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The pharmacokinetics of amoxycillin and potassium clavulanate were studied in 15 sick children after a 30 min iv infusion of 50 mg/kg amoxycillin and 5 mg/kg clavulanic acid as the potassium salt. Levels of both compounds in plasma were assayed mkrobiologically. Mean peak concentrations at the end of the infusion were 121·0 mg/l of amoxycillin and 12·0 mg/l of clavulanate, falling to a mean of 15·8 and 1·92 mg/l respectively after 2h. Mean ( phase T was 0·88 h for amoxycillin and 0·79 h for clavulanate. The elimination half-life of clavulanate in some individuals was much shorter because of higher plasma clearance. The data suggest that the treatment of some infections due to -lactamase producing organisms in such severely ill children may require more frequent iv administration of amoxycillin and potassium clavulanate, than in less severely affected children. [ABSTRACT FROM PUBLISHER]

The pharmacokinetics of the side-chain epimers of temocillin were investigated in four healthy male subjects following a single iv dose of temocillin disodium (1 g pure free acid) containing 64.2% R-epimer. Plasma and urinary concentrations of the epimers were determined by hplc methods. The R-epimer was twice as rapidly cleared, had a 23% larger volume of distribution and a 60% shorter beta half-life than the S-epimer. Intermediate values were obtained for total temocillin (from hplc data). The differences in the pharmacokinetic properties of the epimers are most likely the result of different extents of plasma protein binding. In each plasma sample, the free fraction of the R-epimer was higher (up to two-fold) than that of the S-epimer. In a comparison of temocillin pharmacokinetic parameters derived from hplc and microbiological assay data, the values obtained from the latter analyses reflected most closely those for the R-epimer. Further indications that the R-epimer is more microbiologically active against Pseudomonas aeruginosa NCTC 10701 from other assessments of relative antibacterial activity are discussed. [ABSTRACT FROM AUTHOR]

BRL 20330 is the o-methyl phenyl ester of temocillin which is well absorbed after oral administration and converted to temocillin in the body. BRL 20330 was administered to healthy subjects in a three-part cross-over study with single doses equivalent to 400, 600 and 800 mg of temocillin. Peak serum concentrations of temocillin were 9.8, 12.8 and 15.8 mg/l respectively and concentrations of 3.0-6.0 mg/l were measured at 12 h after dosing. High and prolonged concentrations of temocillin were measured in the urine. The mean urinary recovery was 22-25% and only 0.2% of unhydrolyzed BRL 20330 was detected in the urine. Little difference in the extent of absorption was noted when BRL 20330 was administered with food although the peak levels of temocillin were delayed and reduced slightly. Urinary concentrations of temocillin, even after 24 h, were bactericidal for a number of Gram-negative bacteria including multi-resistant strains. BRL 20330 was well tolerated and there was no evidence of gastro-intestinal adverse effects. [ABSTRACT FROM AUTHOR]

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously.No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin.Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate.The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium. [ABSTRACT FROM PUBLISHER]

Each year, people spend less time reading and more time viewing images 1 , which are proliferating online 2-4 . Images from platforms such as Google and Wikipedia are downloaded by millions every day 2,5,6 , and millions more are interacting through social media, such as Instagram and TikTok, that primarily consist of exchanging visual content. In parallel, news agencies and digital advertisers are increasingly capturing attention online through the use of images 7,8 , which people process more quickly, implicitly and memorably than text 9-12 . Here we show that the rise of images online significantly exacerbates gender bias, both in its statistical prevalence and its psychological impact. We examine the gender associations of 3,495 social categories (such as 'nurse' or 'banker') in more than one million images from Google, Wikipedia and Internet Movie Database (IMDb), and in billions of words from these platforms. We find that gender bias is consistently more prevalent in images than text for both female- and male-typed categories. We also show that the documented underrepresentation of women online 13-18 is substantially worse in images than in text, public opinion and US census data. Finally, we conducted a nationally representative, preregistered experiment that shows that googling for images rather than textual descriptions of occupations amplifies gender bias in participants' beliefs. Addressing the societal effect of this large-scale shift towards visual communication will be essential for developing a fair and inclusive future for the internet., (© 2024. The Author(s).)

