bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin-6 Facilitates Lipopolysaccharide-Induced Disruption in Working Memory and Expression of Other Proinflammatory Cytokines in Hippocampal Neuronal Cell Layers
Authors: Sparkman Nathan L. , Buchanan Jessica B. , Heyen Jonathan R. R. , Chen Jing , Beverly James L. , Johnson Rodney W.
Published: October 2006

Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6+/+) and IL-6 knock-out (IL-6−/−) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6+/+mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6−/−mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1β and tumor necrosis factor α (TNFα), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1β and TNFα mRNA in neuronal layers of the hippocampus were determined in IL-6+/+and IL-6−/−mice after injection of LPS. Plasma IL-1β and TNFα and c-Fos immunoreactivity in the NTS were increased similarly in IL-6+/+and IL-6−/−mice after LPS, indicating high circulating levels of IL-1β and TNFα and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1β and TNFα mRNA that was evident in hippocampal tissue of IL-6+/+mice was greatly attenuated or entirely absent in IL-6−/−mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.
Neural Basis of Dyslexia: A Comparison between Dyslexic and Nondyslexic Children Equated for Reading Ability
Authors: Hoeft Fumiko , Hernandez Arvel , McMillon Glenn , Taylor-Hill Heather , Martindale Jennifer L. , Meyler Ann , Keller Timothy A. , Siok Wai Ting , Deutsch Gayle K. , Just Marcel Adam , Whitfield-Gabrieli Susan , Gabrieli John D. E.
Published: October 2006

Adults and children with developmental dyslexia exhibit reduced parietotemporal activation in functional neuroimaging studies of phonological processing. These studies used age-matched and/or intelligence quotient-matched control groups whose reading ability and scanner task performance were often superior to that of the dyslexic group. It is unknown, therefore, whether differences in activation reflect simply poorer performance in the scanner, the underlying level of reading ability, or more specific neural correlates of dyslexia. To resolve this uncertainty, we conducted a functional magnetic resonance imaging study, with a rhyme judgment task, in which we compared dyslexic children with two control groups: age-matched children and reading-matched children (younger normal readers equated for reading ability or scanner-performance to the dyslexic children). Dyslexic children exhibited reduced activation relative to both age-matched and reading-matched children in the left parietotemporal cortex and five other regions, including the right parietotemporal cortex. The dyslexic children also exhibited reduced activation bilaterally in the parietotemporal cortex when compared with children equated for task performance during scanning. Nine of the 10 dyslexic children exhibited reduced left parietotemporal activation compared with their individually selected age-matched or reading-matched control children. Additionally, normal reading fifth graders showed more activation in the same bilateral parietotemporal regions than normal-reading third graders. These findings indicate that the activation differences seen in the dyslexic children cannot be accounted for by either current reading level or scanner task performance, but instead represent a distinct developmental atypicality in the neural systems that support learning to read.
Anonymous IV as an Informant on the Craft of Music Writing
Authors: HAINES JOHN
Published: October 2006

For the 13th-century music writer known as Anonymous IV, the craft of music writing was a primary literary concern, though one virtually ignored by previous modern writers on music. The importance of music writing to Anonymous IV is evident from the variety and quantity of references in his treatise, many of which are found in its central second chapter. This information-rich chapter includes a history of music notation and a miniature handbook for music scribes. The Anonymous is indebted to the then recent surge in production of how-to manuals of all kinds; his miniature handbook for music scribes partakes of their style and vocabulary. This practical work of Anonymous IV is tied to the revival of Euclidean geometry in the liberal arts curriculum at Paris. The specialized geometric terms he uses are attested in numerous sources, including student handbooks from the university. It is possible that the anonymous writer came under the spell of Roger Bacon, also an Englishman at the University of Paris in the late 13th century, whose writing and pedagogy reveal several similarities with the music treatise of Anonymous IV.
Syncope Fever: James Weldon Johnson and the Black Phonographic Voice
Authors: BIERS KATHERINE
Published: October 2006

ABSTRACT This essay examines links between James Weldon Johnson's novel The Autobiography of an Ex-Colored Man and the cultural logic of ragtime and the phonograph during the pre-WWI era, in order to reconsider critical conceptions of voice within the African-American tradition.
Briefing: UK's ‘green’ civil engineering schemes approach £2 billion
Authors: Venables Roger
Published: October 2006

Nearly £2 billion of UK civil engineering projects have achieved or are seeking a CEEQUAL environmental quality award. CEEQUAL chief executive Roger Venables reports on the positive influence of the ICE-backed awards scheme that was launched just three years ago.
Briefing: Civil engineers remain positive about Middle East
Authors: Spragg Richard
Published: October 2006

Despite most engineers believing that the Middle East has become a more dangerous place to work since the invasion of Iraq in 2003, over half would still recommend a posting there—particularly civil engineers. Richard Spragg of staffing company EPCglobal reports on a recent attitude survey.
Management of rural water services in sub-Saharan Africa
Authors: Harvey Peter , Uno Junko , Reed Robert
Published: October 2006

