bluuebunny/crossref_metadata_2025 huggingface dataset:
End-Stage Renal Disease Due to Hydronephrosis in a Patient with Artificial Urinary Sphincter
Authors: Kosmadakis George , Smirloglou Despoina , Gobou Athina , Draganis Theodoros , Michail Spiridon
Published: March 2013

In this report we describe the case of a 65-year-old diabetic patient who developed hydronephrosis and irreversible end-stage renal disease nine years after the placement of an AMS 800™ artificial urinary sphincter. This was due to non-compliance with the voiding regime and lack of follow-up after the placement of the urinary sphincter.
B Vitamins and Cognitive Performance in Older Adults: Review
Authors: Reay J. L. , Smith M. A. , Riby L. M.
Published: March 2013

A copious amount of scientific scrutiny has been dedicated to documenting typical and atypical human ageing, with a substantial body of work focusing upon the impact of lifestyle choices. One such lifestyle choice is that of diet and, in particular, micronutrient ingestion. Epidemiological studies have reported positive associations between B vitamin status and cognitive function, including negative associations between biological markers (i.e., homocysteine) of dysregulated one-carbon metabolism and cognitive function. This has led to a surge of randomised control trials (RCTs) investigations into B vitamin therapy. However, results have continuingly failed to show beneficial behavioural effects. Despite this, results reliably show treatment-related increases in B vitamin level and decreases in homocysteine level—both of which have been identified as risk factors for atypical ageing. In this paper we argue that it would be premature to conclude that B vitamin therapy has no potential and that more research is needed to systematically investigate the optimal dose, the therapeutic “window,” and individual differences in therapy responders and nonresponders. We start with a brief look at one-carbon metabolism and then consider the evidence from epidemiological studies and RCTs in relation to three specific B vitamins: folic acid (B9), pyridoxine (B6), and cobamides (B12).
Korpusová analýza jazykové přesnosti v písemném projevu studentů angličtiny jako cizího jazyka
Authors: Tůma F.
Published: March 2013

V této studii prezentujeme dílčí výsledky výzkumu z oblasti didaktiky cizích jazyků, ve kterém bylo využito analýzy žákovského korpusu. Hlavní výzkum se zaměřoval na rozvoj komunikační kompetence v oblasti psaní v tzv. blended learning kurzu u vysokoškolských neoborových studentů angličtiny jako cizího jazyka. Ve studii nejdříve stručně konceptualizujeme procesy rozvíjení komunikační kompetence a poté se zaměřujeme na měření výsledků těchto procesů v oblasti jazykové přesnosti. Výzkumný soubor tvořilo 18 studentů v kurzu angličtiny na úrovni A2 dle SERRJ (2002), kteří participovali ve třech diskusních úkolech provedených v online prostředí za použití asynchronního diskusního fóra. Projektování diskusí vycházelo ze sociálně-konstruktivistických teorií učení. Hlavním výzkumným nástrojem byl žákovský korpus založený na textech napsaných studenty ve dvou online diskusích. Výsledky ukázaly, že se u studentů celková úroveň komunikační kompetence v oblasti psaní zvýšila. Zjištění vyplývající z analýzy korpusu zaměřené na jazykovou přesnost se ovšem jeví v některých oblastech jako ne zcela průkazná. Výsledky výzkumu naznačují, že jazyková přesnost studentů souvisela s vyjadřovaným obsahem. Studie ukazuje možné využití žákovských korpusů ve výzkumu zaměřeného na jazykovou přesnost a upozorňuje na některá jejich omezení.
 Língua brasileira de sinais e implante coclear: relato de um caso
Authors: Valadao Michelle Nave , Nomura Jilma Andrade , Mazer Debora Hungria , Isaac Myriam De Lima
Published: March 2013

http://dx.doi.org/10.5902/1984686X2318A perda auditiva é uma das privações sensoriais mais comum nos homens. A principal consequência da perda auditiva reside em sua repercussão no desenvolvimento da linguagem oral e, consequentemente, interferindo em todo o processo de aprendizagem da leitura e escrita. O implante coclear é um dispositivo eletrônico, parcialmente implantado, que visa a proporcionar aos seus usuários sensação auditiva próxima ao fisiológico. É uma boa opção aos portadores de surdez sensorioneural profunda, entretanto, não assegura o desenvolvimento das habilidades auditivas e de linguagem oral. Assim, por não desenvolverem a linguagem oral, os indivíduos com implante coclear não podem ser privados da possibilidade da aquisição e do desenvolvimento da linguagem, pois podem fazer isso utilizando outra forma de comunicação – a língua de sinais. O objetivo deste relato é descrever a experiência do atendimento multidisciplinar de uma criança usuária de implante coclear. B.V.S.R. oito anos, gênero masculino, portador de perda auditiva sensorioneural profunda, bilateral desde o período neonatal. Realizou cirurgia de implante coclear aos três anos de idade, sendo acompanhado segundo abordagem aurioral. Devido ao baixo desempenho escolar apresentado, foi discutido com a equipe multidisciplinar e decidido modificar a abordagem, optando-se por iniciar aprendizagem de língua brasileira de sinais.  Após um período de dois anos, segundo a nova abordagem, a criança apresentou considerável evolução em todos os aspectos do desenvolvimento. A mudança de abordagem influenciou positivamente na evolução da criança, pois a mesma alcançou adequado desempenho em diversas habilidades linguísticas.Palavras-chave: Surdez. Implante coclear. Língua brasileira de sinais.
 Estudo comparativo de observação de habilidades sociais de gêmeas com e sem deficiência visual
Authors: Costa Carolina Severino Lopes da , Prette Almir Del
Published: March 2013

