bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemodynamic Response to the Upright Posture
Authors: Smith James J. , Porth Carol M. , Erickson Molly
Published: March 2013

The authors' objective was to review previous studies of immediate (first 30 seconds) and stabilized (30 seconds to 20 minutes) hemodynamic responses of healthy adults to the head‐up posture, with particular reference to alteration of such responses in the elderly and the usefulness of such data in the diagnosis of orthostatic hypotension. The immediate response in healthy young adults is characterized by a prompt rise in heart rate, which peaks at about 8 to 15 seconds and then tapers; the arterial pressure and total vascular resistance decrease sharply at 5 to 10 seconds, followed by a rapid rebound and overshoot. Over the first 30 seconds there is a steady parallel decline of thoracic blood volume and stroke volume; there is also an initial surge of cardiac output followed by a steady decrease. During the stabilized response (30 seconds to 20 minutes), the hemodynamic variables are relatively steady, showing average increases in heart rate of about 15 to 30%, in diastolic pressure of 10 to 15%, and in total vascular resistance of 30 to 40%; during the 5th to 20th minutes there are also decreases in thoracic blood volume averaging about 25 to 30%, in cardiac output 15 to 30%, and in pulse pressure about 5 to 10%. It is evident that in normal human subjects, assumption of the upright posture results in profound hemodynamic changes, most of them occurring during the first 30 seconds. In elderly subjects (aged 60–69 years), there are, in the upright posture, lesser increments of heart rate and diastolic pressure, but no significant differences from younger age groups in the response of thoracic blood volume, cardiac output or total vascular resistance. However, beginning at about age 75, there is an increasing incidence of orthostatic hypotension, which averages about 14 to 20% at age 75 and older. The tendency toward orthostatic hypotension in the elderly is due (1) to the structural and functional changes in the circulation itself, (2) to a decline in autonomic function, and (3) to a probable functional deficiency of the skeletal muscle pump. The authors believe that closer hemodynamic monitoring of orthostatic hypotension patients would considerably increase our understanding and aid in the diagnosis of this condition.
Cardiovascular Responses to Standing: Effect of Hydration
Authors: Frey Mary Anne Bassett , Lathers Claire , Davis John , Fortney Suzanne , Charles John B.
Published: March 2013

Many astronauts experience intolerance to orthostatic stress after space flight, despite the ingestion of salt tablets and water equivalent to 0.9% saline just before their return to Earth. Previous research indicates that the ingestion of 1.07% saline solution increased plasma volume more than did 0.9% saline. Therefore, the authors hypothesized that the 1.07% saline would be more effective in reducing orthostatic stress during standing. In this study, six men (22–47 years) performed a 5‐minute “stand test” (5 minutes supine followed by 5 minutes standing) under four hydration conditions: 1) hypohydrated (HYPO, 20 mg intravenous [IV] Lasix), 2) euhydrated (EU), 3) rehydrated with 1 L 0.9% saline 2 hours after Lasix, or 4) rehydrated with 1 L 1.07% saline. Stand tests were done 4 to 5 hours after rehydration. Plasma volume was reduced 10% after Lasix, and was restored by both rehydration solutions. When subjects stood, their diastolic pressure, mean pressure, heart rate (HR), and peripheral resistance increased (P < .05), and their stroke volume (SV), cardiac output (CO), and thoracic fluid (TF, by impedance cardiography) decreased (P < .05). Systolic arterial pressure (SBP) increased when subjects stood after saline, but decreased if subjects were HYPO or EU (P < .05 for 1.07% versus HYPO and EU). Heart rate (HR), another indicator of orthostatic stress, did not differ among hydration states. During the last minute of the stand test, TF was greater if subjects had fluid countermeasures. Stroke volume, CO, and TF were significantly less during minute 5 of standing than during minute 3. Whether they would continue to fall in a longer stand test is not known. The results for SBP indicate that 1.07% saline may have advantages over 0.9% saline as a countermeasure to postspace‐flight or postbedrest orthostatic intolerance.
Orthostatic Hypotension in Patients, Bed Rest Subjects, and Astronauts
Authors: Lathers Claire M. , Charles John B.
Published: March 2013