Rural water supplies in sub-Saharan Africa generally rely on community management and have low levels of service sustainability. This paper reports on a review of rural water supplies throughout the sub-continent including results of field research in Uganda. It reveals that private sector approaches to service delivery have been implemented in a small number of cases but have demonstrated considerable potential for enhanced levels of sustainability. It concludes that the rural African private sector can only develop if decision-makers are prepared to accept the limitations of community management and the need to explore more sustainable alternatives.
The first sustainable industrial building projects
Authors: San José J.-T. , Garrucho I. , Cuadrado J.
Published: October 2006

The construction sector is a natural-resource-consuming agent. As a result environmental criteria and other key factors must be integrated into construction processes throughout their life cycle. On the other hand, a more general concept of sustainability considers equally economic, social and functional factors. All these matters entail the management of much information and disciplines that require a specific methodology to quantify their real influence on constructive models. In recent years, there has been progress in favour of buildings being more environmentally friendly. However, sustainable construction has centred on residential and office buildings. It could be said that there is a lack of focus on sustainability in the construction of industrial buildings, which present specific characteristics that differentiate them from residential buildings. This paper aims to analyse the sustainable environmental requirements for an industrial building by defining a system of specific indicators to assess building behaviour against these requirements, ultimately generating an assessment model as a basis for measuring a building's ‘environmental sustainability index’.
Sickness in government science: case, cause and cure
Authors: Stone M.
Published: October 2006

This paper is concerned with the poor state or ‘sickness’ of ‘government science’ —a science characterised by its statistical or operational research character, its purported usefulness to government departments in the effective implementation of public policies or projects, and the contracting of the apparently necessary research to agents whose expertise usually exceeds that which is available within a department. The paper refers to cases of ‘sickness’ drawn from the author's own experience, contractual and non-contracted. It pays particular attention to the case of the continuing Safety Camera Partnership Project: its mishandling by the Department of Transport and the consequent level of public concern. The current prevalence of such cases has deep historical roots, going back to the role of Viscount Haldane before the First World War and the neglect of the principles he later formulated. The paper concludes with a practical suggestion for how to avoid ‘sickness’ in any particular project.
Trismus‐pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8
Authors: Toydemir Reha M. , Chen Harold , Proud Virginia K. , Martin Rick , van Bokhoven Hans , Hamel Ben C. J. , Tuerlings Joep H. , Stratakis Constantine A. , Jorde Lynn B. , Bamshad Michael J.
Published: October 2006

Trismus‐pseudocamptodactyly syndrome (TPS) is a rare autosomal dominant distal arthrogryposis (DA) characterized by an inability to open the mouth fully (trismus) and an unusual camptodactyly of the fingers that is apparent only upon dorsiflexion of the wrist (i.e., pseudocamptodactyly). TPS is also known as Dutch‐Kentucky syndrome because a Dutch founder mutation is presumed to be the origin of TPS cases in the Southeast US, including Kentucky. To date only a single mutation, p.R674Q, in MYH8 has been reported to cause TPS. Several individuals with this mutation also had a so‐called “variant” of Carney complex, suggesting that the pathogenesis of TPS and Carney complex might be shared. We screened MYH8 in four TPS pedigrees, including the original Dutch family in which TPS was reported. All four TPS families shared the p.R674Q substitution. However, haplotype analysis revealed that this mutation has arisen independently in North American and European TPS pedigrees. None of the individuals with TPS studied had features of Carney complex, and p.R674Q was not found in 49 independent cases of Carney complex that were screened. Our findings show that distal arthrogryposis syndromes share a similar pathogenesis and are, in general, caused by disruption of the contractile complex of muscle. © 2006 Wiley‐Liss, Inc.
Frontonasal malformation, first branchial arch anomalies, congenital heart defect, and severe central nervous system involvement: A possible “new” autosomal recessive syndrome?
Authors: Guion‐Almeida Maria Leine , Richieri‐Costa A.
Published: October 2006

Here we report on a girl presenting with midline cleft lip/palate, prominent forehead, macrocephaly, first branchial arch anomalies, and tetralogy of Fallot. Imaging studies showed polymicrogyria, enlarged ventricles with a large cystic lesion extending postero‐superiorly over the cerebellum, abnormally modeled cerebellum, and congenital aqueductal stenosis. To our knowledge, this combination of clinical signs involving the frontonasal process, midline lip clefting, congenital heart malformation, and severe CNS developmental abnormalities has not previously been reported. Clinical, imaging data, as well as differential diagnosis are discussed. © 2006 Wiley‐Liss, Inc.
Nitramine, 17. Mitt. Alkyl‐arylmethyl‐nitramine
Authors: Unterhalt Bernard , Mohr Rolf , Thamer Dieter
Published: October 2006

Die Darstellung der Alkyl‐benzyl‐nitramine 3, 5 und 6, des Benzhydryl‐methyl‐nitramins (7) sowie des Methyl‐triphenylmethyl‐nitramins (9) wird beschrieben; die Diazen‐oxide 8 und 11 werden charakterisiert.
Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects
Authors: Waller A. R. , Chasseaud L. F. , Taylor T. , Darragh A. , O'Kelly D. A.
Published: October 2006

After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47·0 ng ml−1 ± 11·0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half‐lives of 0·57 and 4·96 h respectively.

Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3·9 ng ml−1 ± 1·7 S.D. (n = 7) occurred at 1–2 h after dosing with dihydralazine sulphate and declined to 1–5 ng ml−1 ± 1·5 S.D. at 6 h.

Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1·63 1 min−1 ± 0·32 S.D.) when compared to slow acetylators (1·31 1 min−1 ± 0·31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration‐time curves were not significant (p > 0·1).
Biliary excretion of chlorthalidone in humans
Authors: Fleuren H. L. J. , Verwey‐Van Wissen C. P. W. , Thien Th. A.
Published: October 2006

A single oral dose of the diuretic chlorthalidone (100 or 200 mg) was given to six cholecystectomized patients with T‐tube drainage of the common bile duct, and the 24 h bile and urine were collected during 3–7 days. Urinary recovery of chlorthalidone was 23–27 per cent of the dose, which is in the range of that in healthy volunteers. Chlorthalidone concentration in bile was 11–44 times lower than urine concentration in corresponding periods, and biliary recovery was only 0·6–1·4 per cent of the dose. When compared from equal periods of sampling of bile and urine, the same relative amount of drug was found in bile, whether the 100 or 200 mg dose had been given (viz., a fraction of 2·5–4·7 per cent and 2·5–5·7 per cent of corresponding urinary amounts respectively). It was concluded that excretion into bile constitutes only a minor route of elimination for unchanged chlorthalidone. Bile samples treated with glucuronidase and sulphatase showed no increase of chlorthalidone concentration. The open acid analogue of chlorthalidone, 3‐(4‐chloro‐3‐sulphamoylbenzoyl)‐benzoic acid, was apparently not formed as a human metabolite, as evidenced by gas chromatographic analysis of both urine and bile.
A determinant solution for infinity values of multi‐exponential equations using equal time intervals
Authors: Newburger Jerold , Stavchansky Salomon
Published: October 2006

A determinant solution for the infinity values of multi‐exponential equations using the Guggenheim method of equal time intervals is demonstrated. The resultant solution is independent of the rate constants and can be applied using data in the early non‐log‐linear phase of the process. The minimum number of data points needed for an nth exponential equation is (2N+ 1).
Pharmacokinetics of acetylmethadols I: Gas‐liquid chromatographic determination of L‐α‐acetylmethadol and its major metabolites in plasma
Authors: Tse Francis L. S. , Welling Peter G.
Published: October 2006

A gas chromatographic method is reported for simultaneously determining acetyl‐methadol, noracetylmethadol, and dinoracetylmethadol in plasma. Minimum detectable concentrations are 10 ng ml−1 for acetylmethadol using a flame ionization detector, and 5 and 25 ng ml−l for noracetylmethadol and dinoracetylmethadol respectively using electron capture detection. Extraction efficiency is quantitative for acetylmethadol but lower for the metabolites. The method is useful for monitoring drug levels following therapeutic doses of acetylmethadol.
Pharmacokinetics of acetylmethadols II: Plasma levels of D‐ and L‐α‐acetylmethadol and their major metabolites in the dog
Authors: Tse Francis L. S. , Welling Peter G.
Published: October 2006

The pharmacokinetics of the synthetic narcotic agent LAAM, its pharmacologically active, demethylated metabolites NORLAAM and DINORLAAM, and also the dextro‐enantiomer DAAM, were examined following intravenous doses of all four compounds, and oral doses of LAAM and DAAM to dogs.

Extensive tissue uptake of all compounds occurred following intravenous doses. NORLAAM penetrated into tissues to a greater extent than LAAM or DINORLAAM and also exhibited the longest biological half‐life (11·7 h) in plasma compared to LAAM (6·5 h) and DINORLAAM (3·6 h). The elimination rate of DINORLAAM was prolonged following oral doses of LAAM and intravenous doses of NORLAAM, and it is suggested that prolonged pharmacologic activity of LAAM may be associated with rate‐limiting demethylation of NORLAAM. DAAM was taken up exrensively by tissues but to a smaller extent than LAAM.

Following oral doses, the bioavailability of LAAM as unchanged drug was 22·6 and 32·5 per cent in two dogs while that of DAAM was 4·9, 9·3, and 14·6 per cent in three dogs. Poor bioavailability of unchanged drug from oral doses appears to be due partly to first‐pass metabolism and is partially compensated for by increased plasma levels of pharmacologically active metabolites.