http://dx.doi.org/10.5902/1984686X3552O objetivo geral foi descrever e caracterizar o desempenho social de duas crianças, gêmeas idênticas, com dez anos de idade: uma cega e outra vidente. Os dados foram obtidos pela realização de filmagens das crianças em situações livres. As filmagens foram avaliadas por meio de um protocolo de observação das situações livres, de modo que os desempenhos das crianças possibilitaram inferir as classes de habilidades sociais. Os resultados mostraram que a criança vidente apresentou repertório de habilidades sociais mais amplo e refinado do que o de sua irmã. Com base nos dados, pode-se concluir que, neste caso, crianças cegas e videntes possuem repertórios de habilidades sociais distintos, sendo que as diferenças podem estar relacionadas tanto à variável cegueira quanto às diferenças na maneira como o ambiente estimula as crianças.Palavras-chave: Deficiência Visual. Habilidades Sociais. Irmãos gêmeos.
 Inclusão escolar, redes de apoio e políticas sociais
Authors: Bendinelli Rosanna Claudia , Prieto Rosângela Gavioli , Andrade Simone Girarde
Published: March 2013

http://dx.doi.org/10.5902/1984686X4058A educação como direito de todos e a qualidade de ensino são metas que ainda requerem investimentos intensos do poder público e da sociedade brasileira. Quando se trata de pessoas com deficiência, transtornos globais do desenvolvimento e altas habilidades/superdotação, o seu acesso e permanência na escola, muitas vezes depende de articulação de políticas para além das de educação. Nas orientações normativas nacionais e em recomendações internacionais preconiza-se a constituição de redes de apoio. Os resultados da pesquisa aqui apresentados focalizam itinerários do município de São Paulo para implementar sua política de educação especial e destaca as ações relativamente às redes de apoio. Para sua realização foram compiladas fontes documentais; aplicadas entrevistas semiestruturadas com profissionais da educação especial; e preenchidos formulários de caracterização dos profissionais. Na análise, com procedimentos afeitos à abordagem qualitativa, o conjunto de informações foi cotejado com a legislação de onde buscou-se apreender os avanços e pontos a serem fortalecidos na referida política municipal. Os resultados mostraram que nos quatro anos foram inegáveis os avanços da educação especial no município, muito embora a profusão de demandas dirigidas aos centros de apoio municipais se sobrepusesse à necessária implementação e consolidação de parcerias e redes de apoio. Destaca-se que redes intersecretariais eram indicadas como necessárias e que estas dependiam de ações no âmbito da gestão pública, pois extrapolava o status político-administrativo dos centros a realização de intervenções dessa natureza junto a instâncias hierarquicamente superiores, sejam secretarias municipais da educação ou de outras áreas sociais.Palavras-chave: Educação especial. Política educacional. Direito à educação.
Les formes sociales de l’homosexualité masculine à Bamako dans une perspective comparée : entre tactiques et mobilisations collectives
Authors: Broqua Christophe
Published: March 2013

La situation actuelle des hommes qui ont des pratiques homosexuelles à Bamako, comme dans d’autres métropoles africaines, présente de fortes similarités avec celle des homosexuels occidentaux durant les décennies qui ont précédé les mouvements dits de « libération ». Parmi les observateurs extérieurs, ces similarités nourrissent parfois l’idée que la situation de ces Africains pourra connaître un sort comparable à celui des homosexuels des pays occidentaux, implicitement positionnés au sommet d’une hiérarchie du développement socio-sexuel, conduisant ainsi à l’adoption d’une lecture évolutionniste. Cet article propose de penser les effets de la mondialisation sur l’évolution des formes sociales de l’homosexualité en Afrique en évitant le double écueil d’une conception évolutionniste et d’une lecture en termes d’homogénéisation des cultures sexuelles.
Morphological and sedimentological assessment of submarine dune fields on the coast of Yucatan, Mexico
Authors: Cuevas Eduardo , Liceaga-Correa María de los Ángeles , Rincón-Sandoval Luis Alberto , Mexicano-Cíntora Guadalupe , Arellano-Méndez Leonardo , Euán-Ávila Jorge I , Hernández-Núñez Héctor , Mulsow Sandor
Published: March 2013

Conspicuous sedimentary deposits forming well-structured and prominent submarine dunes are found on the coast of Yucatan (Mexico), close to the ports of Dzilam de Bravo, San Felipe, and El Cuyo. The objective of this study was to evaluate the morphological and sedimentological features of these submarine dunes. Sub-bottom seismologic profiles were obtained and standardized sedimentological analyses were performed on sediment samples collected at the three study sites. Both the height and wavelength of dunes were different between the three sites, mean heights ranging from 0.84 to 2.28 m and mean wavelengths from 98 to 330 m. Most of the dunes showed a wellmarked asymmetry, which is related to the direction of their movements. Their granulometric composition was dominated by medium, moderately well-sorted sand. This study provides bases for future systematic monitoring of these peculiar ecosystems, including information to be considered for the evaluation of their ecological role in the marine system.
Oxidative damage associated with thermal stress in Pocillopora verrucosa from the Mexican Pacific
Authors: Rodríguez-Troncoso Alma Paola , Carpizo-Ituarte Eugenio , Cupul-Magaña Amilcar
Published: March 2013