Orthostatic hypotension after even short space flights has affected a significant number of astronauts. Given the need for astronauts to function at a high level of efficiency during and after their return from space, the application of pharmacologic and other treatments is strongly indicated. This report addresses the clinical problem of orthostatic hypotension and its treatments to ascertain whether pharmacologic or physiologic treatment may be useful in the prevention of orthostatic hypotension associated with space flight. Treatment of orthostatic hypotension in patients now includes increasing intravascular volume with high sodium intake and mineralocorticoids, or increasing vascular resistance through the use of drugs to stimulate alpha or block beta vascular receptors. Earlier treatment used oral sympathomimetic ephedrine hydrochloride alone or with “head‐up” bed rest. Then long‐acting adrenocortical steroid desoxycorticosterone preparations with high‐salt diets were used to expand volume. Fludrocortisone was shown to prevent the orthostatic drop in blood pressure. The combination of the sympathomimetic amine hydroxyamphetamine and a monoamine oxidase inhibitor tranylcypromine has been used, as has indomethacin alone. Davies et al. used mineralocorticoids at low doses concomitantly with alpha‐agonists to increase vasocontrictor action. Schirger et al used tranylcypromine and methylphenidate with or without a Jobst elastic leotard garment or the alpha‐adrenergic agonist midodrine (which stimulates both arterial and venous systems without direct central nervous system or cardiac effects). Vernikos et al established that the combination of fludrocortisone, dextroamphetamine, and atropine exhibited a beneficial effect on orthostatic hypotension induced by 7‐day 6° head‐down bed rest (a model used to simulate the weightlessness of space flight). Thus, there are numerous drugs that, in combination with mechanical techniques, including lower body negative pressure to elevate transmural pressure, could be studied to treat orthostatic hypotension after space flight.
Atrial Natriuretic Factor as a Volume Regulator
Authors: Inagami Tadashi
Published: March 2013

Atrial natriuretic factor, originally isolated from the atrium of the heart, has been found to consist of three major groups: atrial natriuretic peptide (ANP), B‐form natriuretic peptide (BNP), and C‐form natriuretic peptide (CNP). In addition, ANP exists in its precursor form, pro‐ANP, an active ANP with a longer peptide chain (urodilatin) and an antiparallel dimer of active ANP. Sites and production of these diverse forms of the peptides are also diverse, depending on pathologic states. Three major subtypes of ANP receptors exist; these include a clearance receptor and two types of a transmembrane receptor with guanylyl cyclase structures in their intracellular domain. The latter exists at least in two forms, one of which is found mainly in the brain. All the actions of ANP mediated by the transmembrane form of ANP receptors are mediated by cGMP generated by the guanylyl cyclase in the cytosolic domain of the receptor. Among the numerous effects of ANP, its major effects are stimulation of natriuresis and diuresis by the kidney through its hemodynamic and tubular effects. In addition, ANP causes vasodilatation and fluid volume reduction by direct actions on vascular smooth muscle cells, and inhibition of secretion of hormones, such as aldosterone, from adrenal cortex and norepinephrine from peripheral adrenergic neurons. Centrally mediated effects on the regulation of the fluid volume may also be important.
A Comparison of Postspace‐Flight Orthostatic Intolerance to Vasovagal Syncope and Autonomic Failure and the Potential Use of the Alpha Agonist Midodrine for These Conditions
Authors: Piwinski Stephen E. , Jankovic Joseph , McElligott Mary Ann
Published: March 2013

After space‐flights of less than ten days, orthostatic hypotension upon reentry is characterized by plasma volume depletion that may lead to activation of the Bezold‐Jarisch reflex which is also considered to be the mechanism of vasovagal (neurocardiogenic) syncope. For space‐flight of longer duration, loss of cardiovascular reflex control may take precedence over volume depletion and thus may have similarities to the orthostatic hypotension seen in patients with autonomic failure secondary to basal ganglial disease and peripheral neuropathies. Midodrine is an alpha‐one agonist that produces arterial and venous constriction and leads to a decrease in heart rate by baroreceptor reflexes. The efficacy of Midodrine in successfully treating orthostatic hypotension secondary to autonomic failure has been shown in clinical trials. Midodrine's ability to vasoconstrict without increasing heart rate suggests that it might be a useful treatment for vasovagal syncope since stimulation of the Bezold‐Jarisch reflex would be less likely. For post‐space flight orthostatic hypotension, midodrine may be a useful adjunctive treatment to the measures currently being used.
Cardiovascular Responses to Repetitive Exposure to Hyper‐ and Hypogravity States Produced by Parabolic Flight
Authors: Mukai Chiaki N. , Lathers Claire M. , Charles John B. , Bennett Barbara S.
Published: March 2013

Physiologic changes to repetitive hyper‐ and hypogravity stresses occurring during eight to ten parabolas on NASA's KC‐135 aircraft were studied. Hemodynamic responses in 11 subjects in 4 different postures (supine, standing, sitting, and semisupine Space Shuttle launch position) were determined using noninvasive impedance cardiography. Five seconds of heart rate, cardiac index, thoracic fluid index, stroke index, ejection velocity index, and ventricular ejection time data were averaged during four different gravity (g) states: 1.3g (before parabola onset); 1.9g (parabola entry); 0g (parabola peak); and 1.7g (parabola exit) for each subject. The standing position was associated with the largest changes in the cardiovascular response to hypo‐ and hypergravity. The thoracic fluid index did not indicate a headward redistribution during transition from a simulated launch position to weightlessness. Analysis of the eight to ten parabolas revealed that, in general values obtained at 1.8g differed from 1.6g, 0g differed from 1.6 and 1.3g, and 1.6g differed from 1.3g. The factors of gravity, thoracic fluid index, and cardiac index exhibited significant differences that were most likely to occur between parabola 1 versus parabolas 6, 7, and 8, and parabola 2 versus parabolas 4 through 8. Only the parameter of thoracic fluid index exhibited significance for parabolas 3 versus parabolas 6 and 7.
Medical Management of U.S. Astronauts
Authors: Billica Roger
Published: March 2013