Deep neural networks (DNNs) are increasingly proposed as models of human vision, bolstered by their impressive performance on image classification and object recognition tasks. Yet, the extent to which DNNs capture fundamental aspects of human vision such as color perception remains unclear. Here, we develop novel experiments for evaluating the perceptual coherence of color embeddings in DNNs, and we assess how well these algorithms predict human color similarity judgments collected via an online survey. We find that state-of-the-art DNN architectures - including convolutional neural networks and vision transformers - provide color similarity judgments that strikingly diverge from human color judgments of (i) images with controlled color properties, (ii) images generated from online searches, and (iii) real-world images from the canonical CIFAR-10 dataset. We compare DNN performance against an interpretable and cognitively plausible model of color perception based on wavelet decomposition, inspired by foundational theories in computational neuroscience. While one deep learning model - a convolutional DNN trained on a style transfer task - captures some aspects of human color perception, our wavelet algorithm provides more coherent color embeddings that better predict human color judgments compared to all DNNs we examine. These results hold when altering the high-level visual task used to train similar DNN architectures (e.g., image classification versus image segmentation), as well as when examining the color embeddings of different layers in a given DNN architecture. These findings break new ground in the effort to analyze the perceptual representations of machine learning algorithms and to improve their ability to serve as cognitively plausible models of human vision. Implications for machine learning, human perception, and embodied cognition are discussed., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: This study examined the safety and pharmacodynamic effects of selective muscarinic M 1 receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day., Methods: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition., Results: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7-21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post-dose, HTL0018318-related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up-titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints., Discussion: HTL0018318 was well tolerated in mild-to-moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil., Competing Interests: The study was sponsored by Heptares Therapeutics Ltd. P.J.N., S.B.M., A.G., O.D., J.L., B.R., S.P.J., G.B, A.H.J.B., P.P.W., M.C., and T.T. are employees of Heptares Therapeutics Ltd. S.B.M., A.G, B.R., A.H.J.B., P.P.W., M.C., and T.T. hold shares in the company. D.M.C., P.M., and G.A.L., are independent consultants who were engaged by Heptares Therapeutics Ltd., for their specific technical expertise during the design of the study. All the authors declare that no other financial support or compensation has been received from any individual or corporate entity in the writing of this manuscript, and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Chondrocytes that are impregnated within hydrogel constructs sense applied mechanical force and can respond by expressing collagens, which are deposited into the extracellular matrix (ECM). The intention of most cartilage tissue engineering is to form hyaline cartilage, but if mechanical stimulation pushes the ratio of collagen type I (Col1) to collagen type II (Col2) in the ECM too high, then fibrocartilage can form instead. With a focus on Col1 and Col2 expression, the first part of this article reviews the latest studies on hyaline cartilage regeneration within hydrogel constructs that are subjected to compression forces (one of the major types of the forces within joints) in vitro . Since the mechanical loading conditions involving compression and other forces in joints are difficult to reproduce in vitro , implantation of hydrogel constructs in vivo is also reviewed, again with a focus on Col1 and Col2 production within the newly formed cartilage. Furthermore, mechanotransduction pathways that may be related to the expression of Col1 and Col2 within chondrocytes are reviewed and examined. Also, two recently-emerged, novel approaches of load-shielding and synchrotron radiation (SR)-based imaging techniques are discussed and highlighted for future applications to the regeneration of hyaline cartilage. Going forward, all cartilage tissue engineering experiments should assess thoroughly whether fibrocartilage or hyaline cartilage is formed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alizadeh Sardroud, Wanlin, Chen and Eames.)

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic., Competing Interests: Declaration of interests T.T. and M.W. are shareholders and board members of Sosei Heptares. The authors A.J.H.B., G.A.B., K.A.B., J.B., J.E.C., M.S.C., R.M.C., J.C.E., E.H., A.J., C.J.L., J.L., F.H.M., P.J.N., K.O., G.O., J.C.P., M.P., N.R., P.R., B.G.T., R.T.S., C.d.G., G.M., and B.T. are or have been employees of Heptares Therapeutics and are shareholders of Sosei Heptares., (Copyright © 2021. Published by Elsevier Inc.)