Coral communities are under increasing pressure from anomalous increases in sea surface temperature. These events have had negative effects on reef ecosystems and it is important to get a better understanding of the cellular mechanisms that allow organisms to survive the stress period before bleaching is evident. To gain insight into the effect of increased temperature on coral communities off the Pacific coast of central Mexico, we evaluated CuZnSOD (superoxide dismutase) activity in branches of Pocillopora verrucosa by simulating stress conditions (31 ºC) and non-stress conditions. There was an increase in SOD activity after 18 h of exposing the corals to 31 ºC, while no increase in activity was observed at 28 ºC. These results were used to quantify the maximum levels of CuZnSOD activity before Symbiodinium were expelled to prevent cell damage due to oxidative stress. We determined that CuZnSOD can be used as a molecular marker to quantify stress levels, prior to bleaching, in coral communities of the region.
Incentivising resource sharing in social clouds
Authors: Punceva Magdalena , Rodero Ivan , Parashar Manish , Rana Omer. F. , Petri Ioan
Published: March 2013

Social Clouds provide the capability to share resources among participants within a social network—leveraging on the trust relationships already existing between such participants. In such a system, users are able to trade resources between each other rather than make use of capability offered at a (centralized) data center. Although such an environment has significant potential for improving resource utilization and making available additional capacity that remains dormant, incentives for sharing remain an important hurdle limiting its effective. In this paper, we utilize the socioeconomic model proposed by Silvio Gesell to demonstrate how a ‘virtual currency’ can be used to incentivise sharing of resources within a ‘community’. We subsequently demonstrate, through simulations, the benefit provided to participants within such a community using a variety of economic (such as overall credits gained) and technical (number of successfully completed transactions) metrics. Further, we describe our implementation of such a Social Cloud using CometCloud. CometCloud is an autonomic computing engine for cloud and grid environments. It supports highly heterogeneous and dynamic federated cloud/Grid infrastructures, integration of public/private clouds and autonomic cloudbursts. We demonstrate the implementation of two designs on the basis of the master/worker approach: (i) one tuple space per cluster and (ii) one coordination tuple space and multiple transient spaces—one per each cluster. Finally, we discuss an extended version of our Social Cloud model where intermediary relay nodes take on more active roles as traders in a transaction. Copyright © 2013 John Wiley & Sons, Ltd.
Genetic Predisposition and Environmental Danger Signals Initiate Chronic Autoimmune Hepatitis Driven by CD4+ T Cells
Authors: Hardtke-Wolenski Matthias , Fischer Katja , Noyan Fatih , Schlue Jerome , Falk Christine S. , Stahlhut Maike , Woller Norman , Kuehnel Florian , Taubert Richard , Manns Michael P. , Jaeckel Elmar
Published: March 2013

Autoimmune hepatitis (AIH) is defined as a chronic liver disease with loss of tolerance against liver tissue eventually leading to cirrhosis if left untreated. 80%-90% of patients can be treated with a life-long immunosuppression. Unfortunately, there are strong drug-related side effects and steroid-refractory patients. Therefore, there is a need for a model system to investigate the complex immunopathogenesis of this chronic disease and subsequently to develop new therapeutic interventions. We developed a new model of experimental murine AIH (emAIH) by a self-limited adenoviral infection with the hepatic autoantigen formiminotransferase cyclodeaminase (FTCD). After an initial transient hepatitis there was a chronic evolving AIH, finally leading to portal and lobular fibrosis. We could show that the genetic predisposition provided by the NOD background was essential for creating a fertile field for the development of liver-specific autoimmunity. However, a strong environmental trigger was additionally necessary to initiate the disease. Besides the break of humoral tolerance, T-cell tolerance against hepatic self-antigens was also broken and CD4+ T cells were identified as essential drivers of the disease. As the disease was successfully treated with prednisolone and budesonide, the model will be helpful to develop and test new therapeutic interventions.

Conclusion

: We developed a new murine AIH model closely resembling AIH in patients that explains the mechanisms of AIH pathophysiology. In addition, emAIH provides options to test therapeutic alternatives for patients not achieving remission, with reduced side effects of chronic nonspecific immunosuppression. (Hepatology 2013;58:718–728)
Effect of Food on the Bioavailability and Pattern of Release of a Sustained‐Release Theophylline Tablet
Authors: LEEDS NORMAN H. , GAL PETER , PUROHIT ANAL A. , WALTER JONNE B.
Published: March 2013

Abstract: The effect of food on the bioavailability, time to peak level, and pattern of release of a sustained‐release theophylline preparation was examined in six normal volunteers. The average bioavailability for the 100‐ and 300‐mg tablets was 98 ± 0.03% (S.E.M.). This is consistent with previously published data. Food decreased measured theophylline concentration during the first 4 hours for the 100‐mg tablets and at the fourth‐hour sample following the 300‐mg tablets. The decreased rate of absorption resulted in a shift of the absorption curve to the right with a delay in the time to peak level. Peak serum concentrations for tablets given with a meal occurred 6 hours after the 100‐mg tablets and 8 hours after the 300‐mg tablets, as opposed to 4 and 6 hours, respectively, for tablets in the fasting state. The release pattern of the theophylline preparation approximated zero‐order kinetics for all fasting and food treatments.
Dose—Response Studies of Lormetazepam: Efficacy, Side Effects, and Rebound Insomnia
Authors: KALES ANTHONY , BIXLER EDWARD O. , SOLDATOS CONSTANTIN R. , MITSKY DAVID J. , KALES JOYCE D.
Published: March 2013

