermittent famotidine regimen was determined to be as effective as the continuous ranitidine regimen with respect to the following parameters: (1) the percentage of the 24‐hour dosing period during which gastric pH exceeded 4.0; (2) the area under the pH ≥ 4 versus time curve; and (3) median gastric pH.
Effects of Diltiazem and Cimetidine on Theophylline Oxidative Metabolism
Authors: Ohashi Kyoichi , Sakamoto Kouichi , Sudo Toshiaki , Tateishi Tomonori , Fujimura Akio , Shiga Tsuyoshi , Ebihara Akio
Published: March 2013

The effect of diltiazem or cimetidine pretreatment on the inhibition of theophylline oxidative metabolism was investigated in nine healthy male nonsmokers. Diltiazem 60 mg, cimetidine 400 mg, or placebo was given orally three times daily for 3 days in a randomized three‐way crossover manner. Both diltiazem and cimetidine pretreatment decreased the mean theophylline clearance (0.702 on placebo versus 0.641 on diltiazem, P < .05, and 0.542 mL/minute/kg on cimetidine, P < .01), resulting in prolonged mean theophylline half‐life (7.56 on placebo versus 8.59 on diltiazem, P < .05, and 10.08 hours on cimetidine, P < .01) with no change in volume of distribution. The mean metabolic clearances for three major theophylline metabolites, 1‐methyluric acid (1‐MU), 1,3‐dimethyluric acid (1,3‐DMU), and 3‐methlxanthine (3‐MX), were reduced significantly by cimetidine (28%; P < .05, 32%; P < .01, and 33%; P < .01, respectively). Conversely, diltiazem significantly reduced only the mean metabolic clearance of 1,3‐DMU by 21% (P < .05) without changes in that of 1‐MU or 3‐MX. These results suggest that cimetidine inhibited both N‐demethylation and 8‐hydroxylation of theophylline, whereas diltiazem exerted little influence on N‐demethylation in spite of inhibition in 8‐hydroxylation.
The Effect of Stress on Glycemic Control in Patients with Type II Diabetes During Glyburide and Glipizide Therapy
Authors: Jaber Linda A. , Lewis Nancy J. W. , Slaughter Richard L. , Neale Ann Victoria
Published: March 2013

Stress adversely affects glycemic control in patients with type II diabetes mellitus. In addition, stress reduction with relaxation techniques or medication use in the management of hyperglycemia has been recommended. This study examined the relationship of glycemic control to self‐reported stress in 19 patients with type II diabetes mellitus who were randomly allocated to receive either glyburide or glipizide for 16 weeks in a double‐blind crossover design. Each treatment phase was preceded by a 2‐week washout period. A previously designed and validated nine‐item stress questionnaire was used to assess areas such as safety, financial wellbeing, energy level, health, etc. These areas were evaluated as more/less, better/worse, or no change. The stress questionnaire, fasting blood glucose (FBG), and glycosylated hemoglobin (GHb) concentrations were completed or measured at the end of glyburide and glipizide treatment periods. By assigning a value of 1, 2, or 3 to a positive, no change, or negative response, respectively, a composite stress score was computed and compared with glycemic control as assessed by FBG and GHb. Regression analysis showed highly significant correlations (P < .05) between stress scores and FBG (r = .70) as well as GHb (r = 0.84) with glipizide therapy. No such correlation was noted with glyburide (FBG: r = 0.29; GHb: r = 0.29). These findings suggest that during glyburide treatment, in contrast to glipizide, an increase in stress was not associated with a corresponding rise in blood glucose or worsening of metabolic control. In view of the clinical relevance of this glyburide “blunting” effect on stress‐induced hyperglycemia, further investigations measuring circulating catecholamines and cortisol concentrations are required to confirm this ending and to characterize the underlying mechanism.
Risk Factors Not Addressed in Antihypertensive Therapy Based Solely on Blood Pressure Control
Authors: Somberg John , Ehrenpreis Seymour , Shroff Girish , Khosla Sandeep
Published: March 2013