Extensive tissue uptake of LAAM and its active metabolites, and their long plasma half‐lives, may be partially responsible for the prolonged pharmacologic activity of LAAM reported in patients maintained on this drug.
Bioavailability and disposition of prednisone and prednisolone from prednisone tablets
Authors: Rose James Q. , Yurchak Anthony M. , Nsko William J. , Powell David
Published: October 2006

The relative bioavailability of two 50 mg prednisone tablet formulations was determined in 18 healthy male volunteers who were not pretreated with dexamethasone. Plasma and urine samples were collected over a 24‐h period and their concentrations of prednisone and prednisolone were assayed by a specific and sensitive high pressure liquid chromatography (HPLC) method. Bioavailability was assessed by comparing the areas under the plasma concentration‐time curves and by the relative amounts of prednisone and prednisolone in urine. There were no significant differences between the bioavailability of the film‐coated and standard 50 mg tablets. Eight subjects subsequently received a 40 mg equivalent intravenous dose of prednisolone as prednisolone succinate to provide plasma concentrations of prednisolone similar to concentrations found after oral doses of prednisone. The systemic bioavailability of prednisolone, the active metabolite generated from film‐coated and standard prednisone tablets, was estimated to be 0·77±0·15 and 0·80±0·11, respectively. The nonlinear distribution, the interconversion, and the simultaneous elimination of these drugs, however, complicate any assessment of their relative and absolute bioavailability.
The effect of buffering on oxyphenbutazone absorption kinetics and systemic availability
Authors: Ducal Robert , Dupuis Claire , Bertrand Michel , Gagnon Marc‐André
Published: October 2006

A systemic availability study comparing an investigational buffered tablet formulation of oxyphenbutazone and a commercially available product, the efficacy of which has been well established by usage, is reported. The experiment was designed to dissociate formulation factors from all other sources of variation including differences between subjects, sexes, sequences of administration, experimental periods, as well as sex by sequence, sex by period, and sex by formulation interactions. Systemic availability was assessed by conventional pharmacokinetic techniques.

Results show that buffering of a tablet formulation consistently increased the rate and degree of absorption. Although the relative magnitude of bioavailability indicators is slightly different according to the method of calculation, the estimates are always higher with the buffered formulation. No statistical difference was observed for plasma concentration‐time profiles between sexes. The wide range of observed concentrations over the time interval of this study confirms other reports of individual variations in handling oxyphenbutazone. The differences noted between the two formulations may be attributed to faster dissolution rate characteristics and better dispersion of oxyphenbutazone. Some aspects of the clinical relevance of this situation are discussed briefly.
Theoretical considerations in calculation of terminal phase half‐ times following oral doses, illustrated with model data
Authors: Curry Stephen H.
Published: October 2006

Concentrations of drugs in plasma following oral doses, when plotted as a function of time, invariably display a growth and decay curve. The terminal phase of this curve is commonly used for calculation of a half‐time (sometimes designated the ‘half‐life’) of the drug concentration in plasma. However, difficulty is often experienced in assigning a suitable time point as that of commencement of the terminal phase. This paper examines theoretically and with model data the issue of whether there is a useful systematic relation between this time and other identifiable times such as that of maximum concentration. The conclusion is reached that no rule of thumb can be applied. It is stressed that computer simulation, statistical testing for linearity, and comparison with data obtained following intravenous doses are all necessary before a conclusion can be reached that a particular half‐time has been validly assessed.
Bioavailability of propranolol and bendrofluazide formulations
Authors: McAinsh James , Holmes Brian F. , Baber Nigel S. , Young Jean
Published: October 2006

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles of both propranolol and bendrofluazide were studied following the multiple oral administration of the drugs as a fixed combination (Inderetic®) and as a free combination at doses of 80 mg propranolol twice daily and 2.5 mg bendrofluazide twice daily.

There were no statistically significant differences between the two regimens in terms of individual propranolol blood levels, half‐lives and area under the curve. The half‐lives were between 5 and 8 h. Thus the bioavailability of propranolol from the fixed combination is equivalent to that from the free combination.

The mean peak bendrofluazide blood levels were slightly higher following the administration of the fixed combination. This difference was statistically significant only at 1 and 2 h after the first dose. There were no statistically significant differences between these two bendrofluazide regimens in terms of half‐life and area under the curve. Thus the bioavailability of bendrofluazide from the fixed combination is equivalent to that from the free combination.

It is concluded therefore that by combining bendrofluazide and propranolol in a fixed capsule formulation does not affect significantly the systemic bioavailability of either component.
Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally‐induced renal impairment
Authors: Garcia M. J. , Dominguez‐Gil A. A. , Cepeda M. , Dominguez‐Gil A.
Published: October 2006

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg−1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two‐compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K12, K12, Ka and an increase in Vd and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK13 and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.
Binding of tolmetin and salicylic acid to human serum albumin as a function of temperature
Authors: Behm Harriet L. , Flynn Gordon L. , Wagner John G.
Published: October 2006

When drug‐protein binding data are evaluated thermodynamically standard free energy (ΔG°), standard enthalpy (ΔH°) and standard entropy (ΔS°) are usually estimated from association constants (Ka) derived from binding data obtained at only two temperatures. Estimation of ΔH° involves the assumption of its constancy in the temperature range studied and linearity of a van't Hoff plot of In Ka versus 1/T. Sometimes the assumption of such linearity is invalid for theoretical reasons and data obtained at only two temperatures contain no information concerning linearity of this plot. We present data for the binding of both tolmetin and salicylic acid to human serum albumin as a function of temperature which make doubtful the validity of using association constants of these drugs to derive thermodynamic constants other than ΔG° values.
Isosorbide 5‐mononitrate pharmacokinetics in humans
Authors: Taylor T. , Chasseaud L. F. , Major R. , Doyle E. , Darragh A.
Published: October 2006