Abstract: Lormetazepam, an investigational hypnotic, was evaluated for efficacy and withdrawal phenomena in doses of 0.5, 1.0, 1.5, and 2.0 mg in four separate sleep laboratory protocols, each including four placebo baseline nights, seven drug nights, and three placebo withdrawal nights. A moderate degree of efficacy was shown across the four doses, but this was quite variable. There was no dose—response effect for efficacy for either the first three or last three nights of this short‐term administration period. In general, there was less efficacy on the later drug nights, indicating a potential for the development of tolerance over a relatively short period of time. Following drug withdrawal, there was a dose‐related worsening of sleep above baseline levels (rebound insomnia). The peak degree of worsening of sleep following drug withdrawal was more than two times greater than the peak degree of improvement of sleep with drug administration.
The Acute and Chronic Effects of Betaxolol on Blood Pressure, Renin‐Aldosterone, and Renal Function in Essential Hypertension
Authors: Reams Garry P. , Bauer John H. , Lau Alisa
Published: March 2013

The effects of betaxolol, a long‐acting, lipid‐soluble, cardioselective, beta‐adrenergic antagonist on renal function have not been previously reported. The present study was designed to prospectively assess the acute and chronic antihypertensive, humoral and renal response to betaxolol, administered once daily, to patients with essential hypertension. After a four‐week placebo run‐in period, 13 patients with essential hypertension were treated with betaxolol monotherapy for a total of eight months. Results indicate that blood pressure is reduced, and renal function remains stable. These findings are consistent with previous observations with other beta‐adrenergic antagonists.
The Effect of Acute Withdrawal from Cigarette Smoking on Indocyanine Green and Antipyrine Clearance
Authors: Eldon M. A. , Luecker P. W. , MacGee J. , Ritschel W. A.
Published: March 2013

The effects of acute withdrawal from cigarette smoking on indocyanine green (ICG) clearance and antipyrine pharmacokinetics were studied in healthy young male volunteers. Two separate crossover clinical trials, each using 12 subjects, were used to compare the disposition of the drugs from 24 to 36 hours after withdrawal to the disposition found under control conditions. The median difference of ICG clearance and all antipyrine pharmacokinetic parameters from smoking control was less than 13%, indicating that short‐term smoking withdrawal had no effect large enough to be of clinical significance on hepatic blood flow or hepatic drug‐metabolizing capacity. Rates of hepatic blood flow were normal in comparison with values published for larger sample populations. The lack of any clinically significant effect of smoking withdrawal on hepatic blood flow or on the disposition of antipyrine, a drug with very low hepatic extraction, indicates that on a pharmacokinetic basis, changes in dosage regimens for most drugs are not necessary on acute withdrawal from smoking.
Pharmacokinetic Studies of Intermediate‐ to High‐Dose 1‐β‐D‐Arabinofuranosylcytosine in Children With Acute Leukemia and Lymphoma
Authors: Takashima Yoshiki , Matsuyama Kouji
Published: March 2013

Pharmacokinetic studies of intermediate and high dose 1‐β‐d‐arabinofuranosylcytosine (araC) therapy were performed in 14 children with acute leukemia and four with non‐Hodgkin's lymphoma (NHL). AraC administration differed by method, dosage, and time of infusion to obtain the optimal tumorcidal concentration. The toxicity of these regimens was limited to transient severe nausea and vomiting, which were tolerable. Infusion time and dose are important factors to obtain optimal and clinically effective cerebrospinal fluid (CSF) araC concentrations. A concentration of araC above 1 μg/mL in CSF, which was lethal to cells in culture, was obtained by intravenous infusion of more than 2,000 mg/m2 of araC for four hours. We propose that araC 2,000 mg/m2 by constant intravenous infusion is preferable in the treatment of leukemia and is associated with the fewest side effects.
Relative and Absolute Bioavailability of Prednisone and Prednisolone After Separate Oral and Intravenous Doses
Authors: Ferry J. J. , Horvath A. M. , Bekersky I. , Heath E. C. , Ryan C. F. , Colburn W. A.
Published: March 2013

A randomized, four‐way cross‐over study was conducted in eight healthy male volunteers to determine the relative and absolute bioavailability of prednisone (PN) and prednisolone (PL). PN and PL were administered as single, oral 10‐mg tablet doses and as 10‐mg zero‐order 0.5‐hour intravenous infusions. Comparable mean PN and PL maximum plasma concentrations (Cmax), times for Cmax, areas under the plasma concentration‐time curves (AUC), and apparent elimination rate constants between tablet treatments demonstrated that PN and PL tablets were bioequivalent. Absolute bioavailability (F) determinations based on plasma PL concentrations were independent of which IV treatment was used as reference and indicated complete systemic availability of PL from both PN and PL tablets. However, F based on plasma PN data was contradictory. Using IV PN as reference, approximately 70% systemic availability was observed from both tablets, whereas using IV PL as reference, systemic availability was greater than unity. PN and PL are model compounds that exemplify the difficulties involved in accurately determining the relative and absolute bioavailability of substances that undergo reversible metabolism.
Treatment of Gram‐Negative Infections in Patients with Renal Impairment: New Alternatives to Aminoglycosides
Authors: Whelton Andrew
Published: March 2013