There has been a considerable revolution in the field of hypertension therapy. We have gone through an era in which patients with severe hypertension and those with accelerated hypertension had a very short life expectancy. Currently blood pressure can be readily controlled with a marked improvement in longevity. We have gone from an era in which stroke was common due to hypertensive cardiovascular disease to an era in which patients are effectively treated and there has been a marked reduction in the incidence of stroke. The challenge is whether we can reduce the very high mortality due to coronary artery disease in patients with hypertension as we have done with stroke. New groups of drugs that may have a more favorable effect on metabolic and hemodynamic risk considerations have been developed over the last decade. These agents may reduce the risk for coronary heart disease to a greater extent than previously employed therapy. While there are no randomized placebo‐controlled studies demonstration this, a theoretical basis does exist to give the physician reason to think about prioritizing therapies and tailoring them to the needs of the individual patient.
Hemofiltrability of Histamine H2‐Receptor Antagonist, Nizatidine, and its Metabolites in Patients with Renal Failure
Authors: Saima Shigeki , Echizen Hirotoshi , Yoshimoto Keiko , Ishizaki Takashi
Published: March 2013

To study if an H2‐receptor antagonist, nizatidine, and its metabolites [N‐2‐monodesmethylnizatidine (N‐2‐MDMN) and nizatidine sulfoxide (nizatidine S‐Ox)] would be removed by an arteriovenous hemofiltration, the authors measured their plasma concentrations and amounts recovered in ultrafiltrate during 11 sessions of an intermittent hemofiltration performed in seven patients with renal failure who were given an oral administration of nizatidine (150 mg). The concentrations of the parent drug and its metabolites in plasma and ultrafiltrate were determined with a high‐performance liquid chromatography with ultraviolet absorbance detection. The mean (± standard deviation [SD]) amounts of nizatidine removed by the procedure performed at the mean ultrafiltration rate of 18 (range, 11–25) mL/min over the mean duration of 179 (60 to 300) minutes accounted for 1.9 ± 1.4% of the dose administered. The corresponding values for N‐2‐MDMN and nizatidine S‐Ox were 0.3 ± 0.2% and 0.2 ± 0.2% of the molar dose of nizatidine, respectively. There was a significant correlation between the filtration rate and the hemofiltration clearance of nizatidine (r = .94, P < .001) or its active metabolite, N‐2‐MDMN (r = 0.83, P < .01), indicating that the sieving coefficient (Sc), an index of filtration efficiency, for these compounds is largely constant (0.59 and 0.67 for nizatidine and N‐2‐MDMN, respectively) under the current hemofiltration conditions. Assuming that the respective Sc values for the compounds observed in the current study could be extrapolated into a 24‐hour continuous arteriovenous hemofiltration performed at a commonly used filtration rate (i.e., 6–12 mL/min), the 24‐hour hemofiltration clearances of both nizatidine and N‐2‐MDMN would be less than 10 mL/minute. The hemofiltration clearance value for nizatidine corresponded to, at most, 5% of the mean plasma clearance reported from patients with renal failure (about 140 mL/min). Based on the current data coupled with the above‐described theoretical extrapolation, the authors recommend that no supplemental doses of nizatidine be required for patients with renal failure during or after such an intermittent hemofiltration as performed in the current study.
Effect of Concomitantly Administered Cimetidine or Ranitidine on the Pharmacokinetics of the 5‐HT2‐Receptor Antagonist Ritanserin
Authors: Trenk Dietmar , Seiler Klaus‐Ulrich , Buschmann Monika , Szathmary Stefan , Benn Hans‐Peter , Jähnchen Eberhard
Published: March 2013

The effects of concurrent administration of either cimetidine 800 mg once daily or ranitidine 300 mg once daily on the single‐dose pharmacokinetics of ritanserin 10 mg were investigated in an open, randomized three‐way cross‐over, controlled investigation in 9 healthy volunteers. Concurrent administration of cimetidine had no significant effect on the area under the plasma concentration‐time curve of ritanserin compared with control experiments. The maximum plasma concentration of ritanserin was decreased significantly (105.0 ± 9.2 versus 125.0 ± 13.8 ng/mL; P = .0039), whereas time to reach maximal concentration (tmax) of ritanserin was only slightly but not significantly increased, if the subjects were pretreated with cimetidine. After concurrent ingestion of ranitidine, only a trend to a decrease in the maximum plasma concentration of ritanserin was observed. Time to achieve the maximum plasma concentration, terminal half‐life of elimination, and the total area under the plasma concentration‐time curve of ritanserin were not altered in comparison with control experiments. The results of the study show that concurrent treatment with cimetidine 800 mg once daily or ranitidine 300 mg once daily has no apparent effect on the systemically available amount of ritanserin after a single oral dose of 10 mg. Both H2‐antagonists cause a significant (cimetidine) or borderline significant (ranitidine} decrease of the maximum plasma concentration of ritanserin and a slight but not significant increase in tmax (cimetidine). These effects are of minor clinical importance and seem most likely be due to a decrease of the rate of absorption of ritanserin during concurrent administration of cimetidine/ranitidine.
Antihypertensive Action of Heparin: Role of the Renin‐Angiotensin Aldosterone System and Prostaglandins
Authors: Susie D. , Mandal A. K. , Jovovic D. , Stojanov M. , Djordjevic‐Denic G. , Kentera D.
Published: March 2013