When isosorbide 5‐mononitrate was intravenously infused at a rate of 4 mg h −1 for 2.5 h to five human subjects, its concentrations in plasma increased slowly to 185 ng ml−1 ± 5 per cent C.V. at 2.5 h and a steady‐state plasma level was not reached during the infusion. When the infusion was discontinued, plasma drug concentrations declined with an elimination half‐life of 4.2 h ± 6 per cent C.V. The systemic clearance after the infusion doses was 132 ml min−1 ± 18 per cent C.V. and the volume of distribution was 48.4 1 ± 16 per cent C. V. After equal oral doses of 10 mg, the peak plasma isosorbide 5‐mononitrate concentration of 191 ng ml−1 ±16 per cent C.V. was reached at 1.1 h ± 30 per cent C.V., and plasma levels declined with a terminal half‐life of 4.9 h. The complete systemic availability of isosorbide 5‐mononitrate indicated that pre‐systemic elimination after the oral doses was negligible. A one‐compartment open model appeared adequate to describe the plasma level data after intravenous infusion and oral doses. After single oral doses of 10 mg isosorbide dinitrate, the peak plasma concentration of the 5‐mononitrate metabolite of 72 ng ml−1 ± 27 per cent C. V. occurred at l.7h.41 per cent C.V. Approximately 50 per cent (range 22–68 per cent) of the oral dose of isosorbide dinitrate circulated in plasma as the 5‐mononitrate metabolite. The pharmacokinetics of isosorbide mononitrates are markedly different to those of the parent dinitrate and these differences follow from the greater systemic availability and volume of distribution of the mononitrates.
Plasma concentrations and bioavailability of isosorbide dinitrate and pindolol from a combination formulation
Authors: Chasseaud L. F. , Doyle E. , Taylor T. , Darragh A.
Published: October 2006

The plasma concentrations and bioavailability of sustained‐release isosorbide denigrate and standard‐release pindolol have been compared after administration of these drugs in combination and alone.

Bioavailability parameters of isosorbide dinitrate and pindolol obtained after administration of the drugs in combination were not significantly different (P>0.05) to those obtained after administration of either drug alone.

Two peaks of mean concentrations of isosorbide dinitrate occurred in plasma after administration of 30 mg of this drug in combination with 7.5 mg pindolol (4.4 ng ml−1 at 1 h and 4.5ng ml−1 at 5h), or alone (5.9ngml−1 at 2h and 5.7ng ml−1 at 5h). In each case, plasma concentrations of isosorbide dinitrate were maintained during at least 8 h, whereas the drug was not detected in plasma at 2.5 h after administration of a standardrelease formulation.

The peaks of mean concentrations of pindolol were 39.7ng ml−1 at l.5h after administration of 7.5 mg drug in combination with isosorbide dinitrate and 38.0 ng ml−1 at 1 h after administration of the drug alone. Concentrations of pindolol in plasma declined with a half‐life of 3 h.
An alternative method for calculating simple pharmacokinetic parameters for zero‐order absorption and first‐order elimination processes
Authors: Bialer Meir
Published: October 2006

An alternative way to the classical method is presented for calculating the relevant pharmacokinetic parameters for zero‐order absorption and first‐order elimination processes. Although the equations were derived using the one compartment body model, some of them are applicable to the multicomponent body model as well. The method presented is useful whether or not a steady state is reached.
Surgically affected sulfisoxazole pharmacokinetics in the morbidly obese
Authors: Garrett Edward R. , Suverkrup Richard S. , Eberst Kathleen , Yost Richard L. , Patrick O'Leary J.
Published: October 2006

Intestinal bypass surgery in 4 morbidly obese females (110‐150 kg) had no permanent effect on the rate or amount of sulfisoxazole absorption. The loss of weight up to 44 per cent within an individual over a year's time had no significant effect on the apparent volumes of distribution or other pharmacokinetic parameters of sulfisoxazole and its N4‐ acetylsulfisoxazole metabolite. Dosing of this drug on a mgkg− 1 basis is contraindicated. Renal clearances of sulfisoxazole were reasonably constant within a study but those of the N4‐acetylsulfisoxazole decreased with time. Integrated pharmacokinetic models were applied to plasma and urine data to estimate the metabolic clearance of sulfisoxazole and the apparent volume of distribution of the N4‐acetylsulfisoxazole. Sulfisoxazole solution is absorbed readily by primarily a zero order process after a short lag period, indicative of rate‐determining gastric emptying. The classical Bratton‐Marshall assays were compared with an HPLC assay of both drug and metabolite. There was greater confidence in plasma levels of the metabolite from the HPLC method.
Biopharmaceutical characteristics of a new propranolol/ hydrochlorothiazide tablet combination
Authors: Kraml M. , Dubuc J. , Dvornik D. , Patterson‐Kreuscherv S. , Perdue H. , Lee T. Y. , Mullane J.
Published: October 2006