Aminoglycosides have become an indispensable component in the armamentarium against serious gram‐negative infections. In spite of the availability of effective guidelines for prevention, the frequency of toxic side effects associated with aminoglycoside therapy is an impetus for the substitution of safer and equally efficacious alternatives, particularly in the setting of renal impairment. Recently, three new classes of antibiotics with potent gram‐negative activity have become available. These are the monobactams, the carbapenems, and the fluorinated 4‐quinolones. The antimicrobial spectrum of aztreonam, a monobactam, closely resembles that of aminoglycosides. Imipenem, a carbapenem, is a broad spectrum antibiotic with activity against gram‐negative aerobes as well as gram‐positive aerobes and many anaerobes. Ciprofloxacin, an orally active quinolone, has gram‐positive and gram‐negative coverage against aerobes but not anaerobes. These agents offer an alternative therapeutic option to aminoglycosides and, in the setting of pre‐existing renal impairment, are particularly attractive in view of their safety.
Cardioselectivity of Cetamolol Compared With Atenolol and Nadolol
Authors: Klausner Mark A. , Ventura Daniel F. , Coelho Jaime , Mullane John F. , Irwin Christopher , Hitzenberger Gerhart , Magometschnigg Dieter , Kaik Gerhard , Garg Dyal C. , Weidler Donald J.
Published: March 2013

The selectivity of the beta‐adrenoceptor blockade produced by single oral doses of cetamolol, atenolol, and nadolol was compared in normal male subjects. Study 1 established the dose at which each drug provides equivalent beta‐1 blockade. Beta‐1 blockade was estimated using the degree of inhibition of the increased heart rate (HR) response to graded exercise. Cetamolol (30 mg), atenolol (100 mg), and nadolol (80 mg) all attenuated the HR response to a comparable extent. This result established that the dose ratio of cetamolol:atenolol:nadolol of 1.00:3.33:2.67 provides equipotent beta‐1 blockade. This ratio of doses was used in Studies 2 and 3 to evaluate the antagonism of beta‐2‐mediated responses to titrated doses of intravenous isoproterenol (ISO) by low and high doses of each drug. Beta‐2 blockade was assessed using the attenuation of ISO‐induced reductions in diastolic blood pressure (DBP) in Study 2 and ISO‐induced increases in specific airway conductance (sGAW) in Study 3. For within drug comparisons, antagonism of the HR increase induced by ISO (a response mediated by both beta‐1 and beta‐2 receptors) was also examined. Treatments included cetamolol (15 and 60 mg), atenolol (50 and 200 mg), and nadolol (40 and 160 mg in Study 2; 40 mg only in Study 3). All drugs tested suppressed the HR, DBP, and sGAW responses to ISO, and this blockade was dose dependent. Cetamolol and nadolol produced approximately equipotent beta‐1 blockade, whereas cetamolol at both doses produced a less potent beta‐2 blockade. Atenolol antagonized ISO effects on all parameters less than either cetamolol or nadolol. Quantitative cardioselectivity indices revealed that cetamolol 60 mg was the most cardioselective and nadolol 40 mg the least. Data from the three studies demonstrate that cetamolol is cardioselective relative to nadolol and that, in contrast to atenolol, cardioselectivity appears to increase at the higher dose.
Cefamandole Pharmacokinetics During Standard and Pulsatile Cardiopulmonary Bypass
Authors: Weiner Bruce , Melby Michael J. , Faraci Philip A. , Shargel Leon , Cleveland Richard J.
Published: March 2013

The pharmacokinetics of cefamandole during standard or pulsatile cardiopulmonary bypass were studied in 13 adult cardiac surgery patients. All patients received 20 mg/kg of cefamandole intravenously at midnight be/ore surgery, 6 am on the morning of surgery and just prior to the initiation of cardiopulmonary bypass (CPB) surgery. Serum, skeletal muscle, and fat samples were taken at the beginning of CPB and at 30‐minute intervals thereafter and assayed for cefamandole concentration. The average elimination rate constant and elimination half‐life for cefamandole in patients undergoing standard CPB were 0.73 ± 0.09 hour−1 and 0.94 ± 0.11 hour, respectively. In contrast patients undergoing pulsatile CPB had significantly slower elimination rate constants (0.50 ± 0.1 hour−1 and 1.4 ± 0.28 hours, respectively; P ≥ .05). Area under the curve (AUCJ values for cefamandole in fat and muscle tissue were higher in patients undergoing pulsatile CPB, but the differences were not statistically significant. Prolonged elimination from the serum, skeletal muscle, and adipose tissue, as compared with normal subjects, is seen with both pulsatile and standard CPB but is greater for the pulsatile method. Intraoperative dosing of cefamandole is required to maintain adequate serum and tissue levels for operations lasting longer than 4 or 6 hours in which standard or pulsatile CPB, respectively, are used.
Effect of Cetamolol on Epinephrine‐Induced Hypokalemia
Authors: Klausner Mark A. , Irwin Christopher , Mullane John F. , Shand David G. , Leese Philip T. , Arnold John D. , Wollberg William , Wagner Nancy B. , Wagner Galen S.
Published: March 2013