Chronic subcutaneous administration of heparin consistently lowers blood pressure in hypertensive rats. This antihypertensive effect is related at least in part to a concomitant decrease in hematocrit. Groups of spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats were treated with subcutaneous heparin (700 U/d) for 6 weeks. Weekly determinations of systolic blood pressure (tail‐cuff) and hematocrit were done. Peripheral plasma renin activity, plasma aldosterone, plasma prostaglandins (PGs) (PGF2alpha, PGI2), thromboxane A2, and urinary kallikrein were measured. Blood pressure responses of acute and chronic heparin treatment to vasoconstrictor substances, including angiotensin I, angiotensin II, and norepinephrine, were determined. As before, heparin produced a significant (P < .01) decrease in hematocrit in both SHRs and NWRs, but a parallel decrease in blood pressure was noted only in SHRs. A significant (P < .001) increase in plasma renin activity was found in heparin‐treated SHRs and NWRs; however, a corresponding elevation of plasma aldosterone level was noted only in heparin‐treated NWR. Plasma aldosterone level significantly (P < .01) decreased in heparin‐treated SHRs. Plasma PGs and urinary kallikrein levels were not different among the groups. The blood pressure responses to vasoconstrictor substances were essentially similar among the heparin‐treated and control groups. These findings suggest that PGs or kallikrein have a slight or no role in determining the antihypertensive effect of heparin. Conversely, the results suggest that a reduced aldosterone level contributes to the antihypertensive mechanism of heparin.
Short‐ and Long‐Term Effects of Spirapril on Renal Hemodynamics in Patients with Essential Hypertension
Authors: Reams Garry P. , Lau Alisa , Knaus Vicki , Bauer John H.
Published: March 2013

Sixteen essential hypertensive patients were entered into a protocol assessing the effect of Spirapril, an angiotensin‐converting enzyme (ACE) inhibitor, on blood pressure, the renin‐aldosterone system, and renal function. Specifically monitored before, during 6 weeks, and 6 months of Spirapril therapy were plasma renin activity, plasma aldosterone, serum ACE, the renal clearances of creatinine, inulin, and para‐aminohippurate, and urinary albumin excretion. Blood pressure was well controlled. Spirapril stimulated plasma renin activity and suppressed ACE throughout the entire protocol. Renal clearances were unchanged. Renal vascular resistance was decreased. Urinary albumin excretion was decreased. The authors conclude that the ACE inhibitor, Spirapril, when used as an effective antihypertensive agent, preserves renal function, lowers renal vascular resistance, and decreases urinary albumin excretion.
Hypoglycemic and Insulin Response to a Continuous Intravenous Infusion of CGP‐35126 Recombinant Human Insulin‐Like Growth Factor‐I (rhIGF‐I) in Healthy Males
Authors: Morgan John M. , Saris Steven D. , Capuzzi David M. , Good William R. , John Vivian A. , Guler Hans‐Peter , Seaman John , Piraino Anthony J.
Published: March 2013

