bluuebunny/crossref_metadata_2025 huggingface dataset:
ChemInform Abstract: Biocatalytically Derived cis‐1,2‐Dihydrocatechols: Enantiopure and Versatile Building Blocks for Chemical Synthesis
Authors: Bon David J.‐Y. D. , Lee Bora , Banwell Martin G. , Cade Ian A.
Published: March 2013

Review: 71 refs.
The role of actin and myosin in PtK2 spindle length changes induced by laser microbeam irradiations across the spindle
Authors: Sheykhani Rozhan , Baker Norman , Gomez‐Godinez Veronica , Liaw Lih‐Huei , Shah Jagesh , Berns Michael W. , Forer Arthur
Published: March 2013

This study investigates spindle biomechanical properties to better understand how spindles function. In this report, laser microbeam cutting across mitotic spindles resulted in movement of spindle poles toward the spindle equator. The pole on the cut side moved first, the other pole moved later, resulting in a shorter but symmetric spindle. Intervening spindle microtubules bent and buckled during the equatorial movement of the poles. Because of this and because there were no detectable microtubules within the ablation zone, other cytoskeletal elements would seem to be involved in the equatorial movement of the poles. One possibility is actin and myosin since pharmacological poisoning of the actin–myosin system altered the equatorial movements of both irradiated and unirradiated poles. Immunofluorescence microscopy confirmed that actin, myosin and monophosphorylated myosin are associated with spindle fibers and showed that some actin and monophosphorylated myosin remained in the irradiated regions. Overall, our experiments suggest that actin, myosin and microtubules interact to control spindle length. We suggest that actin and myosin, possibly in conjunction with the spindle matrix, cause the irradiated pole to move toward the equator and that cross‐talk between the two half spindles causes the unirradiated pole to move toward the equator until a balanced length is obtained. © 2013 Wiley Periodicals, Inc
Polyunsaturated fatty acids induce polarized submembranous F‐actin aggregates and kill Entamoeba histolytica
Authors: Manna Dipak , Grewal Jaspreet Singh , Sarkar Bidyut , Maiti Sudipta , Lohia Anuradha
Published: March 2013

We have recently identified a novel galacto‐glycerolipid (GGL) from the plant Oxalis corniculata that killed the human pathogen Entamoeba histolytica. In this study, we show that the anti‐amoebic activity of GGL was due to the polyunsaturated fatty acid α‐linolenic acid (C18:3) side chain. Treatment of α‐linolenic acid to E. histolytica trophozoites disrupted the cytoskeletal network and led to polarization of F‐actin at one end of the cells with prominent filopodial extensions. In addition, clustering of surface receptors and signaling molecules was also observed adjacent to the polarized actin similar to concanavalin‐A‐(Con‐A) induced capping. But, in contrast to Con‐A‐induced capping, α‐linolenic acid induced caps were not shed and showed accumulation of long and numerous filopodia at the cap site. We found that α‐linolenic acid disrupts the actin cytoskeletal network, which led to the detachment of plasma membrane from the underlying cytoskeleton. A similar effect was observed with other dietary fatty acids such as linoleic acid (C18:2), arachidonic acid (C20:4), eicosapentaenoic acid (C20:5), and docosahexaenoic acid (C22:6). Our findings showed that dietary polyunsaturated fatty acids are powerful anti‐amoebic agents that lead to disruption of the actin cytoskeleton. © 2013 Wiley Periodicals, Inc
Diacetylplatinum(II) and ‐platinum(IV) Complexes Bearing κ2‐ and κ3‐Coordinated Tris(pyrazolyl)methane Ligands: Investigations on the Synthesis, Fluxionality, and Reactivity in Relation to the Substitution Pattern of the Ligands
Authors: Bette Martin , Schmidt Jürgen , Steinborn Dirk
Published: March 2013

Reactions of the dinuclear platina‐β‐diketone [Pt2{(COMe)2H}2(μ‐Cl)2] (1) with HC(pz)3 and HC(3,5‐Me2pz)3 (pz = pyrazol‐1‐yl; 3,5‐Me2pz = 3,5‐dimethylpyrazol‐1‐yl) afforded cationic, thermally labile diacetyl(hydrido)platinum(IV) complexes [Pt(COMe)2H{(pz)3CH}]Cl (3a) and [Pt(COMe)2H{(3,5‐Me2pz)3CH}]Cl (3b) with κ3‐coordinated tris(pyrazolyl)methane ligands, which were found to react with NaOH or NEt3 to yield neutral diacetylplatinum(II) complexes with κ2‐coordinated tris(pyrazolyl)methane ligands {[Pt(COMe)2{(pz)3CH}] (4a); [Pt(COMe)2{(3,5‐Me2pz)3CH}] (4b)}. In 4a/b, a molecular rearrangement (decoordination of a pyrazolyl ring and coordination of the originally pendant one) has been found that has been investigated by variable‐temperature 1H NMR spectroscopic measurements (coalescence method) as well as by DFT calculations. Diacetylplatinum(II) complexes 4 were found to react in oxidative addition reactions with ROTf (R = H, Me; OTf = trifluoromethanesulfonate) and methyl iodide to yield cationic diacetylplatinum(IV) complexes of the type [Pt(COMe)2R{(pz)3CH}]X (R/X = H/OTf, 5a; Me/OTf, 6a; Me/I, 7a) and [Pt(COMe)2R{(3,5‐Me2pz)3CH}]X [R/X = H/OTf (5b), Me/OTf (6b), Me/I (7b)] with κ3‐bonded tris(pyrazolyl)methane ligands. Treatment of 4b with alkynyliodine(III) reagents of the type [IPh(C≡CR)]X (R/X = SiMe3/OTf, Ph/OTf, tBu/OTos, iPr/OTos; OTos = p‐toluenesulfonate) led to the formation of cationic diacetyl(alkynyl)platinum(IV) complexes [Pt(COMe)2(C≡CR){(3,5‐Me2pz)3CH}]X [R/X = SiMe3/OTf (8a), Ph/OTf (8b), tBu/OTos (8c), iPr/OTos (8d)]. The identities of all platinum complexes were unambiguously proven by high‐resolution mass spectrometric investigations, by NMR (1H, 13C, 195Pt) and IR spectroscopy, as well as by single‐crystal X‐ray diffraction analyses (4a, 4b, 7a, 8a/d). The constitution of the thermally labile complexes 3a/b has been confirmed by low‐temperature (–80 °C) NMR (1H, 13C) spectroscopic measurements. The electronic and steric influence of the additional methyl groups in HC(3,5‐Me2pz)3 on reactivity, stability, and properties of the investigated compounds will be discussed.
Evaluation of fundamental period of low‐rise and mid‐rise reinforced concrete buildings
Authors: Hatzigeorgiou George D. , Kanapitsas George
Published: March 2013