The effect of cetamolol (an investigational cardioselective beta blocker with intrinsic sympathomimetic activity) on the hypokalemic response to epinephrine infusions in normal subjects was evaluated and compared with placebo and two other beta‐adrenergic blocking drugs. After two daily doses of cetamolol 15 mg, atenolol (a cardioselective beta blocker) 50 mg; a long‐acting propranolol preparation (a nonselective beta blocker) 80 mg; or placebo, 12 men (mean age, 26.7 years) were infused with epinephrine. The resulting average plasma epinephrine level was 1123 pg/mL, whereas average baseline serum potassium levels for the four treatment groups ranged from 3.94 to 4.07 mEq/L. Epinephrine‐induced hypokalemia occurred in the placebo group (maximum potassium decrease of 1.00 mEq/L) and in the atenolol group (maximum potassium decrease of 0.59 mEq/L); potassium levels did not decrease but rose slightly in subjects receiving cetamolol or propranolol. Subjects treated with placebo or atenolol also demonstrated statistically significant prolongation of the QTCinterval (0.039 seconds with placebo; 0.023 seconds with atenolol) and frequently developed T‐wave flattening and U‐wave appearance. After pretreatment with cetamolol or propranolol however, the QTCinterval was unaffected, T‐wave abnormalities did not occur, and U waves appeared only rarely. The results of this study indicate that cetamolol blocks epinephrine‐induced hypokalemia and associated electrocardiographic changes.
Reduced Renal Clearance of Oxypurinol During a 400 Calorie Protein‐Free Diet
Authors: Kitt Therese M. , Park Glen D. , Spector Reynold , Tsalikian Eva
Published: March 2013

A decrease in dietary protein intake lowers the clearance of a number of substances excreted principally by the kidney including uric acid and oxypurinol, the major metabolite of allopurinol. We studied the kinetics of uric acid and oxypurinol in seven healthy volunteers on a normal protein diet (2600 calories; 100 g protein) followed by a 400 calorie, protein‐free diet. A 600 mg dose of allopurinol was given orally after 6 days of the normal protein diet and again after 2 days of the 400 calorie, protein‐free diet. Two major findings emerged: first, the renal clearance of oxypurinol was reduced from 21.2 ± 1.9 ml/min during the normal protein diet to 12.3 ± 1.2 ml/min (P < .05) during the 400 calorie, protein‐free diet, and second, there was a striking diurnal difference in oxypurinol renal clearance with a 41% decrease in the oxypurinol clearance at night (8 pm to 8 am) versus day (8 am to 8 pm) on the 400 calorie, protein‐free diet.
Availability and Timing of New Drugs in Israel: Analysis and International Comparison
Authors: Sax Philip
Published: March 2013

Whereas the latest data suggest that the number of new chemical entities (NCE) launches worldwide may be on the increase, both recent and longer term data show a decline in the rate of NCE introductions into Israel. In terms of percentage availability, only 30% of NCEs available worldwide during 1978–1987 were introduced in Israel during the same period, compared with 42% for the U.S.A. In both countries there has been a decreasing percentage availability since 1983/84. The percentage availability of commercially significant NCEs was greater (47%) compared to all NCEs introduced in Israel. Whereas in the U.S.A. the lower the therapeutic rating the higher the proportion of NCEs, in Israel the B‐ and C‐rated drugs were equally represented. NCEs with an A‐rating had a similar share of all NCEs (ca 15%) in both countries. The average time lag for NCEs launched worldwide to reach Israel during 1978–1987 was 4 to 5 years, but in recent years there has been a considerable decline. Commercially significant NCEs introduced in Israel had on average a shorter time lag of 0.5 years than the average for all NCEs introduced. In spite of a preponderance of NCEs first launched in the U.S.A. there was on average a slight relative lag into the U.S.A. compared to Israel. This was probably due to there being a number of NCEs first introduced in Israel with a long delay before they were subsequently approved in the U.S.A. There was an average delay for A‐rated new drugs into the U.S.A. of 7 years compared to their Israeli introduction dates, with half of these top‐rated drugs being available in Israel before they had received NDA approval. The results are discussed in terms of the regulatory process and the influence of prior registration in the U.S.A., U.K. and in other countries. Most NCEs introduced in Israel are marketed or registered beforehand in either the U.S.A. or U.K. or both. In Israel the overseas application lag is usually considerable in relation to the registration lag, which is the opposite to the U.S.A. situation. Nevertheless, in cases where there is a clear therapeutic need for a drug in Israel then it appears that the assumed influence of prior U.S.A. and U.K. registration is less of a factor. Furthermore, for NCEs with commercial potential in Israel one can assume a reduced overseas application lag.
The Efficacy and Safety of Dilevalol in Patients with Chronic Stable Angina Pectoris
Authors: Glasser Stephen P. , Bittar Neville , Kinhal Vithal , Bennett W. Tyson , Koehn Donna K.
Published: March 2013