Recombinant human insulin‐like growth factor‐I (rhIGF‐I) produced by expression in a yeast vector was evaluated in seven normal men to determine effects on plasma glucose and insulin levels. Each subject received an initial intravenous infusion of normal saline and on the following day, rhIGF‐I at a rate of 21.4 μg/kg/hour. Each infusion lasted for 7 hours. The subjects' fasting baseline glucose and insulin levels were not statistically different (P > .05) from their pre‐dose levels. Compared with the saline (control) infusion, serum glucose levels were statistically lower (P < .05) 2 hours into the rhIGF‐I infusion. These lower glucose levels were maintained until the subjects consumed a standard lunch (4 hours into the infusion). Insulin levels demonstrated a similar response to rhIGF‐I, but decreases in insulin levels occurred after the rhIGF‐I hypoglycemic effect. This observation suggests that suppression of insulin levels may be due to secondary hypoglycemia rather than to a direct rhIGF‐I effect. This study demonstrated the desired rhIGF‐I effect of lowering subjects' glucose levels without clinically significant hypoglycemia. This finding suggests that rhIGF‐I may have potential clinical utility in hyperglycemic states.
A Phase I Dose‐Ranging Safety and Pharmacokinetics Study of a Novel Oral Thromboxane Synthase Inhibitor, FCE 22, 178
Authors: Li Ronald C. , Narang Prem K. , Lewis Richard C. , Hatfield Naomi Z. , Rossi David T. , Colborn David C.
Published: March 2013

A 100‐ to 3200‐mg dose range of FCE 22,178 was studied in this phase I single‐dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half‐life of FCE 22, 178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0‐∞) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100‐ to 400‐mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, Λs/F) for FCE 22, 178 increased from 0.75 L/kg at the 100‐mg dose to 3.00 L/kg at the 3200‐mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22, 178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200‐mg dose. The disposition of M1 appeared to be formation‐rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug‐related adverse experiences were observed over the studied dose range after single doses at FCE 22, 178.
A Relationship Between Blood Pressure Control, Hematocrit Level, and Renal Function in Treated Essential Hypertension
Authors: Mandal Anil K. , Markert Ronald J. , Bell Richard D.
Published: March 2013

The effect of rigid blood pressure control on renal function is an unsettled issue. This study describes a retrospective analysis on the relationships between blood pressure control, hematocrit levels, and renal function in 97 treated hypertensive patients. Data analysis was done on systolic and diastolic blood pressure, hematocrit levels, renal function assessed by serum urea nitrogen (SUN), serum creatinine (Scr), and hydrochlorothiazide (HCTZ) dose at entry and at four anniversary dates thereafter. The patients were divided into two groups: group I and group II on the basis of HCTZ dose. Group I received an average of 100 mg HCTZ daily, whereas group II received an average of 50 mg HCTZ daily. In group I, the decrement in both systolic and diastolic blood pressure over time was highly significant (P < .0001); however, no change in renal function was noted. In group II, systolic blood pressure decreased significantly (P < .01) from entry to year 1, then leveled off. In year 4, systolic blood pressure was not different from that of entry. Conversely, the difference between entry and year 4 diastolic blood pressure was highly significant (P < .0001). In group II, significant decreases were noted between entry and year 4, SUN (16.5 ± 5.7 versus 14.9 ± 4.1 mg/dL; P < .0012) and Scr (1.29 ± .23 versus 1.24 ± .19 mg/dL; P < .0192). Hematocrit showed diverse responses; in group I, hematocrit significantly increased from entry to year 4 (44.8 ± 2.5 versus 47.2 ± 3.9%; P < .01); whereas, in group II, hematocrit significantly decreased (47.7 ± 3.8 versus 44.9 ± 3.4%; P < .001). A separate analysis between blacks and whites showed that black patients did better with high‐dose (very high dose according to current concept) of HCTZ in both blood pressure and renal function controls, whereas white subjects tend to do better with low‐dose (high dose according to current concepts) of HCTZ. This study concludes that high‐dose (or very high dose) HCTZ is beneficial for black hypertensives, however, low‐dose (or high‐dose) HCTZ appears to be universally beneficial.
Single and Multiple Oral Dose Pharmacokinetics of Clentiazem in Normal Volunteers
Authors: Bhargava Vijay O. , Shah Ajit K. , Weir Scott J. , Nordbrock Earl E. , Giesing Dennis H.
Published: March 2013