The medical management of U.S. astronauts involves a comprehensive health care program and a variety of NASA and support organizations. The scope of this program includes aspects of medical monitoring and certification, health maintenance and counter‐measures programs, medical intervention, psychosocial support, and environmental health monitoring. Each of these areas have activities in all mission phases preflight, inflight, and postflight. The wide range of potential health hazards from space flight mandates an aggressive health care program to maintain crew health and performance, and to prevent unwanted mission and long‐term health consequences.
Strategies for the Preflight Circadian Shifting of Space Shuttle Crews
Authors: Santy Patricia A. , Faulk Dean M. , Davis Jeffrey R.
Published: March 2013

In June, 1990, a workshop was put together at NASA/Johnson Space Center to address difficulties the astronauts were having in adjusting their wake and sleep schedule, both immediately before and during Space Shuttle missions. The workshop members, prominent investigators in human circadian research, developed a number of strategies by which astronauts could tackle the problem of circadian adaptation within the demanding timetable of a Space Shuttle mission. The strategies included both abrupt and gradual methods, and some approaches used artificial “very bright lights” to reset the physiologic circadian pacemaker. The strategies have since been operationally implemented on Space Shuttle flights, with good success. This is a report of the problems addressed by the workshop and its recommendations.
Insulin Resistance in Systemic Hypertension: Pharmacotherapeutic Implications
Authors: Mediratta Sundeep , Fozailoff Alan , Frishman William H.
Published: March 2013

Systemic hypertension, a vascular disease with multiple origins, now is being linked to subtle abnormalities in glucose metabolism, which include insulin resistance and hyperinsulinemia. These conditions often occur together in patients with obesity, noninsulin‐dependent diabetes, or both. Hyperinsulinemia and insulin resistance may cause systemic hypertension through multiple mechanisms. Insulin has a salt‐retaining effect on the kidney. Also, insulin can augment catecholamine release, increase vascular sensitivity to vasoconstrictor substances, and decrease vascular sensitivity to vasodilator substances. In addition, insulin can increase production of tissue growth factors and help retain sodium and calcium in cells. Insulin resistance in patients can be treated with regular aerobic exercise, weight reduction, and a high‐fiber diet. Pharmacologic approaches include hypoglycemic drugs, weight‐reducing agents, and certain antihypertensive drugs that may have a favorable impact on both blood pressure and insulin resistance.
Effect of Food on the Bioavailability of Atorvastatin, an HMG‐CoA Reductase Inhibitor
Authors: Radulovic Louis L. , Cilla Donald D. , Posvar Edward L. , Sedman Allen J. , Whitfield Lloyd R.
Published: March 2013

To determine whether atorvastatin, a new HMG‐CoA reductase inhibitor, could be administered with food in Phase II and III clinical trials, a nonblind, randomized, two‐way crossover study was conducted to assess the effect of food on rate and extent of atorvastatin absorption. Sixteen healthy volunteers received single 80‐mg atorvastatin capsule doses on two occasions one week apart: once after an 8‐hour overnight fast and once with a medium‐fat breakfast. The single 80‐mg atorvastatin capsule doses were well‐tolerated. Mean maximum plasma atorvastatin equivalent concentration (Cmax) and area under the concentration—time curve (AUC) values with food were 47.9% and 12.7% lower, respectively, than without food. Mean time of maximum observed concentration (tmax) and elimination half‐life (t1/2) values were 5.9 and 32.0 hours, respectively, with food and 2.6 and 35.7 hours, respectively, without food. A medium‐fat breakfast decreased the rate of atorvastatin absorption significantly, but had little impact on extent of drug absorption. Changes in rate of atorvastatin absorption are not expected to have a clinically significant effect, as subsequent multiple‐dose clinical studies have shown that dose but not plasma atorvastatin concentration profiles correlates with lipid‐lowering effects.
Pharmacokinetics of Carboplatin in a Patient with Cervical Cancer with Ureteric Obstruction Before, During, and After Hemodialysis
Authors: El‐Yazigi Adnan , Alfurayh Osman , Amer Magid
Published: March 2013