This is the first reported large clinical trial of the antianginal and acute ischemic effectiveness and safety of dilevalol (the R, R‐isomer of labetalol) in patients with chronic stable angina pectoris. This was a multicenter double blind fixed‐dose parallel group placebo controlled trial. Patients with chronic stable angina and positive and reproducible exercise tests (±20%) were included. If randomized, patients entered one of four fixed dose groups (twice a day placebo, 100 mgm, 200 mgm and 400 mgm bid for 2 weeks). Exercise testing was performed at 2 hours (peak) and 12 hours (trough) postdosing. This was followed by a 2‐week once‐a‐day dosing regimen in which patients received the same total daily dose as the prior 2 weeks, with the full dose in the morning and a matched placebo in the evening. Exercise testing was performed at 2 hours (peak) and 24 hours (trough) postdosing. Anginal frequency and NTG consumption were significantly reduced, and equally so, by qd and bid regimens. The time of exercise to the onset of angina increased and the proportion of patients terminating exercise because of moderate angina decreased in a dose response fashion for both peak and trough tests and for both qd and bid regimens. There was also a dose related decrease in exercise induced ST segment depression and an increase in time to 1 mm ST depression. In 15 patients, 24‐hour ambulatory monitoring also revealed a decrease in episodes of silent ischemia. No significant side effects related to the study drug occurred. Thus, dilevalol was effective in the treatment of angina pectoris since it was well tolerated, favorably improved exercise induced ischemia (both painful and silent ischemia), and reduced anginal frequency and NTG consumption.
The Effect of Everyday Exercise on Steady State Digoxin Concentrations
Authors: Hall Philip D. , Garnett William R. , Kolb Kenneth W. , Rock William L. , Stanley Holly
Published: March 2013

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58–74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P < .01) change in serum digoxin concentrations. Significant (P < .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t‐test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations. Failure to consider the activity level of the patient at the time that digoxin blood samples are drawn could result in inappropriate dosage adjustments.
Clinical and Biochemical Responses to Nadolol and Clonidine in Hyperthyroidism
Authors: Herman V. S. , Joffe B. I. , Kalk W. J. , Panz V. , Wing J. , Seftel H. C.
Published: March 2013

Some features of hyperthyroidism mimic sympathetic nervous system overactivity. We have compared the clinical (scored on the Wayne Therapeutic Index), hemodynamic (blood pressure and heart rate) and biochemical (plasma epinephrine, norepinephrine, glucose, free fatty acids, insulin, growth hormone and free thyroxine index) effects of clonidine (α2‐agonist, which reduces plasma catecholamine levels) with those of nadolol (non‐selective beta adrenergic receptor antagonist) in ten female hyperthyroid patients. Each patient received nadolol for 1 week followed by clonidine for 1 week in a single‐blind manner. All measurements were made before treatment and then repeated at the end of the nadolol and clonidine treatment periods. Thyroid function remained unaltered during the study. Both agents caused significant clinical improvement— the mean Wayne Index score was 18 pretreatment, 2 on nadolol and 6 on clonidine (P < .003 for each). Heart rate was reduced by both drugs, but blood pressure was unchanged. Side effects occurred in eight out of ten patients while on clonidine. Nadolol increased plasma concentrations of epinephrine from 47 ± 18 pg/mL to 87 ± 24 pg/mL, and norepinephrine from 241 ± 154 pg/mL to 338 ± 224 pg/mL (P < .001 for each). In contrast, clonidine depressed norepinephrine levels from 241 ± 154 pg/mL to 110 ± 49 pg/mL (P < .001) without lowering plasma epinephrine significantly. Plasma free fatty acids tended to fall on both agents compared to pretreatment levels. The blood glucose, insulin and growth hormone concentrations were unaffected by either drug. We conclude that, despite the similar clinical effects of nadolol and clonidine, these drugs have contrasting effects on plasma catecholamine concentrations. Beta‐adrenergic receptor antagonists remain the drugs of choice for the symptomatic relief of hyperthyroidism, because of the high incidence of side effects caused by clonidine. However, clonidine could be considered for patients with conditions in which beta‐adrenergic antagonists are contraindicated.
Tonazocine Mesylate in Postoperative Pain Patients: A Double‐Blind Placebo Controlled Analgesic Study
Authors: Lippmann Maurice , Mok Martin S. , Farinacci John V. , Lee John C. M.
Published: March 2013

One hundred‐fifty post‐operative adult patients with moderate to severe pain were enrolled into this analgesic efficacy study comparing single doses of tonazocine mesylate, a new mixed agonist‐antagonist opioid analgesic, with morphine. The patients were randomly assigned to five treatment groups: tonazocine mesylate 2, 4, 8 mg; morphine sulfate 10 mg and a placebo group. The results showed mean total pain relief scores for tonazocine 4 mg were nearly identical with that of morphine sulfate 10 mg while 8 mg of tonazocine were superior to 10 mg of morphine. All the active medication groups were superior to the placebo group (P < 0.02) for both pain intensity and pain relief. Relative potency determined by the dose response indicates that 3.2 mg of tonazocine is equivalent to 10 mg of morphine. Drowsiness was the main adverse reaction seen in all active treatment groups. Tonazocine mesylate appears to be a potent analgesic with promising clinical usefulness and warrants further study.
Labetalol Compared with Propranolol in Patients with Both Angina Pectoris and Systemic Hypertension: A Double‐Blind Study
Authors: Frishman William H. , Shapiro William , Charlap Shlomo
Published: March 2013