This study was designed to determine the pharmacokinetics and dose proportionality of clentiazem (CLZ) after single doses (SD) of 20, 40, and 80 mg and multiple dose administration (SS) of 40, 80, and 160 mg/day for 5 days. The study was an open‐label, randomized four‐period complete crossover design. Twenty‐four healthy male volunteers participated in the study, and blood samples were drawn over 48 hours after both SD and SS. Plasma samples were analyzed for CLZ and three metabolites by high‐pressure liquid chromatography. After SD, the area under the plasma concentration‐time curve (AUC0‐∞) and maximum concentration (Cmax) increased disproportionately with the increase in dose. At steady‐state, a twofold increase in dose (20 to 40 mg twice daily and 40 to 80 mg twice daily) resulted in an increase in AUCss of 2.14‐ and 2.51‐fold, respectively. Oral clearance of CLZ decreased (203.8 L/h at 40 mg/d to 140.2 L/h at 160 mg/d) and bioavailability increased (0.35 at 40 mg/d to 0.50 at 160 mg/d) with increasing doses. The terminal half‐life of CLZ remained unchanged with increasing doses (13.7–15.5 hours). The ratios of AUCss to AUC0‐∞ at SD ranged from 1.13 to 1.27, indicating no significant accumulation of CLZ (P > .05). The AUC ratio of N‐desmethyl CLZ to that of CLZ remained constant after SD. On SS, however, there was a small decrease in this ratio with increasing dose (0.77 at 40 mg/d to 0.61 at 160 mg/d). These results indicate that the degree of nonlinearity observed with CLZ pharmacokinetics may largely be due to saturable first‐pass metabolism.
Effects of Hypoxia on the Use‐Dependent Inhibition of Conduction Velocity Induced by Cibenzoline in Guinea Pig Ventricular Myocardium
Authors: Hasegawa Junichi , Watanabe Masashi , Kaneda Takafumi , Osaki Shuichi , Hisatome Ichiro , Kotake Hiroshi , Mashiba Hiroto
Published: March 2013

The use‐dependent effects of cibenzoline, a new anti‐arrhythmic drug, on the maximal rate of rise (V̇max) of the action potential and on conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea pigs under normal and hypoxic conditions. Standard microelectrode techniques were applied to monitor the action potential of the muscles and their conduction. Under control conditions, the amount of use‐dependent block of V̇max, conduction velocity, and square of conduction velocity, induced by 10 μmol/L cibenzoline were 26.5 ± 3.9, 13.8 ± 1.4, and 25.6 ± 2.4%, respectively; under hypoxic conditions, these values increased to 32.3 ± 4.8, 19.7 ± 1.2, and 35.5 ± 2.0%, respectively. In the presence of 10 μmol/L cibenzoline, the mean values of time constants for the onset of the use‐dependent inhibition of V̇max, conduction velocity, and the square of conduction velocity, during a 2‐Hz stimulation, were 3.65 ± 0.27, 2.77 ± 0.33, and 2.56 ± 0.26 seconds, respectively. Under hypoxic conditions, these values changed to 5.10 ± 0.96, 3.05 ± 0.44, and 2.84 ± 0.39 seconds, respectively. The recovery time constants averaged 14.72 ± 4.08 seconds (for V̇max), 22.23 ± 3.78 seconds (for conduction velocity), and 23.17 ± 13.38 seconds (for the square of conduction velocity) in the presence of 10 μmol/L cibenzoline, and 17.19 ± 8.59 seconds (for V̇max), 15.77 ± 2.37 seconds (for conduction velocity), and 16.82 ± 2.61 seconds (for the square of conduction velocity) under hypoxic conditions. These results showed that the characteristics of the use‐dependent inhibition of V̇max and conduction velocity induced by cibenzoline are similar to those of the intermediate (slow) kinetic drugs, and that the amount of the use‐dependent block increases under hypoxic conditions, whereas the time constants of onset and recovery from the use‐dependent block show little change (not significant).
Psychomotor and Memory Effects of Two Adinazolam Formulations Assessed by a Computerized Neuropsychological Test Battery
Authors: Fleishaker Joseph C. , Sisson Theresa A. , Sramek John J. , Conrad Julie , Verof Amy E. , Cutler Neal R.
Published: March 2013