Experiments have been carried out in dogs and man to determine the effect of hydrochlorothiazide (HCT) on the pharmacokinetics of propranlol and to evaluate the bioavailability of two dosage forms containing both propranolol and HCT (40/25 and 80/25 mg, respectively). In adult male beagles, 50 mg of HCT had no apparent effect on AUC, Cmax, Tmax, and T1/2 of propranolol administered concurrently. In man, INDERIDE® (40/25 mg) and INDERIDE® (80/25 mg) were shown to be similar in bioavailability to the reference formulations, i.e. the same amount of drugs administered as the separate tablets of INDERAL® plus HYDRODIURIL®.
Bretylium pharmacokinetics and bioavailabilities in man with various doses and modes of administration
Authors: Garrett Edward R. , Green J. Russell , Bialer Meir
Published: October 2006

The pharmacokinetics and bioavailabilities of bretylium tosylate were studied in 9 male normal volunteers by 60 min constant rate intravenous infusions of 200, 300, and 400 mg, by intramuscular injection of 300 and 400 mg, by oral administration of 100, 200, and 400 mg in solution, and by oral administration of 200 mg tablets. The latter studies were repeated in the same 5 volunteers which were also studied by all modes of administration and at several doses. Intravenous studies showed a sum of 3 exponentials to characterize plasma level‐time studies with a terminal half‐life of 535±32 (S.E.M.) min (n=12). The urinary recovery of unchanged drug was 77±4(S.E.M.)(n = 14). Half‐lives within a subject were correlated and independent of dose. Intramuscular administration showed an apparent half‐life of first‐order invasion of 79±13(S.E.M.)min (n = 6) with no apparent dose dependency and a urinary recovery of unchanged drug of 95.4±3.2 (S.E.M.) per cent with a terminal half‐life similar to the intravenous studies. Oral solutions had smaller lag times of absorption [17±4(S.E.M.)min] than tablets [56±9 (S.E.M.)min] and longer apparent half‐lives of first‐order absorption [231 ± 23(S.E.M.)min] than tablets [87±15(S.E.M.)min]. The tablets had slightly greater bioavailabilities [27±2.3 (S.E.M.) per cent] than the oral solutions [22.1±2.2 (S.E.M.) per cent] but with no apparent dose dependencies. Renal clearances were the same for all modes of administration. Means±S.E.M. were 735±32, i.v., 686±38, i.m., and 623±57ml min−1, p.o. Apparent overall volumes of distribution were 589±401, i.v. and 450±671 (S.E.M.), i.m. The i.v. studies in three dogs confirmed the three‐compartment body model and the high overall volumes of distribution, had terminal half‐lives similar to humans and had renal clearances of 84, 164, and 207ml min−1 that were in excess of glomerular filtration.
Disposition of cyclophosphamide in the rabbit and human cornea
Authors: Schoenwald Ronald D. , Houseman Jeffrey A.
Published: October 2006

Rabbit (dark irides and albino) and human corneas were excised and mounted in a Lucite® chamber in order to determine the permeability of cyclophosphamide‐14C and to identify its metabolites. The chromatographic scans obtained from the developed thin‐layer plates showed only one peak for either rabbit or human corneas which corresponded to cyclophosphamide.

By measuring the permeability of cyclophosphamide across the intact cornea, stroma alone, epithelium/stroma, and stroma/endothelium, it was possible to determine the resistance to penetration for each layer. The epithelium was the rate determining barrier, whereas both the stroma and endothelium offered little resistance. The stroma behaves as an inert sieve with drug diffusing through an aqueous media of gel‐like mucopolysaccharide interspersed by a matrix of collagen fibrils.
Automated pharmacokinetic analysis: Experiences of a user
Authors: Ruifrok Peter G.
Published: October 2006

Two curve‐stripping and three nonlinear regression computer programs currently in use for automated pharmacokinetic analysis were tested alone and in combination on their suitability to solve a number of pharmacokinetic problems. The five programs, NONLIN, NONLINEAR, CFT3, ESTRIP, and RUGFIT (all non‐commercial and readily available from the particular authors), were compared on these features: reliability, robustness, user convenience, and availability on macro or micro computers. The results show that if reliability and robustness are considered only, a combination of the curve‐stripping program ESTRIP with the nonlinear regression program CFT3 operates better than the other combinations. This combination is even more attractive if, in addition, user convenience and availability on micro computers are taken into account.
Thiazides XIII: Dissolution testing: A bioavailability predictor for benzthiazide tablets
Authors: Shah Vinod P. , Keys Christopher A. , King David M. , Prasad Vadlamani K. , Cabana Bernard E.
Published: October 2006

The dissolution characteristics of benzthiazide tablets were studied under different conditions, and were found to be very poor. It is suggested that these dissolution characteristics are predictive of poor product performance in vivo observed by other authors. The combined dissolution and bioavailability data raise questions as to the clinical value of benzthiazide products.
Personality traits and theophylline metabolism
Authors: Hartzema Abraham G. , Pancorbo Sal , Davis Scott
Published: October 2006

The objectives of this study were to investigate the relationship between personality trait variables and theophylline disposition in asthmatic patients.