Fundamental period of vibration appears to be one of the most critical parameter for the seismic design of buildings because this period strongly affects the magnitude of seismic forces. In this paper, an empirical formula for estimating the fundamental period of reinforced concrete structures is recommended, on the basis of the vibration analysis of 20 different real building configurations. These structures have already been constructed in Greece, and they are analyzed by using in detail 3‐D finite element models and modal eigenvalue analysis. These models take into account the presence of external and internal infill walls, which are usually ignored as nonstructural elements. This neglect leads to unreliable evaluation of period because the infill walls' contribution to the lateral stiffness and therefore to the fundamental period of vibration is also ignored. Furthermore, taking into account that the flexibility of soil elongates the fundamental period, the soil–structure interaction effect is also considered. To achieve a unique, simple, and effective empirical expression for the fundamental period of vibration, a comprehensive nonlinear regression analysis is applied for the datasets of buildings under consideration. This empirical expression is also compared with the similar expressions from the pertinent literature. Copyright © 2013 John Wiley & Sons, Ltd.
Low prevalence of metabolic syndrome and its prediction in Japanese inpatients with schizophrenia
Authors: Suzuki Yutaro , Sugai Takuro , Fukui Naoki , Watanabe Junzo , Ono Shin , Tsuneyama Nobuto , Saito Mami , Someya Toshiyuki
Published: March 2013

Objectives

There have so far been few papers studying the metabolic syndrome (MetS) prevalence rate in Japanese patients with schizophrenia. We studied the MetS prevalence rate in Japanese controls and inpatients with schizophrenia and compared the prediction factors for the occurrence of MetS.

Methods

The subjects were 319 inpatients with schizophrenia and 154 controls. The predictive utilities of body mass index (BMI) and the individual components of MetS for MetS diagnosis were evaluated.

Results

The prevalence of MetS did not differ between schizophrenia and control subjects. Subjects with schizophrenia showed higher prevalences of the MetS criteria for high‐density lipoprotein cholesterol (HDL) (p < 0.001) and waist circumference (WC) (p < 0.001). In subjects with schizophrenia, the predictive power was found to be highest for HDL, followed by WC, BMI, triglyceride, diastolic blood pressure (BP), systolic BP and fasting plasma glucose. However, in control subjects, the predictive power was found to be highest for triglyceride, followed by WC, systolic BP, BMI, HDL, diastolic BP and fasting plasma glucose. HDL was the component most predictive of MetS in subjects with schizophrenia treated with antipsychotics.

Conclusion

Because, in normal clinical practice, it is difficult to obtain temporal measurements for all of the MetS criteria, measurement of HDL may be useful for predicting the MetS. Copyright © 2013 John Wiley & Sons, Ltd.
Acylated ghrelin: A potential marker for fibromyalgia?
Authors: Homann D. , Louzada F.M. , Góes S.M. , Roizenblatt S. , Lopes A.L. , de Oliveira Á.R. , Leite N.
Published: March 2013

Background

Fibromyalgia is characterized by chronic widespread pain and sleep disturbances. Overweight and obesity, which lead to metabolic changes, are additional comorbidities that are rarely explored, although they are highly prevalent in patients with fibromyalgia.

Methods

We compared the plasma levels of leptin and acylated ghrelin in 17 women with fibromyalgia (patients) and 16 healthy women (controls) with similar age, anthropometric measurements and levels of physical activity. We also investigated the relationships between these two neuropeptides and sleep and various pain characteristics in patients with fibromyalgia. Anthropometric measurements were recorded, and physical activity levels were assessed using a questionnaire. Pain intensity was measured using visual analogue scales (weekly general and mean pain scores). Sleep was assessed using an accelerometry technique.

Results

Compared to the control group, the patient group had increased leptin levels (patients: 22.4 ± 10.6 vs. controls: 13.3 ± 17.9 ng/mL; p < 0.01) and decreased acylated ghrelin levels (patients: 126.7 ± 47.8 vs. controls: 183.3 ± 102.2 pg/mL; p = 0.048). The leptin level was not significantly correlated with any of the variables. Acylated ghrelin level was inversely correlated with the weekly mean pain score (r = −0.67, p < 0.01) and the weekly general pain score (r = −0.67, p < 0.01). Multiple regression analysis revealed that the variations in acylated ghrelin levels accounted for 35% of the weekly general pain and 29% of the weekly mean pain variability.