The memory effects of adinazolam were assessed using the computerized neuropsychological test battery (CNTB). In a single‐blind crossover study, 12 volunteers received 2 × 20 mg adinazolam mesylate immediate‐release (CT) tablets, 2 × 30 mg sustained‐release (SR) tablets, and placebo. Plasma adinazolam and N‐desmethyladinozolam (NDMAD) were determined by high‐pressure liquid chromatography. Choice reaction time and word‐list‐learning/delayed‐recall CNTB modules were administered at 0, 1, 3 and 6 hours after dosing. Adinazolam and NDMAD maximum peak plasma concentration were lower after SR tablets. Immediate‐release tablets significantly prolonged reaction time compared with placebo and SR tablets; reaction time after SR tablets did not differ from placebo. Differences between SR and CT tablets in memory were significant only at 1 hour, but memory scores tended to be higher after SR tablet administration than after the CT tablet At all times, memory scores were significantly lower than placebo for active treatments. Results suggest that memory is more impaired at lower NDMAD concentrations than is psychomotor function.
Pharmacokinetics and Dialyzability of Sulindac and Metabolites in Patients with End‐Stage Renal Failure
Authors: Ravis William R. , Diskin Charles J. , Campagna Keith D. , Clark C. Randall , McMillian Carl L.
Published: March 2013

Sulindac was administered as a single 300‐mg oral dose to six patients with end‐stage renal failure and six normal subjects. Plasma concentrations of sulindac and its sulfide and sulfone metabolites were examined over a 48‐hour period. As determined by ultrafiltration methods at 37°C, the percentage free of sulindac and sulindac sulfide in plasma was greater, respectively, in the patients with renal failure (10.50 ± 2.42 and 9.96 ± 1.21) than in the normal subjects (6.78 ± 0.45 and 6.01 ± 0.37). Free sulindac plasma concentrations were not different between the two groups. However, sulindac sulfide, total and free, plasma concentrations were substantially decreased in the group with renal failure. Total area under the curve (AUC) of the sulfide metabolite was 18% in the normal subjects and the free AUC was 29%. In patients with renal failure, the apparent half‐lives of sulindac (1.98 ± 0.76 hours) and sulindac sulfide (15.6 ± 5.8 hours) were not different from those of normal subjects. Sulindac sulfone half‐life was highly variable and longer in the patient group. Studies of dialysis clearance showed that sulindac and its metabolites are poorly dialyzed. A 4‐hour dialysis period increased the plasma binding of both sulindac and sulindac sulfide in the patient group. Based on the decreased plasma concentration of the active sulindac sulfide metabolite in the patient group, dosage adjustments may be required in patients with end‐stage renal failure.
Efficacy of Class 1C Antiarrhythmic Agents in Patients With Inducible Ventricular Tachycardia Refractory to Therapy With Class 1A Antiarrhythmic Drugs
Authors: Tisdale James E. , Kluger Jeffrey , Fisher Jane R. , Chow Moses S. S.
Published: March 2013

The efficacy of class 1C antiarrhythmic agents was determined in 36 patients with inducible sustained monomorphic ventricular tachycardia during baseline electrophysiology study (EPS), who continued to have inducible monomorphic ventricular tachycardia during EPS on class 1A antiarrhythmic therapy. Of 12 patients who partially responded to class 1A drugs, 11 (91.7%) continued to have a partial response during EPS on class 1C therapy, whereas one patient did not respond. Of 24 nonresponders to class 1A therapy, 2 (8.3%) responded during EPS on class 1C therapy, 7 (29.2%) partially responded, and 15 (62.5%) did not respond. In the 24 nonresponders to class 1A therapy, 9 of 17 patients (53%) with left ventricular ejection fraction (EF) 30% responded or partially responded to class 1C therapy, compared with none of 7 patients with EF <30% (P <.05). The EPS on class 1C agents in patients who fail to respond to class 1A therapy may be warranted oniy in those with EF ≥ 30%.
Influence of Lisinopril on Urinary Electrolytes Excretion After Furosemide in Healthy Subjects
Authors: Sudoh Toshiaki , Fujimura Akio , Shiga Tsuyoshi , Tateishi Tomonori , Sunaga Ken‐ichiro , Ohashi Kyo‐ichi , Bbihara Akio
Published: March 2013

It has been reported that the urinary excretions of chloride (CI), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re‐examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double‐blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0–0.5, 0.5–1, 1–1.5, 1.5–2, 2–3, 3–4, and 4–6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5,1,1.5,2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, CJ, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatment with lisinopril.
Nicotine Pharmacokinetics of Nicoderm® (Nicotine Transdermal System) in Women and Obese Men Compared With Normal‐Sized Men
Authors: Prather Richard D. , Tu Tri G. , Rolf Clyde N. , Gorsline Jane
Published: March 2013