The pharmacokinetics of total and free (ultrafilterable) platinum were investigated in a patient with cervical cancer with ureteric obstruction who, at the time of carboplatin administration, appeared to have a mild renal impairment (i.e., creatinine clearance 1 mL/s), but developed an acute renal failure shortly thereafter, which required hemodialysis. The decline in the concentration of total or free Pt in plasma as function of time correlated well (P < 0.0098) with that of serum creatinine concentration. The elimination half‐lives (t1/2) of total and free Pt in this patient were eight‐ and nine‐fold longer than those observed earlier for patients with normal renal function, and the total body clearance was 12.4% and 18.4%, respectively. Although t1/2 of Pt during dialysis was two to three times (total Pt) and eight times (free Pt) shorter than those observed before and after dialysis, three sessions of hemodialysis removed only 5.6% of total Pt and 9.3% of free Pt. Because the pre‐ and post‐dialysis t1/2 values were similar, hemodialysis apparently had no impact on the intrinsic elimination of Pt in this patient.
Effects of Amlodipine on 24‐Hour Ambulatory Blood Pressure Profiles, Electrocardiographic Monitoring, and Left Ventricular Mass and Function in Black Patients with Very Severe Hypertension
Authors: Skoularigis John , Strugo Victor , Weinberg John , Chopamba Agonia , Chautsane Zandile , Lee Andrew , Reddy Karen , Sareli Pinhas
Published: March 2013

In a 3‐month, open‐label study, 54 consecutive black patients with very severe hypertension were treated with amlodipine. Very severe hypertension was defined as an average sitting diastolic blood pressure (BP) ≥ 115 mmHg and ≤ 140 mmHg as a mean of 10 readings over a 30‐minute period using an automatic BP measuring device and a mean 24‐hour diastolic ambulatory blood pressure (ABP) ≥ 110 mmHg and ≤ 140 mmHg). Serial changes in 24‐hour ABP and electrocardiographic monitoring, left ventricular (LV) mass index, and LV systolic function were evaluated. Mean 24‐hour ABP was reduced from 181 ± 14/119 ±6 to 140 ± 15/92 ±9 mmHg at 3 months (P < 0.0001). Target BP (mean 24‐hour diastolic ABP <90 mmHg) was achieved in 35% of the patients. The reduction in BP was sustained for 24 hours after drug administration. Simultaneous BP measurements using the automatic BP measuring device were significantly different from the ABP measurements before and after treatment, suggesting a marked “white coat” pressor effect. At baseline, frequent or complex ventricular arrhythmias (>30 ventricular extrasystoles per hour, ventricular couplets) were present in 2 (4%) patients, with no significant change after treatment. Left ventricular mass index regressed from 140 ± 50 to 111 ± 30 g/m2 at 3 months (P < 0.03); LV performance was not adversely affected. Adverse effects were few and tended to disappear during the treatment period. All of the clinical laboratory parameters tested remained unchanged. In this group of patients, treatment with amlodipine showed a marked and sustained antihypertensive action as demonstrated by 24‐hour ABP monitoring, and was well tolerated and associated with LV mass regression without adverse effect on systolic cardiac function. Further, a low rate of complex ventricular arrhythmias was documented.
Diurnal Variation In the Pharmacokinetics of Nizatidine in Healthy Volunteers and In Patients with Peptic Ulcer Disease
Authors: Jamali F. , Thomson A. B. R. , Kirdeikis P. , Tavernini M. , Zuk L. , Marriage B. , Simpson I. , Mahachai V.
Published: March 2013

Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross‐over fashion. Steady‐state serum nizatidine concentrations and gastric pH were measured over a 24‐hour period. No significant differences in the pharmacokinetic indices were observed between the healthy volunteers and patients with duodenal ulcer disease. In patients with duodenal ulcers, significantly lower peak serum concentrations, longer half‐life (t1/2) and larger volume of distribution (Vd) were observed after the night doses compared with the daytime doses. The diurnal variation in drug kinetics between the nighttime and daytime doses in the twice daily regimen may be caused by a slower absorption rate, paralleled with a higher extent of distribution. Despite lower serum nizatidine concentrations, gastric pH was higher in the evening than in the daytime; it is speculated that this was due to a time‐dependent enhanced distribution of the H2‐receptor blocker into the site of action.
Kidney Function and Age Are Both Predictors of Pharmacokinetics of Metformin
Authors: Sambol Nancy C. , Chiang Janie , Lin Emil T. , Goodman Anita M. , Liu Chui Y. , Benet Leslie Z. , Cogan Martin G.
Published: March 2013

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle‐age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850‐mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high‐performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35–40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74–78% lower than in the healthy young/middle‐age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23–33% lower than in the young/middle‐age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CLcr*; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = α + β·CLcr* + γ · CLcr*·age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non‐insulin‐dependent diabetes) population.
Clinical Pharmacology of Antiepileptic Drug Use: “Clinical Pearls about the Perils of Patty”
Authors: Schraeder Paul L. , Lathers Claire M.
Published: March 2013

This Clinical Pharmacology Problem Solving (CPPS) Unit is for use with fourth‐ or fifth‐year pharmacy students and third‐ or fourth‐year medical students during conferences held when they are taking either a rotation in Neurology or Clinical Pharmacology. It may also be used for house staff teaching of residents in Neurology, Pediatrics, Internal Medicine, and Family Practice and fellows in Clinical Pharmacology. This material was prepared for a Teaching Clinic in Clinical Pharmacology taught by Claire M. Lathers, PhD, FCP, Hugh J. Burford, PhD, FCP, and Cedric M. Smith, MD, FCP, and sponsored by the American College of Clinical Pharmacology, September 19–20, 1992, Washington, DC.