Conclusions

These findings indicate that the decreased acylated ghrelin levels in women with fibromyalgia are related to pain intensity.
Book Reviews
Authors: PROCITA LEONARD
Published: March 2013

Book reviewed in this article:

Psychopharmacology: A Generation of Progress. M. A. Lipton, A. DiMascio, and K. F. Killam, editors.

Medication Guide for Patient Counseling. D. L. Smith.

Quantitative Aspects of Allosteric Mechaisms. (Molecular Biology, Biochemistry and Biophysics, Vol. 28). A. Levitski.
Factors Influencing Procainamide Total Body Clearance in the Immediate Postmyocardial Infarction Period
Authors: WYMAN MILFORD G. , GOLDREYER BRUCE N. , CANNOM DAVID S. , LUDDEN THOMAS M. , LALKA DAVID
Published: March 2013

Abstract: Fifteen acute myocardial infarction patients (only one of whom had evidence of significant renal dysfunction) received a constant‐rate intravenous infusion of procainamide at one rate for at least 24 hours. Steady‐state plasma levels achieved during these infusions were used to calculate total body clearance (C/B). Linear regression analysis of C/B versus a variety of clinical and laboratory patient characteristics yielded only body weight (or parameters derived from it) as a significant covariant (r = 0.713, P ≤ 0.005). Interestingly, the data from these 15 patients suggest that the presence of a significant degree of heart failure at the start of therapy did not result in a significant decrease in C/B (C/B = 5.9 ml/min/kg when class 0‐I failure was present at the start of therapy, and C/B = 5.5 ml/min/kg when class III‐IV failure was present). If the data from five other patients who were studied previously are added to the group reported here, the conclusions reached would be the same. These data suggest that in patients with good renal and hepatic function, initial procainamide infusion rate could be selected on the basis of body weight and need not consider the initial presence of moderate heart failure. However, intense clinical monitoring for signs of impeding serious toxicity is strongly recommended since the observed regression line did not predict total body clearance accurately in 10 to 15 percent of the patients studied.
Growth Hormone Release in Hypertensive Adolescents Treated with Clonidine
Authors: FALKNER BONITA , ONESTI GADDO , MOSHANG THOMAS , LOWENTHAL DAVID T.
Published: March 2013

Abstract: The release of the growth hormone in the basal state and in response to strenuous exercise was studied in a group of 15 hypertensive adolescents receiving clonidine therapy and in a control group of 17 untreated adolescents of which ten were hypertensive volunteers and seven were healthy normotensive volunteers. Mean basal growth hormone in clonidine‐treated adolescents was 2.8 ± 0.50 S.E.M. ng/ml, compared to 2.7 ± 0.48 ng/ml in untreated adolescents. Following exercise stimulation, mean growth hormone was 14.8 ± 3.1 S.E.M. ng/ml in the treated group and 13.5 ± 2.8 ng/ml in the untreated group. Growth hormone release is regulated by α‐adrenergic receptor stimulation. Clonidine acts centrally by α‐adrenergic stimulation. However, this study demonstrates no effect of chronic clonidine therapy on growth hormone release.
Synergistic Effects of Probucol and Cholestyramine to Lower Serum Cholesterol
Authors: BOYDEN THOMAS W. , TOTMAN LAWRENCE
Published: March 2013

Abstract: Ten men with hypercholesterolemia were treated sequentially with a fat‐modified diet, a diet plus probucol (1 Gm/day), and a diet plus probucol plus cholestyramine (16 Gm/day). Each treatment period was 12 weeks. Diet alone reduced mean serum cholesterol by 1.0 per cent. Diet plus probucol caused a mean 7.7 per cent reduction in serum cholesterol below the baseline values (P = 0.001 compared to diet). Adding cholestyramine to probucol and diet resulted in a mean 18.2 per cent reduction in serum cholesterol below baseline values (P = 0.001 compared to probucol and diet). The treatment was well tolerated.
Physostigmine for Treatment of Delirium Tremens
Authors: POWERS JAMES S. , DECOSKEY DARLA , KAHRILAS PETER J.
Published: March 2013

Abstract: Two case reports of complicated delirium tremens are presented with documentation of successful management with physostigmine. The therapy of delirium tremens is reviewed and theoretical considerations discussed, with reference to an adrenergic/cholinergic imbalance model for delirium tremens.
Phase I Study of Ceftizoxime, a New Cephalosporin. Single‐Dose Study
Authors: NAKASHIMA N. , SUZUKI K. , HASHIMOTO H. , NISHIJIMA K.
Published: March 2013

Abstract: A phase I study of ceftizoxime, a new cephalosporin, was performed in 29 subjects. No abnormalities were observed in subjective symptoms, laboratory test results, or physical test results at estimated therapeutic doses of 500 mg intramuscularly, 500 and 1000 mg intravenously, and 2000 mg drip infusion. It is concluded, therefore, that the drug is safe for clinical use. The mean peak serum concentration was dose dependent. The mean serum concentrations of ceftizoxime in man at 5 minutes after 500 and 1000 mg by intravenous bolus were 58.4 and 112.8 μg/ml, respectively, which exceed the MIC80 against most pathogens tested. Thus, 500 or 1000 mg was estimated to be the therapeutic dose. The distribution volume of ceftizoxime was 16.0 to 18.6 liters, the total clearance was 135.6 to 154.9 ml/min, and the half‐life in the β‐phase was 1.36 to 1.39 hours. Ceftizoxime is mainly excreted in the urine as unchanged drug, at an excretion rate in the 24‐hour urine of approximately 80 per cent.
Impairment of Digoxin Clearance by Coadministration of Quinidine
Authors: OCHS HERMANN R. , BODEM GUNTHER , GREENBLATT DAVID J.
Published: March 2013