This study examined the effect of gender and body weight on the pharmacokinetic properties of the Nicotine Transdermal System (NTS) (Nicoderm). This NTS was applied for 24 hours to 13 normal‐sized men, 13 women, and 13 obese men, all of whom were smokers who had abstained from cigarettes for the previous 24 hours. Pharmacokinetic parameters were determined during a single application of the system. The mean nicotine maximal plasma concentration (Cmax) and area under the curve (AUC) values for women did not differ significantly from those for normal‐sized men. Nicotine Cmax and AUC values, however, were significantly lower in obese compared with normal‐sized men; nicotine AUC was strongly correlated to body weight and body mass index. Mean apparent nicotine elimination rate constant values were not significantly different between normal‐sized and obese men, but the apparent elimination rate constant value was significantly higher in women. The possible clinical significance of the differences in nicotine AUC values with body weight is discussed.
Presystemic Extraction: Mechanisms and Consequences
Authors: Greenblatt David J.
Published: March 2013

Many drugs have incomplete systemic availability after oral dosage. This can be attributed to incomplete absorption from the gastrointestinal tract, or to presystemic extraction, in which a fraction of an orally administered dose is biotransformed before reaching the systemic circulation. Presystemic extraction can occur either via biotransformation by gastrointestinal mucosa or enteric flora, or via metabolism during the “first‐pass” through the liver. For drugs with low oral bioavailability due to high presystemic extraction, impaired clearance leads to increased peak plasma levels and greater area under the concentration‐time curve, but minimal change in elimination half‐life.
Participation of Serotonin on Early and Delayed Emesis Induced by Initial and Subsequent Cycles of Cisplatinum‐Based Chemotherapy: Effects of Antiemetics
Authors: Cubeddu Luigi X. , Hoffmann Irene S.
Published: March 2013

The role of serotonin as the possible trigger mechanism of vomiting associated with chemotherapeutic drugs was further investigated in cancer patients (n=86). Increases in 5‐hydroxyindoleacetic acid (5‐HIAA) excretion rates (2.5–2.9 times baseline values) were observed 4 to 8 hours after high‐dose cisplatinum (≥50 mg/m2). The daily excretion of 5‐HIAA from 24–48, 48–72, and 72–96 hours after cisplatinum was not different from pre‐cisplatinum levels. These results, together with the efficacy data for 5‐HT3 antagonists, suggests that serotonin may trigger the early, intense period of emesis, but not the period of delayed emesis, following high‐dose cisplatinum. Compared with the first cycle of chemotherapy, higher peak levels and more sustained elevations of 5‐HIAA excretion were found after subsequent cycles, with high‐dose cisplatinum. Further, no evidence of serotonin depletion was found after a single or after repeated cycles of treatment with high‐dose cisplatinum. These data suggest that the more intense emetic response associated to repeated cycles of treatment may be triggered by greater changes in serotonin release. No significant differences in the rate and amount of 5‐HIAA excreted induced by low‐dose (30±2 mg/m2) and high‐dose (84±3 mg/m2) cisplatinum were found between those patients who received dexamethasone (D) (20 mg IV) and those who received metoclopramide (M) (2 mg/kg, IV), irrespectively of the cycle of treatment. Interestingly, for M but not for D, best antiemetic protection was observed when lower amounts of serotonin were released (i.e., low‐dose cisplatinum and initial cycles of treatment). This suggests, that contrary to D, the effects of M, a purported antagonist of 5‐HT3 receptors, are highly dependent on the quantity of serotonin release induced by a chemotherapeutic drug. Finally, our data suggest that D does not interfere with cisplatinum‐induced serotonin release.
The Disposition of Doxorubicin on Repeated Dosing
Authors: Rushing Daniel A. , Piscitelli Stephen C. , Rodvold Keith A. , Tewksbury Duane A.
Published: March 2013