This workbook includes: (1) an introduction to the Clinical Pharmacology Problem Solving (CPPS) Unit; (2) the learning objectives of the clinical simulation; (3) a pretest; (4) four clinical episodes occurring over many years in the life of a patient; (5) answers to the pretest; (6) a posttest; (7) answers to the posttest.
Concentration‐Guided Strategies in Drug Development: Experience with a Cyclosporine Analog in Transplantation
Authors: Kovarik John M. , Mueller Edgar A. , Kallay Zoltan , Smith Harold T. , Lison Arno E. , Arns Wolfgang , Renner Eckhard
Published: March 2013

A concentration‐guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady‐state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)‐based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2–3), and a microemulsion capsule formulation of CyG in period III (weeks 4–5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG‐ and CyA‐specific high‐performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration‐guided strategy was successful in avoiding over‐exposure, and resulted in comparable values for area under the concentration‐time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration‐guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.
Gender Differences in Exercise and Recovery Blood Pressure Responses in Normal Volunteers Given Diltiazem
Authors: Klassen Gerald A. , Yeung Pollen F. K. , Barclay Katherine D. , Hung Orlando R. , Pollak P. Timothy , Buckley Susan J.
Published: March 2013

This preliminary phase I study was conducted in healthy volunteers to determine whether gender differences exist in the hemodynamic effects of diltiazem at rest, during exercise, and after exercise. At comparable serum concentrations of the drug, women demonstrated lower systolic and diastolic pressure during exercise and after exercise. ST slope after diltiazem administration in women became less positive during exercise and was gender specific. Heart rate and P‐R interval changes were not gender dependent. Results of this study demonstrate that some hemodynamic responses to diltiazem are gender specific while others are not. It indicates that direct comparison studies may be required to detect such differences. In healthy women, hypotension after exercise and the effects of diltiazem are more synergistic than in men. Such a gender difference in response may be an important consideration in determining the correct dosages of this drug for treatment of hypertension.
Sustained Blood Pressure Control with Controlled‐Release Isradipine (Isradipine‐CR)
Authors: Chrysant Steven G. , Cohen Michael
Published: March 2013

The safety and efficacy, as measured by peak/trough blood pressure reduction, of a new, once‐daily, controlled‐release formulation of isradipine (isradipine‐CR, ICR) were evaluated in patients with mild to moderate essential hypertension during a nine‐week trial. After a 3‐week placebo washout period, patients with a sitting diastolic blood pressure between 100 and 114 mm Hg were randomized to either 1 of 4 ICR treatment groups or placebo. Of 402 randomized patients, 384 completed the study (placebo = 77, ICR‐5 mg = 76, ICR‐10 mg = 76, ICR‐15 mg = 78, and ICR‐20 mg = 77). Peak and trough post‐dose blood pressure responses and heart rates were monitored for both the sitting and upright positions. Blood chemistries, urinalyses, complete blood counts, and electrocardiograms were done during the study. Both sitting and upright blood pressures decreased with the 5‐ (P < .05), 10‐, 15‐, and 20‐mg (P < .001) once‐daily ICR doses. The peak blood pressure reduction for all ICR doses occurred at 8 to 10 hours post‐dose. Maximum peak/trough blood pressure response, achieved with the 10‐mg dose, was similar with that of 15 and 20 mg of ICR. No serious clinical or metabolic side effects were noted, except ankle edema, which was dose dependent but did not require discontinuation of treatment. Based on these results we concluded that (1) ICR provided effective peak and trough blood pressure control after once‐daily dosing (5–20 mg) in hypertensive patients, (2) it was safe and well tolerated, and (3) the best overall results were achieved with the 10‐mg once‐daily dose.
Pharmacokinetics of Triamcinolone Acetonide After Intravenous, Oral, and Inhaled Administration
Authors: Derendorf Hartmut , Hochhaus Günther , Rohatagi Shashank , Möllmann Helmut , Barth Jürgen , Sourgens Hildegard , Erdmann Martina
Published: March 2013