Abstract: Seven healthy volunteers received a single 1.0‐mg dose of intravenous digoxin in a drug‐free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half‐life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min‐kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long‐term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P < 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.
Absorption, Biotransformation, and Pharmacokinetics of Salicylsalicylic Acid in Humans
Authors: HARRISON LESTER I. , FUNK MARY L. , RÉ OZVALDO N. , OBER ROBERT E.
Published: March 2013

Abstract: The absorption, biotransformation, and pharmacokinetics of the antiinflammatory drug salicylsalicylic acid (SSA) were studied. Healthy adult males received 1000 mg SSA and 1300 mg aspirin according to a crossover design either as a single oral dose (12 subjects) or three times a day for five days (4 subjects). A newly developed, high‐pressure liquid chromatographic assay permitted selective, direct measurement of SSA in the presence of high concentrations of salicylic acid, one of its metabolites. Following a single dose, SSA was promptly absorbed (mean time to peak level 1.5 hour) and was eliminated from plasma with a mean half‐life of 1.1 hour. Less than 1 per cent was excreted in the urine as unchanged SSA. SSA did not accumulate in the plasma during multiple dosing. Plasma levels of salicylic acid following single and multiple doses of SSA indicate that SSA is extensively hydrolyzed to salicylic acid in the body. The slightly lower levels of salicylic acid after SSA than after aspirin may reflect direct biotransformation of some of the SSA to an SSA conjugate, without hydrolysis to salicylic acid.
Dyphylline Elimination Kinetics in Lactating Women: Blood to Milk Transfer
Authors: JARBOE CHARLES H. , COOK LARRY N. , MALESIC IRENE , FLEISCHAKER JENNA
Published: March 2013

Abstract: A population of 20 normal lactating females between the ages of 20 and 35 years was treated with a single 5 mg/kg intragluteal dose of dyphylline, 7‐(2,3‐dihydroxypropyl)theophylline. The distribution of the drug between blood and milk and its pharmacokinetics of elimination were determined. The apparent volume of distribution (Vd) of dyphylline was found to be 0.505 ± 0.162 l./kg, the elimination rate constant (kel) was 0.228 ± 0.055 hr−1, the biological half‐life (t1/2) was 3.21 ± 0.76 hr, and the total body clearance (Cl) was 0.109 ± 0.036 l./kg/hr. The ratio described by dyphylline distribution between milk and serum (M/S) was 2.08 ± 0.52. The elimination rate from milk was equivalent to that from blood.
Lincomycin Serum and Saliva Concentrations After Intramuscular Injection of High Doses
Authors: SMITH R. B. , LUMMIS W. L. , MONOVICH R. E. , DeSANTE K. A.
Published: March 2013

Abstract: Serum and saliva levels of lincomycin were determined in 15 normal adult male volunteers after a single intramuscular injection of 600, 1000, or 1500 mg lincomycin in a three‐way crossover study. The area under the serum concentration—time curve did not increase in proportion to the increase in dose. The increase in concentration of lincomycin in saliva was greater than expected for the increase in dose. There were no significant differences in elimination half‐life between doses. These results suggest that the apparent clearance of lincomycin increases with increasing dose possibly because of a decrease in serum protein binding of lincomycin at high serum concentrations.
Effects of Chronic Prazosin Treatment on the Renin—Angiotensin—Aldosterone System in Man
Authors: BARBIERI CRISTIANO , FERRARI CARLO , CALDARA ROBERTO , RAMPINI PIETRO , CROSSIGNANI ROSA MARIA , BERGONZI MARIO
Published: March 2013

Abstract: The effects of chronic prazosin treatment (3 mg/day for three weeks) on plasma renin activity (PRA) and plasma aldosterone (PA) levels were evaluated in 12 hypertensive patients, under conditions of metabolic balance. After three weeks of drug administration no significant change occurred in PRA as well as PA levels, with respect to pretreatment values, both in basal conditions and following 2 hours of ambulation. No change was observed in heart rate, while a fall in both systolic (P < 0.02) and diastolic (P < 0.05) blood pressure occurred in supine as well as in deambulation‐stimulated condition. A mild increase in body weight (P < 0.05) and a decrease in serum sodium (P < 0.05) was induced by prazosin treatment. These findings are in keeping with the pharmacologic properties of prazosin, which is a selective blocker of postsynaptic alpha adrenoreceptors and therefore lowers vascular resistance without reflex sympathetic overactivity. The moderate volume expansion after prazosin does not appear to be aldosterone mediated.
Flutroline in the Treatment of the Schizophrenic Patient
Authors: KURLAND ALBERT A. , NAGARAJU ARRAMRAJU , HANLON THOMAS E.
Published: March 2013