Twelve cancer patients (aged 49–74 years) receiving doxorubicin (66 ± 8 mg/m2) as a 1‐hour intravenous infusion had serial serum samples (0–48 hours) obtained after the first and second courses of therapy. Mean number of days between courses was 24.3, and all patients had normal liver function. Patients received the same concomitant antineoplastic agents and doses in both courses. Doxorubicin and doxorubicinol concentrations were assayed by high‐performance liquid chromatography and fitted to a two‐ or three‐compartment infusion model. White blood cell and platelet toxicity were evaluated as (initial — nadir/initial)* 100. Differences in pharmacokinetic parameters were determined by a paired t test. Wide intrapatient and interpatient variability was seen between therapeutic courses. A significant decrease in the apparent volume of distribution of the central compartment (Vc = 16.6 versus 10.4 L/m2; P <.05), and a nonsignificant decrease in clearance (CL = 748 versus 658 mL/min/m2) was observed on the second course of therapy. Doxorubicinol area under the curve and elimination half‐life were similar between courses. Extensive chemotherapy‐induced changes in white blood cell and platelet counts were observed but were similar in degree for courses 1 and 2. These data suggest that higher initial doxorubicin concentrations on the second course of therapy are secondary to an alteration in distribution volume (Vc). In this subset of patients, however, these changes were not associated with an increase in hematologic toxicity.
Single‐ and Multiple‐dose Pharmacokinetics of Clarithromycin, a New Macrolide Antimicrobial
Authors: Chu S.‐y. , Wilson D. S. , Deaton R. L. , Mackenthun A. V. , Eason C. N. , Cavanaugh J. H.
Published: March 2013

The pharmacokinetics of clarithromycin and its active 14(R)‐hydroxy metabolite were evaluated after single and multiple oral doses of 250 and 500 mg of clarithromycin. Multiple‐dose regimens used 12‐hour dosing intervals for 7 doses. Plasma and urine concentrations were measured using high‐performance liquid chromatography. Appearance of clarithromycin and its metabolite in plasma were rapid, as reflected by mean times to maximum plasma concentration ranging from 1.8 to 2.6 and 1.8 to 2.9 hours, respectively. The rises in clarithromycin peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) were disproportionate to increase in dose, suggesting nonlinearity in parent compound pharmacokinetics. Clarithromycin terminal disposition half‐life (t1/2) also exhibited dose dependency, ranging from harmonic means of 2.7 to 4.8 hours. In contrast, based on Cmax AUC, and predicted/observed accumulation ratios, nonlinearity in metabolite pharmacokinetics was not observed. Plasma accumulation of metabolite occurred to a much lesser degree than that of the parent compound despite a substantially longer t1/2 for the metabolite (metabolite accumulation ratios based on AUC dose 7/AUC dose 1:250‐mg regimen = 1.03 ± 0.33,500‐mg regimen = 0.81 ± 0.29, parent accumulation ratios: 250‐mg regimen = 1.64 ± 0.47, 500‐mg regimen = 1.65 ± 0.69). This would suggest that formation of this metabolite is capacity‐limited and that this may in part account for the nonlinearity observed in clarithromycin pharmacokinetics. Urinary excretion constituted a relatively important route of elimination of clarithromycin, with renal clearance accounting for 17 to 31% of apparent total body clearance.
Horizontal Component of Electro‐Oculogram as a Parameter of Arousal in Dementia: Relationship between Intellectual Improvement and Increasing Arousal under Pharmacotherapy
Authors: Shigeta Masahiro , Nishikawa Yoshinobu , Shimizu Makoto , Usui Mikiko , Hyoki Kazushi , Kawamuro Yu
Published: March 2013

Although nootropics and metabolically active compounds sometimes attenuate intellectual deficits of dementia patients, this mechanism has not been discussed or investigated. The authors hypothesized that these compounds act to enhance attention and/or concentration by increasing the arousal level, and then improve intellectual functions. Based on this hypothesis, the authors investigated the arousal level and the improvement of intellectual functions in ten patients with Alzheimer type dementia and ten patients with multi‐infarct dementia before and after 3 months pharmacotherapy using bifemelane hydrochloride. They then analyzed whether the increases in arousal level involves or relates to the improvement of intellectual functions. On the 20 patients, psychological tests were carried out, and the arousal level was evaluated using the frequency of rapid eye movements in the electro‐oculogram (EOG) before and after 3 months administration of bifemelane hydrochloride. As a result, a significant positive correlation was observed between the improvement on the Hasegawa's dementia scale and the rate of increase in rapid eye movements in the EOG. The EOG monitoring can be a great help in establishing an objective evaluation method on drug efficacy.