The pharmacokinetics of triamcinolone acetonide were studied after intravenous (2 mg), oral (5 mg), and inhaled (2 mg) administration. Triamcinolone acetonide concentrations were measured in plasma by high‐performance liquid chromatography/radioimmunoassay. After intravenous administration, triamcinolone acetonide was eliminated with a total body clearance of 37 L/h and a half‐life of 2.0 hours. The volume of distribution was 103 L, and oral bioavailability averaged 23%. Absorption was rapid, achieving maximum triamcinolone acetonide levels of 10.5 ng/mL after 1 hour. After inhalation, bioavailability averaged 22% with maximum levels of 2.0 ng/mL observed after 2.1 hours. The resulting systemic levels for all three treatments caused a significant decrease in the number of lymphocytes in blood.
High‐Grade Nucleoside Transport Inhibition Stimulates Ventilation in Humans
Authors: Rongen Gerard A. , Smits Paul , Bootsma Gorben , Donck Kris Ver , De Vries Albrecht , Thien Theo
Published: March 2013

In 6 healthy male volunteers a placebo‐controlled, double‐blind, randomized, crossover trial was done to assess the effect of 1, 2, 4, and 6 mg of draflazine, a specific nucleoside transport inhibitor, on ventilation. Draflazine increased thoracic excursions dose‐dependently by maximally (median with 95% confidence interval) 114.0% (38.3–184.8%) without affecting breathing rate. Ex vivo adenosine transport was inhibited by 0% (0–1%) after placebo, and 70% (59–74%), 81% (76–85%), 90% (86–93%), and 93% (90–96%) after the 4 increasing draflazine dosages, respectively (P < .05 for each draflazine dosage versus placebo). These results indicate that endogenously released adenosine may play a role in the regulation of ventilation.
Does Tetanus Immune Globulin Interfere with the Immune Response to Simultaneous Administration of Tetanus—Diphtheria Vaccine? A Comparative Clinical Trial in Adults
Authors: Dal‐Ré Rafael , Gil Angel , González Antonio , Lasheras Luisa
Published: March 2013

In the management of wounds, sometimes it is recommended to give an adult‐type tetanus—diphtheria (Td) vaccine dose plus tetanus immune globulin (TIG). Sixty and 59 healthy young adults previously immunized against tetanus (T) and diphtheria (D) were randomized to receive intramuscularly either Td vaccine alone (group 1) or Td vaccine plus 500 IU of TIG (group 2) simultaneously. Antitoxin response was assessed after 4 weeks and 4 months. Circulating antibodies were measured by enzyme‐linked immunosorbent assay (ELISA). The cutoff of these tests was 0.1 IU/mL. Titers of 0.1 IU/mL or greater were considered protective. For geometric mean titers (GMT), antibody titers below the cutoff of the assay were given, arbitrarily, 0.05 IU/mL. At 4 weeks, 98% or more of the subjects in group 1 had circulating T and D antitoxin levels of 0.1 IU/mL or higher; in group 2, 95% and 90% of the subjects had titers above this limit for T and D, respectively. At 4 months, these percentages were 98% and 95% for T antitoxin levels in groups 1 and 2, respectively; whereas 96% and 88% of the subjects in groups 1 and 2 had D antitoxin levels of 0.1 IU/mL or higher, respectively. Significantly (P < .05) higher GMTs were seen at the 4‐week assessment (but not at 4 months) in group 1, as compared with group 2, in both T and D antitoxin levels (9.91 IU/mL versus 5.60 IU/mL for T antitoxin, and 2.86 IU/mL versus 1.45 IU/mL for D antitoxin). This finding resulted from those participants with low (<0.1 IU/mL) prevaccination antibody titers. Among these, D antibody GMTs at 4 weeks were 1.94 IU/mL and 1.06 IU/mL for those receiving Td vaccine or Td vaccine plus TIG, respectively; corresponding values for T antibody GMTs at 4 months were 3.53 IU/mL and 0.64 IU/mL (P = .02), respectively. Concurrent administration of TIG with Td vaccine interferes with the immune response to T toxoid in subjects with low prevaccination antibody titers. Further studies are needed to confirm these results.
Lack of Pharmacokinetic Interaction Between Butorphanol Tartrate Nasal Spray and Sumatriptan Succinate
Authors: Srinivas Nuggehally R. , Shyu Wen Chyi , Upmalis David , Lee James S. , Barbhaiya Rashmi H.
Published: March 2013