Abstract: As an introduction into a clinical study of one of a new group of compounds having neuroleptic potential, the background and characteristics of the gamma carbolines, particularly flutroline, are cited in the general context of a review of the use of antipsychotic drugs in psychiatry. In the four‐week double‐blind trial involving dosages of 1, 5, 10, 20 and 100 mg, 48 hospitalized schizophrenic patients were given the tryptoline derivative flutroline on a once‐a‐day basis. Outcome criteria obtained weekly, including the incidence of side effects, standardized psychiatric ratings, and clinical global impressions of psychopathology, indicated that flutroline was a safe and effective antipsychotic drug. Data suggested that dosages of 20 mg and above offered the best potential for optimal clinical effectiveness.
Long‐Term Captopril Therapy: Evolving Hemodynamic Effects
Authors: SULLIVAN JAY M. , TAYLOR JOHN C. , PATRICK DARRELL R. , JOHNSON JAMES G. , RATTS THOMAS E. , MUIRHEAD E. ERIC
Published: March 2013

Abstract: Nine patients with resistant hypertension received captopril for 12 months. Five received captopril alone, four required additional therapy. In the former, mean blood pressure fell from 109 ± 4.2 mm Hg to 84 ± 7.5 mm Hg (P < 0.025) after seven days. A rise to 101 ± 19 mm Hg was noted at six and 12 months. Total peripheral resistance fell at seven days but returned to levels above control at six and 12 months. Cardiac index was 3.21 ± 0.55 liters/min/m2 before treatment, 3.27 ± 0.56 liters/min/m2 at seven days, and 2.17 ± 4.0 liters/min/m2 (P < 0.025) at 12 months. However, forearm blood flow rose from subnormal levels during the 12 months of observation, suggesting a persistent effect on the arterioles of the extremities. Plasma converting enzyme activity was significantly reduced at seven days but was above control levels at six and 12 months. However, plasma renin activity remained elevated, and plasma aldosterone concentration was significantly reduced. The fall in mean blood pressure was not related to the change in plasma converting enzyme activity in patients receiving captopril alone (five patients) or with diuretic (two patients). In the presence of beta‐adrenergic blockade and volume depletion (two patients), changes in mean blood pressure appeared to be related to changes in converting enzyme activity. The data suggest that patients with essential hypertension whose blood pressure was not adequately controlled by previous medications may initially respond to captopril with a fall in blood pressure and total peripheral resistance. However, in certain individuals, these effects diminish with time despite addition of diuretics and beta‐adrenergic receptor blocking agents.
Protein Binding and Bilirubin Displacing Properties of Bumetanide and Furosemide
Authors: TURMEN TOMRIS , THOM PHILLIP , LOURIDAS A. TOM , LeMORVAN PATRICK , ARANDA JACOB V.
Published: March 2013

Abstract: We evaluated the protein binding and comparative bilirubin displacing properties of bumetanide and furosemide in pooled adult and cord serum by ultrafiltration (UF), difference spectra (DS), and Sephadex Gel‐25 (SG‐25) filtration. By UF, bumetanide was found to be highly protein bound (96.7 per cent), similar to published data on furosemide (97.2 per cent). SG‐25 filtration and DS showed an equal shift to the left of the free bilirubin curve when bumetanide and furosemide were added to serum, in adult and cord, at equimolar concentrations and both shifted the free bilirubin curve equally. Bilirubin displacement was greater (P < 0.001) in cord than in adult serum with both drugs. When “presumed therapeutic” plasma concentration of furosemide (1–2 mg/liter) and bumetanide (0.5 mg/liter) were compared, it was noted that bumetanide displaced significantly less (P < 0.001) bilirubin from albumin in cord blood than furosemide. Hence, bumetanide displaces less bilirubin at “presumed therapeutic” plasma concentrations than furosemide, suggesting that it might be more prudent to use bumetanide in sick neonates with hyperbilirubinemia. Data also provide evidence that bilirubin displacement by both diuretics is greater in neonatal serum albumin than in the adult.
Pharmacokinetics of Tinidazole in Male and Female Subjects
Authors: CHAIKIN PHILIP , ALTON KEVIN B. , SAMPSON CAROLE , WEINTRAUB HOWARD S.
Published: March 2013

Abstract: Tinidazole is a potent nitroimidazole compound active against, and used to treat, Trichomonas vaginalis infections in males and females. Speculation exists in the literature that observed differences in tinidazole plasma concentrations between males and females may be due to sex‐mediated pharmacokinetic differences. To investigate this phenomenon, a study was designed to determine the pharmacokinetics of tinidazole in male and female subjects. Six male and six female volunteers were each administered a single 2‐Gm oral dose of tinidazole. Plasma and urine samples, collected over a 72‐hour period, were assayed by a sensitive and specific HPLC assay. Results demonstrate a significant correlation between tinidazole oral plasma clearance and body weight and apparent volume of distribution of tinidazole and body weight for male and female subjects, respectively. There were no apparent sex‐mediated differences in weight‐normalized pharmacokinetic parameters as documented by statistically equivalent mean oral plasma clearances (36.1 and 35.4 ml/kg/hour), apparent volumes of distribution (0.65 and 0.63 liter/kg), and elimination half‐lives (12.3 and 12.3 hours, males and females, respectively). Mean area under the tinidazole plasma concentration‐versus‐time curve and mean peak plasma concentration of tinidazole were 1.3 times greater for females than for males, apparently due to the smaller mean body weight of females and consequently a 1.3 times greater administered dose to the females on a weight basis.
Flurazepam for Short‐Term Treatment of Complaints of Insomnia
Authors: ROEHRS TIMOTHY , ZORICK FRANK , KAFFEMAN MARK , SICKLESTEEL JEANNE , ROTH THOMAS
Published: March 2013