Labetalol is a non‐selective β‐adrenoceptor antagonist agent with added α1‐adrenergic blocking properties, β2‐stimulating action, and direct vasodilatory activity. A multicenter, double‐blind, parallel group study compared the safety and efficacy of labetalol to propranolol in the treatment of patients with both exertional angina and mild to moderate systemic hypertension. An initial 4 to 5 week placebo washout phase was followed by a five week titration phase and a four month maintenance phase. Labetalol and propranolol had similar effects in reducing supine and standing blood pressures, except for a greater reduction in standing systolic blood pressure seen in the labetalol group. There were comparable effects by both treatments on angina attacks, nitroglycerin use, and exercise tolerance. Adverse effects were frequent with both drugs, but were generally minor. Thus, labetalol appears to be an effective alternative to propranolol in the treatment of patients with coexisting angina pectoris and hypertension, with the choice of agent dependent on the clinical situation.
Pharmacokinetics and Pharmacodynamics of Alprazolam Following Single and Multiple Oral Doses of a Sustained‐Release Formulation
Authors: Fleishaker J. C. , Phillips J. P. , Eller M. G. , Smith R. B.
Published: March 2013

The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained‐release (SR) tablet administration were evaluated in 42 healthy, normal male volunteers. All 42 subjects received a single 1‐mg intravenous (IV) alprazolam dose. After a 1‐week washout period, the subjects received one of three SR treatments as a single dose: one 1‐mg SR tablet, three 1‐mg SR tablets, or six 1‐mg SR tablets. Beginning 2 days after single‐dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple‐dose study was the same as the subject received in the single‐dose study. Serial blood samples were collected after each treatment (single‐dose IV, single‐dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were >0.84 after single SR doses. Maximal sedation was related to dose after single‐dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple‐dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing. These data suggest that an SR formulation for alprazolam may be useful in tailoring high‐dose alprazolam therapy.
Effect of Benazepril Monotherapy in Subjects with Hypertension Associated with Renal Dysfunction
Authors: Reams Garry P. , Lau Alisa , Bauer John H.
Published: March 2013

Nine hypertensive patients with mild to moderate renal dysfunction were entered into a protocol to assess the blood pressure, humoral and renal effects of the angiotensin converting enzyme inhibitor, Benazepril (CGS14824A, 2 to 20 mg twice daily) in patients with hypertension and moderate renal insufficiency (mean creatinine clearance 56 ml/min/1.73 m2). Specifically monitored, prior to and following 12 weeks of Benazepril monotherapy, were plasma renin activity and plasma aldosterone, the clearances of creatinine, Tc99m‐diethylenetriaminepentaacetic acid (TC99m‐DTPA) and para‐aminohippurate, and the 24‐hour urinary excretion of protein. Blood pressure was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed. Mean serum potassium increased from 3.9 to 4.2 mEq/L. Benazepril monotherapy had no adverse renal hemodynamic effect. Benazepril appears to be an effective antihypertensive agent in hypertensive patients with moderately impaired renal function.
Clinical Pharmacology of Dilevalol (I). Comparison of the Pharmacokinetic and Pharmacodynamic Properties of Dilevalol and Labetalol after a Single Oral Administration in Healthy Subjects
Authors: Fujimura Akio , Ohashi Kyoichi , Tsuru Masanobu , Ebihara Akio , Kondo Kazuoki
Published: March 2013

Dilevalol (25 mg → 50 mg → 100 mg) or labetalol (100 mg) was given orally in six healthy subjects. The study was carried out on four occasions with a week interval. Blood samples for plasma drug concentrations were taken for a 24‐hour post‐drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50° tilting and during a submaximal exercise were measured after each treatment.

The mean maximum plasma concentration (Cmax) as well as the mean area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner after dilevalol. These parameters after dilevalol 100 mg were significantly lower than after labetalol 100 mg. No significant differences were observed in the time to maximum concentration (tmax), the distribution half‐life (t1/2α) or the elimination half‐life (t1/2β) between dilevalol and labetalol. There were no significant differences in BP at supine position or during 50° tilting among the dosages. Postural changes in HR during 50° tilting was significantly smaller after dilevalol 100 mg than following labetalol 100 mg. The suppressing effect of dilevalol 100 mg on an increase in HR during a submaximal exercise was significantly greater than during labetalol 100 mg.

These data indicate that although plasma drug concentrations are lower after dilevalol than following labetalol, the β‐blocking activity of dilevalol is more potent than labetalol.
Nonlinear Kinetics of Trimipramine in Depressed Patients
Authors: Musa Mahmoud N.
Published: March 2013

An increase of the dose of trimipramine (TM) results in a markedly disproportionate increase of the steady‐state plasma concentration of the major active metabolite desmethyltrimipramine (DMT). Ten patients receiving 75 mg/day of TM had a mean steady‐state plasma concentration of 53.8 ng/ml TM and 26.3 ng/ml DMT. Ten others receiving 150 ng/ml TM had a mean concentration of 122.5 ng/ml TM and 133.8 ng/ml DMT. This is most likely due to the saturation within therapeutic dosage range of the subspecies of cytochrome P‐450 responsible for hydroxylation of DMT. Available data on metabolism of tricyclic antidepressants shows that the hydroxylation of desmethylimipramine (desipramine) but not that of desmethylamitriptyline (nortriptyline) reaches saturation within therapeutic dosage range. Clinicians should take into consideration the possibility of dose‐dependent kinetics when adjusting the dose of tricyclic antidepressants. This ending highlights the value of monitoring of blood levels of antidepressants.