Aims: HTL0009936 is a selective M 1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF)., Methods: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests., Results: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine., Conclusions: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Mycoplasma genitalium is an emerging, sexually transmitted infection, which is more prevalent than Chlamydia trachomatis in some regions. An increase in antibiotic resistance, that is, azithromycin and moxifloxacin, recommended for treating M. genitalium infections has been noted. This is the first detailed report on the prevalence of M. genitalium and its antimicrobial resistance in Saskatchewan, Canada., Methods: Aptima urine specimens (n = 1977), collected for the diagnosis of C. trachomatis/Neisseria gonorrhoeae, were tested for M. genitalium using the Aptima M. genitalium assay (MG-TMA). Antimicrobial resistance was ascertained using polymerase chain reaction and DNA sequencing of 23S rRNA (azithromycin) and parC (moxifloxacin) from Aptima M. genitalium assay-positive specimens; mutations predictive of resistance were noted., Results: The prevalence of M. genitalium was 9.6% (189/1977). Predicted resistance to azithromycin (substitutions at positions 2058/2059 in 23S rRNA) was observed in 63.6% (70/110) of the specimens tested, whereas resistance to moxifloxacin (S83I in ParC) was observed in 10.6% (9/85) of the specimens. Mutations in both 23S rRNA and ParC were observed in 2.12% (4/189) of the specimens. Women aged 20 to 24 years had the highest prevalence (18.3%, P < 0.001), and in females, M. genitalium was significantly associated with C. trachomatis or N. gonorrhoeae/C. trachomatis (P < 0.001) coinfection. The prevalence of M. genitalium (9.6%) in the province of Saskatchewan was higher than that of the other 2 bacterial sexually transmitted infections (N. gonorrhoeae (3.09%) and C. trachomatis (6.85%)., Conclusions: The prevalence of M. genitalium (9.6%) and associated resistance to azithromycin (63.6%) in Saskatchewan high, suggesting that empiric azithromycin therapy may not be adequate for treating M. genitalium infections., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

Introduction: HTL0018318 is a selective muscarinic M 1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil)., Objective: We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil., Methods: This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics., Results: AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics., Conclusion: HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil., Clinical Trial Registration: Netherlands Trial register identifier NL5915, registered on 28 October 2016., (© 2021. The Author(s).)

Aims: HTL0018318 is a selective M 1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses., Methods: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects., Results: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance., Conclusion: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The cholinergic system and M 1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M 1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects., Methods: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions., Results: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes., Conclusion: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB., Trial Registration: Netherlands Trial Register identifier NTR5781 . Registered on 22 March 2016.

Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Polyacrylamide (PAM) based friction reducers are a primary ingredient of slickwater hydraulic fracturing fluids. Little is known regarding the fate of these polymers under downhole conditions, which could have important environmental impacts including decisions on strategies for reuse or treatment of flowback water. The objective of this study was to evaluate the chemical degradation of high molecular weight PAM, including the effects of shale, oxygen, temperature, pressure, and salinity. Data were obtained with a slickwater fracturing fluid exposed to both a shale sample collected from a Marcellus outcrop and to Marcellus core samples at high pressures/temperatures (HPT) simulating downhole conditions. Based on size exclusion chromatography analyses, the peak molecular weight of the PAM was reduced by 2 orders of magnitude, from roughly 10 MDa to 200 kDa under typical HPT fracturing conditions. The rate of degradation was independent of pressure and salinity but increased significantly at high temperatures and in the presence of oxygen dissolved in fracturing fluids. Results were consistent with a free radical chain scission mechanism, supported by measurements of sub-μM hydroxyl radical concentrations. The shale sample adsorbed some PAM (∼30%), but importantly it catalyzed the chemical degradation of PAM, likely due to dissolution of Fe 2+ at low pH. These results provide the first evidence of radical-induced degradation of PAM under HPT hydraulic fracturing conditions without additional oxidative breaker.

Objective: Two doses of EVT 201, a partial positive allosteric modulator of the GABA(A) system, were evaluated in elderly primary insomnia patients with daytime sleepiness., Patients and Methods: Participants were 149 elderly patients with DSM-IV primary insomnia including evidence of daytime sleepiness (53 males, 96 females; mean age 71.3yrs, range 65-86yrs). A randomized, multicentre, double-blind, placebo-controlled, parallel-group design was used to assess the hypnotic efficacy of EVT 201 1.5 and 2.5mg during seven consecutive nights. Polysomnography (PSG) was performed on nights 1, 6 and 7 of treatment. Daytime assessments on Day 8 included the multiple sleep latency test (MSLT), Rey Auditory Verbal Learning Test (RAVLT), Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale (KSS). The primary endpoint was total sleep time (TST) and the key secondary endpoint was mean MSLT latency., Results: Compared to placebo, EVT 201 1.5 and 2.5mg increased TST (30.9, 56.4min, respectively; p=0.0001, p<0.0001); reduced wake after sleep onset (WASO; -15.2, -36.1min, respectively; p=0.014, p<0.0001); reduced latency to persistent sleep (LPS; -15.9, -19.9min, respectively; p=0.009, p=0.001). The 2.5mg dose also reduced WASO in hours 5-8 (-16.3min, p=0.001). Both doses also improved subjective sleep quality and usual subjective efficacy measures. A significantly longer mean MSLT latency was observed on Day 8 with both doses, compared to placebo (2min increase; p=0.03, both doses). The PVT, RAVLT, and POMS did not differ among treatment groups. No serious or unexpected treatment emergent adverse events were noted., Conclusion: EVT 201 improved PSG measures of sleep onset and sleep maintenance and significantly reduced daytime physiological sleep tendency. These findings suggest that treatment of primary insomnia in older patients has the potential to improve daytime sleepiness as well as sleep., (Copyright 2009 Elsevier B.V. All rights reserved.)