Abstract: The short‐term hypnotic efficacy of 15 mg flurazepam was evaluated in nine patients (mean age 37.2 ± 15.9 years) who complained of insomnia and had polysomnographic evidence of disturbed sleep. Patients slept in the laboratory 14 consecutive nights, and their sleep was monitored using standard polysomnographic procedures. Prior to bedtime, they received a placebo the first four nights, 15 mg flurazepam on nights 5 through 11, and a placebo again on nights 12 through 14. Flurazepam significantly increased total sleep time while reducing the latency to stage 1 sleep, the number of awakenings in the night, and the amount of wakefulness after sleep onset. Sleep stage patterns also were altered significantly with flurazepam: percentage stage 2 sleep increased, and percentages of stage 3–4 sleep and REM sleep (on drug night 1 and nights 1–3) decreased. With the exception of REM sleep, most of these drug effects were first detected on the second night of administration, did not diminish over the next six nights, and persisted during the three‐day withdrawal period. Subjective evaluations of sleep generally corresponded with the polysomnographic data. It was concluded that 15 mg flurazepam has significant hypnotic properties with minimal adverse side effects.
Pharmacokinetics of Primidone Elimination by Uremic Patients
Authors: LEE CHING‐SAN C. , MARBURY THOMAS C. , PERCHALSKI ROBERT T. , WILDER BUNA J.
Published: March 2013

Abstract: The hemodialyzability of primidone was investigated in four patients on long‐term hemodialysis. Primidone, 500 or 250 mg, was given orally 2 hours before hemodialysis. Blood and dialyzate samples were collected periodically during the 4‐hour dialysis and measured by gas‐liquid chromatography and high‐performance liquid chromatography for primidone. Dialysis clearance calculated by the instantaneous dialyzate method averaged 97.7 ml/min, which is considerably greater than the metabolic clearance of 30 ml/min for the drug. The extraction efficiency of the hollow‐fiber dialyzers averaged 40.2 per cent for plasma samples. A mean of 31.7 per cent of the administered dose of primidone was removed during hemodialysis. The half‐life was 5.1 hours in our patients during hemodialysis, a nearly two‐thirds reduction of the 13.9‐hour half‐life calculated in uremic patients. Because of the reduction in elimination half‐life, greater dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, we conclude that primidone is dialyzable.
Oral Clonidine for Rapid Control of Accelerated Hypertension
Authors: Marks Allan D. , Adlin E. Victor , Channick Bertram J.
Published: March 2013

Thirty emergency‐room patients, 15 men and 15 women, from 27 to 64 years old with diastolic blood pressures (DBP) >115 mm Hg, were admitted to an open‐label, oral loading trial of clonidine. At this time, their supine mean arterial pressures (MAP) averaged 150 ± 2 mm Hg. An initial clonidine dose of 0.1 to 0.2 mg was to be followed every hour by another 0.1 mg until the DBP had been lowered to a level allowing treatment to be continued on an ambulatory basis or until a total of 0.5 mg had been given. A satisfactory response—defined as a reduction of the supine DBP to 105 mm Hg or lower if the baseline was between 115 and 135 mm Hg, or reduction of a baseline DBP >135 mm Hg by at least 30 mm Hg—was achieved in all but one of the patients in an average of 118 minutes; the mean dose required was 0.26 mg. The mean reduction from the baseline MAP was 23.1 ± 0.9%. Drug‐related adverse experiences comprised drowsiness and dry mouth in 13 patients. Thereafter, 28 of the patients were chronically treated with clonidine for an average of 73 days. In 24 patients treated for at least 80 days, the daily clonidine dose averaged 0.375 mg. All the patients required concurrent diuretic therapy. A satisfactory response (as defined above) to this maintenance treatment was shown by 85% of the patients, and full blood‐pressure control (supine DBP <95 mm Hg) was attained in 78%. The mean decreases from the baseline systolic and diastolic readings (taken before the acute treatment phase) amounted to 28.6% ± 2.5% and 19.8% ± 1.3%, respectively. Side effects were essentially the same as during the oral loading phase.
Elevation of Serum Aluminum in Humans on a Two‐Day Sucralfate Regimen
Authors: Pai Sudhakar , Melethil Srikumaran , Cuddy Paul , Hall Thomas
Published: March 2013

Serum aluminum concentrations were determined in ten healthy subjects treated with phenytoin 500 mg and with sucralfate and phenytoin in a crossover fashion. Each subject received four 1,000‐mg sucralfate tablets between 8 am and 10 pm one day before the study, and this was repeated during the study day. A total of eight doses of sucralfate was administered over the two‐day period. Serum samples were drawn at 0, 2, 4, 8, 12, 24, 32, and 48 hours after administration. The areas under the serum aluminum concentration‐time curves before and after sucralfate (mean ± SD) were 496.0 ± 80.9 and 770.9 ± 146.6 hr‐ng/mL, respectively. This increase is statistically significant (P < .01), indicating that serum aluminum levels are elevated even after two days of treatment with sucralfate. The results from this study are not in agreement with the only other report on this subject.
Nalmefene: Safety and Kinetics After Single and Multiple Oral Doses of a New Opioid Antagonist
Authors: Dixon Ross , Gentile Joseph , Hsu Hon‐Bin , Hsiao Jane , Howes John , Garg Dyal , Weidler Donald
Published: March 2013