Twenty‐five patients admitted to a hospital who required intravenous theophylline for bronchodilation were studied. Data on theophylline half‐life, and the patients' histories on congestive heart failure, liver disease, and smoking behaviour were abstracted. Eysenck's personality inventory was administered to obtain a score on the two personality traits: neuroticism and extroversy.

High neurotic patients showed a significantly (p< 0.005) lower theophylline half‐life. Neuroticism appeared to be, in this patient population, a more important determinant of theophylline half‐life than variables such as congestive heart failure, liver disease, or smoking behaviour.
Bioavailability of bemetizide and triamterene from a combination formulation
Authors: Brodie R. R. , Chasseaud L. F. , Darragh A. , Taylor T. , Walmsley L. M.
Published: October 2006

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (P < 0.01) from that from a tablet containing 25mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3ngml−1) was lower than that after administration of bemetizide alone (87.9 ngml−1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml−1) was higher than and significantly different (p< 0.001) from that after administration of triamterene alone (15.7 ng ml−1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post‐dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post‐dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data.

The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.
The pharmacokinetics of chlorbutol in man
Authors: Tung C. , Graham G. G. , Wade D. N. , Williams K. M.
Published: October 2006

The pharmacokinetics of chlorbutol were studied after oral administration in 4 healthy subjects on two occasions. Following the rapid attainment of peak concentrations, plasma concentrations fell by approximately 50 per cent in 24 h. After the first dose of chlorbutol, the terminal elimination half‐life was 10.3 ± 1.3 days (mean ± S.E.M), the volume of distribution was 233 ± 141 and the plasma clearance was 11.6 ± l.0 ml min −1. The binding to plasma proteins was 57 ± 3 per cent. In 3 of the 4 subjects, there was a small but significant decrease in the terminal half‐life of chlorbutol after the second dose. The mean urinary recovery over 17 days in two of the subjects accounted for only 9.6 per cent of the dose, 7.4 per cent of the total as the glucuronide and sulphate conjugates and 2.2 per cent as unchanged chlorbutol. A significant factor in the elimination of chlorbutol may be its instability under physiological conditions. Its half‐life in vitro is 37 days at pH7.4. The long terminal half‐life of chlorbutol makes it unsuitable as a sedative drug because of the considerable accumulation which will occur when the drug is taken in multiple doses.
Some novel observations of a drug (indoprofen)—albumin interaction
Authors: Juni K. , Nieves E. A. , Perrin J. H.
Published: October 2006

Indoprofen, a new‐steroidal anti‐inflammatory agent, binds to human serum albumin in an endothermic reaction at low degrees of saturation and with an exothermic reaction at higher drug to protein ratios. Although indoprofen appears to bind to the same primary site as diazepam, dialysis studies show an increased binding of both drugs in the presence of the other. This novel observation is probably due to the effect of the drugs on the N → B conformational change of human serum albumin.
Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses
Authors: Caillé G. , Spénard J. , Lacasse Y. , Brennan J.
Published: October 2006

The pharmacokinetic profiles of a sublingual and a conventional oral lorazepam tablet formulation were established following chronic administration to twelve healthy male volunteers. Fitting a multi‐dose equation based on a one‐compartment model to the observed data, the average elimination half‐lives for the sublingual and oral doses are estimated to be 11 and 8 h, respectively, while the corresponding absorption half‐lives are 15 and 55min; this confirms earlier reports that the sublingual formulation is more rapidly absorbed.

The observed time to steady‐state for both formulations was approximately 3 days, which agrees well with that predicted from previous single dosing studies. Although the sublingual formulation yields a higher average steady‐state minimum plasma concentration than the oral formulation (41·6 versus 38·1 ngml−1), the maximum lorazepam concentration achieved during steady state was approximately 83 ng ml−1 for both formulations. The average steady‐state plasma concentration is estimated to be 63ngml−1, independent of the formulation used.
Human platelet response to three salicylate dosage forms
Authors: Thiessen J. J. , Grad H. , Macleod S. M. , Spino M.
Published: October 2006

Acetylsalicylic acid (ASA) inhibition of platelet aggregation as evaluated by collagen‐induced 14C‐serotonin release, has been measured in 12 healthy male subjects. Each subject received a single oral dose (650 mg) of enteric‐coated ASA (ecASA) and compressed ASA tablets (cASA), or ecASA and sodium salicylate (578 mg) separated by a minimum of 5 weeks. The platelet response was related to plasma ASA and salicyclic acid determined by high‐pressure liquid chromatography. Both ecASA and cASA inhibited 14C‐serotonin release; no significant difference was observed in the maximum effect between these two products (p > 0·05). No relationship was found between the maximum observed plasma ASA level and the maximum effect. Further, no correlation was found between the maximum inhibition of 14C‐serotonin release in vivo and the release predicted from in vitro experiments wherein the effect was measured after incubating plasma containing specified ASA concentrations.
Studies on aminophylline disposition I. A rapid and sensitive HPLC assay for ethylenediamine in plasma and urine
Authors: Cotgreave Ian A. , Caldwell John
Published: October 2006