The pharmacokinetics of butorphanol tartrate given in a nasal spray with and without the co‐administration of sumatriptan succinate were studied in 24 healthy men and women. In this crossover design study, all subjects received 2 treatments: a single 1‐mg dose of butorphanol nasal spray and a 1‐mg dose of butorphanol nasal spray plus a single 6‐mg subcutaneous (SC) dose of sumatriptan. There was a two‐week washout period between sessions. Serial blood samples were collected and plasma samples analyzed using validated radioimmunoassay and high‐performance liquid chromatography/electrochemical procedures to determine the concentrations of unchanged butorphanol and sumatriptan, respectively. There were no statistically significant differences for butorphanol between the 2 treatments on any of the following pharmacokinetic parameters: Cmax, tmax, AUC, t1/2, CL/f, and Vz/f. Similarly, the pharmacokinetic parameters obtained for sumatriptan (given with butorphanol nasal spray) were comparable with the literature values obtained for a single 6‐mg SC dose of sumatriptan. These data show a lack of pharmacokinetic interaction between butorphanol nasal spray and sumatriptan. Butorphanol nasal spray and sumatriptan were well tolerated. The adverse experience profiles of butorphanol nasal spray were comparable between the treatments, with and without sumatriptan. It can be concluded that regimens of butorphanol nasal spray and sumatriptan need not be changed for either pharmacokinetic or safety considerations when the two compounds are co‐administered in treating acute migraine attacks.
Calcium Antagonist Use in Congestive Heart Failure: Still a Bridge Too Far?
Authors: Piepho Robert W.
Published: March 2013

Calcium antagonists continue to be used to treat congestive heart failure (CHF), despite clinical evidence that they may exacerbate the disease. The systemic vasodilatory actions of these drugs make them potentially attractive for use as afterload reducing agents in patients with CHF. Newer calcium antagonists of the 1,4‐dihydropyridine class, with claims of little or no negative inotropic properties and minimal effects on the sympathetic nervous system, seem a promising treatment of this disease. All calcium antagonists, however, consistent with their ability to block transmembrane calcium transport in cardiac muscle cells, are intrinsically negative inotropes. Moreover, clinical trial data are inconclusive about the ability of these newer calcium antagonists to activate the sympathetic nervous system. The relatively small numbers of patients with CHF, the differing degrees of CHF in different patient groups, and the variation in route of administration, dosage, and schedule of hemodynamic measurements make analyses of published data difficult. Although some patients with CHF respond positively to treatment with calcium antagonists, there is great individual variability of response, and the majority of patients show deterioration of myocardial function when taking calcium antagonists. Until conclusive clinical evidence of the safety and effectiveness of calcium antagonists in the treatment CHF is available, they should not be used to treat this disease unless individual patient characteristics clearly indicate a positive benefit/risk ratio.
Surrogate Biochemical Markers: Precise Measurement for Strategic Drug and Biologics Development
Authors: Lee Jean W. , Hulse James D. , Colburn Wayne A.
Published: March 2013

More efficient drug and biologics development is necessary for future success of pharmaceutical and biotechnology companies. One way to achieve this objective is to use rationally selected surrogate markers to improve the early decision‐making process. Using typical clinical chemistry methods to measure biochemical markers may not ensure adequate precision and reproducibility. In contrast, using analytical methods that meet good laboratory practices along with rational selection and validation of biochemical markers can give those who use them a competitive advantage over those who do not by providing meaningful data for earlier decision making.
A Bioequivalence Study of Oral Controlled‐Release Morphine Using Naltrexone Blockade
Authors: Kaiko Robert F. , Grandy Robert P. , Reder Robert F. , Goldenheim Paul D. , Sackler Richard S.
Published: March 2013

Twenty‐three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two‐way crossover comparison of the bioavailability of one 200‐mg oral controlled‐release morphine sulfate tablet with two 100‐mg MSC tablets. Morphine effects were blocked by three 100‐mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100‐mg MSC tablets, the 200‐mg tablet was 96% bioavailable (90% confidence interval, 88.14–105.74%). The 90% confidence intervals for mean Cmax and AUC0–24 for one 200‐mg MSC tablet were within ±20% of the Cmax and AUC0–24 of two 100‐mg tablets, indicating the two dosage forms are bioequivalent. Single 200‐mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled‐release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.
The Influence of Orlistat on the Pharmacokinetics and Pharmacodynamics of Glyburide in Healthy Volunteers
Authors: Zhi J. , Melia A. T. , Koss‐Twardy S. G. , Min B. , Guerciolini R. , Freundlich N. L. , Milla G. , Patel I. H.
Published: March 2013

To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose‐lowering effect) of glyburide, an open‐label, placebo‐controlled, randomized, two‐way crossover study was done in 12 healthy male volunteers. Each subject received single 5‐mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80‐mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five‐day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80‐mg three times daily does not significantly alter the pharmacokinetics and blood glucose‐lowering effect of a single 5‐mg oral dose of glyburide in healthy volunteers.
Single‐Dose Interaction Study of Diprafenone HCl and Propranolol HCl in Healthy Volunteers
Authors: Hinderling Peter H. , Tendolkar Amol , Dee Cathryn M. , Barr William H. , Seiberling Michael , Duerr Helga
Published: March 2013