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double‐blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model‐independent pharmacokinetic analysis of the plasma concentration‐time dathowed that nalmefene was rapidly absorbed and had an elimination half‐life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a β‐glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50‐mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven‐day administration period. In most instances, the steady‐state plasma concentrations could be reasonably predicated from the single dose data and had a moderate accumulation factor (about 1.6). There was no significant difference in the mean half‐life following the first and last dose. Both studies indicate that orally administered nalmefene has a wide margin of safety in healthy men and exhibits a linear pharmacokinetic profile at the doses tested.
Cyclosporine Kinetics in Healthy Volunteers
Authors: Ptachcinski Richard J. , Venkataramanan Raman , Burckart Gilbert J. , Gray Jeffrey A. , VAN Thiel David H. , Sanghvi Ajit , Rosenthal J. Thomas
Published: March 2013

The pharmacokinetics of cyclosporine was studied in five healthy male volunteers following intravenous administration. The subjects received 2.1 mg/kg of cyclosporine as a two‐hour intravenous infusion. Blood samples were collected over the subsequent 48 hours. Cyclosporine was extracted from whole blood and analyzed by high‐performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Following the intravenous infusion of cyclosporine, the drug exhibited multicompartmental behavior. The harmonic mean distribution half‐life based on HPLC data was 0.45 hours, and the harmonic mean terminal disposition half‐life was 6.2 hours. The clearance of cyclosporine based on HPLC cyclosporine concentrations was 3.9 mL/min/kg, and the volume of distribution at steady state of cyclosporine was 1.23 L/kg. Cyclosporine has a shorter half‐life, lower clearance, and smaller Vss in healthy persons as compared to patient populations. The differences observed in the pharmacokinetics of cyclosporine in healthy persons as compared to patient populations may be due to differences in hematocrit, lipoprotein profiles, and/or concurrent drug therapy between the groups. Cyclosporine concentrations determined by RIA were consistently higher than those determined by HPLC, resulting in a significantly higher area under the blood concentration versus time curve and lower clearance rate for cyclosporine. We conclude that: (1) kinetic parameter estimates for cyclosporine are different in healthy individuals as compared with organ‐transplant recipients, and (2) the kinetic parameters for cyclosporine are different, depending on the assay technique used.
Dose‐Finding and Pharmacokinetic Study of Intramuscular Midazolam
Authors: Avram Michael J. , Fragen Robert J. , CRNA Nancy J. Caldwell
Published: March 2013

Ten healthy male volunteers received intramuscular (IM) doses of 0.050, 0.075, and 0.100 mg/kg midazolam hydrochloride or its vehicle (placebo) in a double‐blind manner until a dose producing adequate preanesthetic sedation was administered. Level of sedation, degree of impairment of psychomotor function, existence of antegrade amnesia, and incidence of side effects were evaluated after each dose. An adequate level of sedation (awake/drowsy or asleep/easily responds to verbal command for at least one hour after drug administration) was produced, beginning shortly after drug administration, in eight of the volunteers by 0.075 mg/kg; the dose producing the same effect (the optimal dose) was 0.050 mg/kg for the oldest volunteer, and the other volunteer required 0.100 mg/kg. Sedation lasted no more than four hours after administration of the optimal dose. The optimal dose in each volunteer produced an impairment of psychomotor function that lasted no more than six hours and antegrade amnesia that lasted no more than two hours. Mild erythema at the injection site occurred infrequently. The pharmacokinetic variables describing the absorption and disposition of midazolam were determined in five of the volunteers. Pharmacokinetic studies indicated that midazolam hydrochloride is absorbed rapidly from IM injection sites; this is consistent with the observation of a rapid onset of sedation. The relatively high elimination clearance of midazolam after IM administration is similar to that reported after intravenous administration. The results of this study suggest that midazolam hydrochloride 0.075 mg/kg IM provides sedation and amnesia that is satisfactory for preanesthetic medication but does not last too long into the recovery period.
A 52‐Week Comparison of Lisinopril, Hydrochlorothiazide, and Their Combination in Hypertension
Authors: Kochar Mahendr S. , Bolek George , Kalbfleisch John H. , Olzinski Patricia
Published: March 2013

Lisinopril is a long‐acting converting‐enzyme inhibitor. A 52‐week study was undertaken to compare the antihypertensive efficacy and safety of lisinopril, hydrochlorothiazide (HCTZ), and a combination of the two drugs in 24 patients with a sitting diastolic blood pressure (DBP) of 90 to 120 mm Hg. After a four‐week single‐blind placebo‐washout phase, ten patients received lisinopril, ten received HCTZ, and four received the combination in increasing doses in a double‐blind fashion for the next 12 weeks. The target blood pressure was less than 90 mm Hg DBP and a decrease of at least 10 mm Hg. For the next 12 weeks, the responders continued to receive the same medications; however, the nonresponders from the two groups received the combination, increasing the number of patients receiving both to 13. The DBP was controlled in eight of the ten patients with lisinopril, three of the ten patients with HCTZ, and 11 of 13 (four original and nine nonresponders) with the combination. For the next 28 weeks, 17 patients agreed to continue into a single‐blind phase, during which blood pressure was controlled in six of the seven patients who were treated with lisinopril alone and nine of ten who received the combination. The heart rate rose significantly in the HCTZ‐treated patients during the short‐term treatment and decreased significantly in those treated with lisinopril during the long‐term phase. Side effects were more frequent in patients receiving the combination but were always mild and subsided spontaneously. Lisinopril appeared to be more effective than HCTZ as a step‐1 drug, and the combination was superior to either agent alone.
Long‐Term Antiarrhythmic Therapy With Cibenzoline
Authors: Mohiuddin Syed M. , Hilleman Daniel E. , Esterbrooks Dennis , Mooss Aryan N. , Stengel Lois A.
Published: March 2013