Blood samples were obtained from 50 cats admitted for hematologic evaluation at the Royal (Dick) School of Veterinary Studies. Manual platelet counts were done using a hemacytometer, and the average number of platelets per oil immersion field (1,000X magnification) was determined on stained blood smears. A hemacytometer count was not obtained for one sample because of a failure in erythrocyte lysing. In nine samples, obvious platelet clumps in the blood smear prevented accurate determination of the number of platelets per oil immersion field. Hemacytometer counts on these nine samples ranged from 260-587 X 10 (3) platelets/microliter, suggesting that platelet clumps on a blood smear were usually associated with adequate platelet numbers. Simple regression analysis of hemacytometer counts and the average umber of platelets per oil immersion field for the remaining 40 samples yielded correlation coefficients (r) of 0.776 on untransformed data, and 0.892 on log10-transformed data. Each platelet per oil immersion field represented a circulating platelet count of approximately 20 X 10(3)/microliter, similar to conversion factors reported for dogs and human beings. It was concluded that estimation of platelet number on stained blood smears is a simple and quick method that appears to be reliable over a wide range of platelet counts in cats.

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol.hr/L), whereas at steady state the median AUCss tau interphenotype difference was only twofold (4410 versus 2550 nmol.hr/L). Plasma half-life and steady-state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/dehydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

Cromakalim relaxes vascular smooth muscle by increasing potassium channel conductance, thus hyperpolarizing cell membranes. Its interactions in humans with the cardiovascular effects of norepinephrine, angiotensin II, and isoproterenol were investigated. Eight young normotensive male volunteers received on three different study days, 7-14 days apart, placebo, cromakalim at 1 mg, or cromakalim at 2 mg in a single oral dose, followed 2 h later by incremental intravenous doses of norepinephrine, angiotensin II, and isoproterenol. The diastolic blood pressure and total peripheral resistance (TPR) did not decrease significantly, but significant positive inotropic and chronotropic responses were noted after cromakalim. Cromakalim, both at 1 and 2 mg, blunted (p less than 0.05) the increase in TPR induced by norepinephrine, but did not interfere with its positive inotropic effect (P/V ratio). During angiotensin II infusion, TPR was also lower on both doses of cromakalim (p less than 0.05). Cardiac effects and aldosterone release were not affected. Cromakalim blunted the peripheral vasodilation induced by beta-receptor stimulation by isoproterenol, but did not affect the cardiac stimulation. The potassium channel activator, cromakalim, therefore antagonized the changes in TPR induced by norepinephrine, angiotensin II, and isoproterenol, but did not interfere with the cardiac responses, suggesting selectivity for arterial smooth muscle.

Granisetron is a novel specific 5-HT3 receptor antagonist whose effects have been evaluated in an extensive programme of volunteer studies. Single intravenous doses of 2.5-300 micrograms/kg of granisetron over 30 min, and of 40-160 micrograms/kg, administered over 3 min, were very well tolerated. There were no serious adverse events. There were no consistent or clinically important effects on cardiovascular parameters (pulse rate, blood pressure, ECG). Single doses of 40-200 micrograms/kg (30 min infusion) or 160 micrograms/kg (3 min infusion) did not influence subjective state, psychomotor performance or EEG. The only adverse event reported consistently more frequently with granisetron than placebo was constipation; this generally subsided spontaneously after 24-72 h. In volunteers, granisetron was widely distributed and also rapidly eliminated, largely through non-renal mechanisms. Granisetron exhibited essentially linear kinetics over the dose range studied (30-300 micrograms/kg). There was considerable inter-subject variability in terminal phase half-life and total plasma clearance. Biological activity of granisetron, as evidenced by significant inhibition of cutaneous 5-HT-induced, axon-reflex flare, was still apparent 24 h after a single dose of 40 micrograms/kg. Repeated intravenous doses of granisetron (up to 160 micrograms/kg b.d. for 7 days) were also well tolerated. As in the single dose studies, constipation was the only adverse event reported consistently more with active treatment than with placebo, but in no case did this necessitate withdrawal from the study or administration of a laxative.(ABSTRACT TRUNCATED AT 250 WORDS)