Using a 3 × 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific β‐antagonist activity and propranolol HCl was investigated in nine young, healthy, Caucasian, male volunteers. The volunteers randomly received 3 single‐dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled Wood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration‐time curves and apparent disposition half‐lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected “poor” and “extensive metabolizers” of DHCl.
Moexipril in the Treatment of Mild to Moderate Essential Hypertension: Comparison with Sustained‐Release Verapamil
Authors: Abernethy Darrell R. , Fox Alanna A. L. , Stimpel Michael
Published: March 2013

To compare and contrast the antihypertensive efficacy of an angiotensin‐converting enzyme (ACE) inhibitor to a calcium antagonist, 88 and 90 patients with essential hypertension were randomly assigned to receive moexipril and verapamil, respectively. At the end of the first 6 weeks of active therapy, sitting diastolic blood pressure decreased by 11 mmHg in patients receiving moexipril and by 9 mmHg in patients receiving verapamil. The 24‐week treatment period was completed by 72 patients who received moexipril and 71 patients who received verapamil. Mean decreases in sitting diastolic blood pressure of 10 mmHg and 11 mmHg were observed in the respective intent‐to‐treat moexipril and verapamil groups. At doses of 7.5 mg and 15 mg once daily, moexipril had an antihypertensive effect comparable to that of sustained‐release verapamil at doses of 180 mg and 240 mg once daily.
Efficacy and Pharmacokinetics of Two Formulations of Cyclosporine A in Patients with Psoriasis
Authors: Elder Cheryl A. , Moore Marylou , Chang Cheng‐Tao , Jin Judy , Charnick Steve , Nedelman Jerry , Cohen Albert , Guzzo Cynthia , Lowe Nicholas , Simpson Karen , Karara Adel H. , Meligeni John
Published: March 2013

The efficacy and pharmacokinetic profiles of two oral formulations of cyclosporine A (Sandimmune and Neoral; Sandoz Pharmaceuticals, East Hanover, NJ) were evaluated in 37 patients with moderate to severe plaque psoriasis in a randomized, double‐blind, modified, crossover study. Cyclosporine A (150 mg twice daily), administered in either formulation, reduced the severity of plaque lesions: 94% of all patients reported at least moderate improvement and 70% reported complete clearing. Approximately 2 weeks of therapy were required for drug exposure to stabilize on either formulation. Cyclosporine A exposure from Neoral was significantly greater relative to that from Sandimmune across all study weeks. At the eighth week (before crossover), AUC and Cmax values for Neoral and Sandimmune were 5618 ± 1705 versus 3202 ± 596 ng·h/mL and 1283 ± 337 versus 623 ± 173 ng/mL, respectively. In crossover analysis at steady state, the relative oral bioavailability of cyclosporine from the Neoral formulation was 54% greater than that from Sandimmune. Some pharmacokinetic parameters showed less variability both between and within groups of patients taking Neoral versus Sandimmune. Both formulations were well tolerated, in that most adverse events were of mild severity.
The Lack of Effect of Aerobic Exercise Training on Propranolol Pharmacokinetics in Young and Elderly Adults
Authors: Panton Linda B. , Guillen Gregorio J. , Williams Leonard , Graves James E. , Vivas Carolina , Cediel Maritza , Pollock Michael L. , Garzarella Linda , Krumerman Jonathan , Derendorf Hartmut , Lowenthal David T.
Published: March 2013

The effects of exercise training on the pharmacokinetics of orally administered propranolol were studied in young and elderly healthy volunteers. Twenty‐three young (30 ± 5 years of age) and 20 elderly (67 ± 5 years of age) adults were randomly assigned to endurance training (N = 12 young subjects, 10 elderly subjects) or nonexercising control (N = 11 young subjects, 10 elderly subjects) groups. Training consisted of treadmill walking, stairclimbing, or both three times per week for 40 minutes at 70–85% of maximal heart rate reserve for 16 weeks. Resting plasma propranolol concentrations after a single dose of 80 mg of oral propranolol were measured by high performance liquid chromatography with fluorescence detection, and estimated hepatic blood flow measured was measured using indocyanine green during supine rest. Aerobic training increased maximal oxygen uptake (VO2max) by 13% and 14% in the exercising young and elderly groups, respectively. There was no change in VO2max in either control group. Adjusted mean estimated hepatic blood flow after exercise corrected for body weight for the young subjects who did not exercise (15.6 mL/min/Kg) and those who did (18.2 mL/min/Kg) groups were of borderline significance. No statistical differences were detected in the experimental propranolol pharmacokinetic parameters (maximal concentration, time of maximal concentration, terminal half‐life, area under the curve, and protein binding) or derived pharmacokinetic parameters (intrinsic clearance, bioavailability, clearance, and volume of distribution). These results provide evidence that changes in aerobic fitness do not produce corresponding changes in propranolol pharmacokinetics in young or elderly adults.