This single‐blind, placebo‐controlled study evaluated long‐term therapy with cibenzoline in 19 patients with chronic ventricular arrhythmias. Antiarrhythmic efficacy, defined as ≥75% reduction in single premature ventricular complexes (PVCs), ≥90% reduction in paired PVCs, and total abolition of ventricular tachycardia (VT), was established after dose titration in 14 of 19 (74%) patients. Mean frequency of single PVCs was reduced by 65%, mean paired PVC frequency was reduced by 68%, and mean VT event frequency was reduced by 82%. Antiarrhythmic efficacy was maintained during long‐term therapy in five of the 14 (36%) short‐term responders. Of the nine patients who discontinued cibenzoline during long‐term follow‐up, five had a loss of arrhythmia control, three failed to redevelop arrhythmias during placebo reintroduction, and one developed an adverse reaction. Three patients (16%) experienced a proarrhythmic effect. Echocardiographic evaluation did not reveal any deleterious effect of cibenzoline on left ventricular function in the group as a whole. In six patients with preexisting left ventricular dysfunction, left ventricular ejection fraction and fractional shortening improved significantly (P < .05) during cibenzoline therapy. Adverse effects occurred in seven patients (37%) but necessitated drug discontinuation in only one patient (5%). Cibenzoline provides effective short‐term therapy for patients with chronic ventricular arrhythmias. Long‐term therapy must be assessed periodically to ensure continued efficacy. Drug‐related adverse effects occur infrequently. Cibenzoline can be used safely in patients with compensated left ventricular dysfunction.
The Effects of Slow Channel Blockers and Beta Blockers on Atrioventricular Nodal Conduction
Authors: Prystowsky Eric N.
Published: March 2013

The PR interval on the electrocardiogram represents the time that it takes an impulse to travel through the atrium and atrioventricular (AV) conduction system to the ventricles. Normally, activation is slowest in the AV node, and variations in PR interval most commonly parallel changes in AV nodal activation time. The AV nodal conduction time and effective refractory period are rate dependent and, in adult humans, are usually prolonged with increasing atrial paced rates, In addition, alterations in autonomic tone effect AV nodal conduction as well as sinus rate. The effect is usually in the same direction but often to different degrees, In patients with normal AV nodal function, parasympathetic and sympathetic tone are balanced at rest, but in patients with abnormal AV conduction, the effect of the parasympathetic system is more marked. Drugs including the slow channel blockers and beta blockers, affect AV nodal function. Slow channel blockers inhibit the slow inward calcium current, which may prolong conduction and refractoriness in the AV node. However, whereas diltiazem and verapamil have been shown to prolong AV nodal conduction and refractoriness in humans, nifedipine, a potent vasodilator, cannot be used in doses large enough to affect the AV node. The increase in PR interval caused by verapamil is minimal, and at doses of less than 480 mg/d, AV block occurs infrequently. When AV block occurs, it is first degree block in most patients, and it is usually asymptomatic. The electrophysiologic effects of diltiazem are similar to those of verapamil. Beta blockers also have a negative dromotropic effect on the AV node. They prolong the AH interval and AV nodal refractory periods and may lengthen the PR interval. The prolonged PR interval rarely results in more than first degree AV block in patients receiving maintenance therapy, In selected patients, combination therapy with a slow channel blocker and a beta blocker rarely causes second‐degree AV block.
The Pharmacokinetics of Oral Isradipine in Normal Volunteers
Authors: Clifton G. Dennis , Blouin Robert A. , Dilea Clifford , Schran Horst F. , Hassell Alan E. , Gonasun Leonard M. , Foster Thomas S.
Published: March 2013

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5‐, 5‐, and 10‐mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5‐mg capsules, one 10‐mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean ± SD) for the 10‐mg solution and 10‐mg capsule in Study 2 were time to maximum concentration, 0.40 ± .28 and 1.57 ± 0.44 hours; oral clearance, 284.9 ± 105.3 and 317.0 ± 138.4 L/hr; elimination half‐life, 5.36 ± 1.8 and 6.63 ± 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.
Comparison of Lorazepam and Flurazepam as Hypnotic Agents in Chronic Insomniacs
Authors: McClure D. J. , Walsh J. , Chang H. , Olah A. , Wilson R. , Pecknold J. C.
Published: March 2013

Hypnotic efficacy and safety of 3 weeks of daily doses of 2 mg lorazepam or 30 mg flurazepam were compared in a double‐blind cross‐over study in eight chronic insomniacs between the ages of 29 and 60 years. Subjects were monitored in the sleep laboratory twice weekly for a total of 25 nights. Also, subjective estimates of sleep, vigilance tests, and adverse effects were recorded throughout the study. Findings indicated lorazepam performed better than flurazepam in most sleep parameters. With lorazepam there was improvement from baseline in percentage of sleep time (P < .05); in total wake time after sleep onset (P < .01) and in last third of night (P < .05); in percentage of stage 2 (P < .05) (weeks 1, 2, 3) and in percentage of night in stage 4 (weeks 2 and 3). Only total wake time from baseline improved (P < .05) with flurazepam (week 2). Objective and subjective sleep parameters did not correlate well for either drug. Neither drug impaired REM sleep or vigilance test performance. Side effects (grogginess, lethargy; flurazepam only) were few and none was unexpected; neither rebound insomnia nor early morning insomnia occurred with either drug, In summary, both lorazepam 2 mg at bedtime and flurazepam 30 mg at bedtime were found to be effective and safe for treating chronic insomnia, as measured by parameters of sleep and daytime functioning. Lorazepam had more favorable effects on sleep than did flurazepam.