A simple and rapid assay for ethylenediamine in plasma and urine is described. Ethylenediamine is treated with m‐toluoyl chloride, yielding its N,N′‐di(m‐toluoyl) derivative, which is extracted into dichloromethane and assayed by reversed‐phase high pressure liquid chromatography (HPLC) with u.v. detection. Quantitation is achieved with reference to the corresponding derivative of cadaverine as internal standard. The assay is reproducible, and the lower limit of detection is 0·05 μg ml−1 Calibration curves in plasma and urine are linear over the concentration range 0·05–100 μg ml−1 The assay has been applied to the analysis of ethylenediamine in plasma and urine following the administration of aminophylline orally and intravenously to a volunteer.
Influence of concentration‐dependent protein binding on serum concentrations and urinary excretion of disopyramide and its metabolite following oral administration
Authors: Haughey David B. , Lima John J.
Published: October 2006

Concentrations of disopyramide (D) and mono‐N‐dealkyldisopyramide (MND) were measured in serum and urine following administration of 100, 150, 200, and 300 mg D to four volunteers. The free fraction of D in serum was drug concentration‐dependent in all four subjects following the administration of the four doses. Areas under the free (unbound) D serum concentration‐time curves (AUC) were linearly related to dose following 100–200 mg D. AUC values were 30–60 per cent higher than expected in two subjects following 300 mg D due to an apparent dose‐dependent decrease in D renal tubular secretion. Renal clearance of free D averaged 10·91h−1. The renal clearance of MND averaged 10·31h−1. The urinary excretion of MND was proportional to disopyramide dose.
Intestinal lymphatic absorption of cyclosporin a following oral administration in an olive oil solution in rats
Authors: Ueda Clarence T. , Lemaire Michel , Gsell Guy , Nussbaumer Kurt
Published: October 2006

The intestinal lymphatic absorption of cyclosporin A (CyA) following oral adminstration of 6·5 0·6 and 25·2±1·4mg kg−1 doses of the drug dissolved in an olive oil solution was studied using a thoracic duct‐cannulated rat model. Cumulative lymph samples were collected for up to 114h post‐dosing and assayed by liquid scintillation counting. In this study, the estimated amount of lymphatically absorbed CyA was 0·35±0·13 and 0·47±0·29 per cent of the respective doses. In terms of the overall oral bioavailability of CyA (Fpo) by all absorptive mechanisms, the intestinal lymphatics accounted for the absorption of approximately 2 per cent of the total amount of absorbed drug. Fpo was 21·3±2·5 per cent. The results of this study suggested that lipophilicity alone was not the only factor governing intestinal lymphatic drug absorption. An explanation for the low level of lymphatic CyA absorption is presented. In addition, some reasons for the low overall oral bioavailability of CyA are discussed.
Interaction of norethindrone and isoniazid following their oral co‐administration to the minipig
Authors: Loo J. C. K. , Jordan N. , Menzies J. A. , Watanabe H.
Published: October 2006

Following the oral co‐administration of isonicotinic acid hydrazide and norethindrone to minipigs, the hydrazone of norethindrone was detected in plasma as its p‐methoxybenzaldehyde derivative, using a high performance liquid chromatographic technique. The suspected precursor of the hydrazone of norethindrone was isonicotinyl hydrazone of norethindrone, a reaction product probably formed between norethindrone and isonicotinic acid hydrazide in the acid environment of the stomach. An in vitro liver metabolite of isonicotinyl hydrazone of norethindrone was isolated following derivatization with p‐methoxybenzaldehyde and characterized by high resolution mass spectrometric and radiochemical techniques. The results demonstrated that the hydrazone of norethindrone is a metabolite of isonicotinyl hydrazone of norethindrone.
Valproic acid pharmacokinetics in the mouse following controlled‐release of pharmacologic and toxic doses via novel implantable and refillable drug reservoirs
Authors: Nau Heinz , Finley Paul , Williams Jane , Brendel Klaus
Published: October 2006

Novel drug reservoirs are described which, after their implantation under mouse skin, continuously released organic liquids such as the anti‐epileptic drug valproic acid at preselected rates for periods up to several weeks. The liquids, which were filled into the reservoirs, diffused through silastic membranes. The area and thickness of these membranes determined the administered dose. Administration of the anti‐epileptic drug valproic acid at various selected doses resulted in persistent drug concentrations spanning from subtherapeutic to toxic levels. The drug reservoirs were easily refillable in situ which greatly extended the duration of the experiment. The dose administered could be determined within 5–15 per cent (rel. S.D.). It is suggested that the maintenance of persistent drug levels in small laboratory animals may be an appropriate model for the pharmacological and toxicological study of those compounds with short half‐lives and high clearance rates in these species.