Carnitine is widely distributed in the tissues of animals, plants and microorganisms. However, whilst there is an abundance of literature on the role of carnitine in animal metabolism, its role in plant metabolism has been less well studied. This chapter reviews work carried out on carnitine in plants and discusses its possible roles in plant metabolism, in particular the shuttling of activated acyl groups between membranebound organelles.

N-desmethylclozapine (NDMC) has been reported to display partial agonism at the human recombinant and rat native M1 mAChR, a property suggested to contribute to the clinical efficacy of clozapine. However, the profile of action of NDMC at the human native M1 mAChR has not been reported. The effect of NDMC on M1 mAChR function was investigated in human native tissues by assessing its effect on (1) M1 mAChR-mediated stimulation of [35S]-GTPγS-Gq/11α binding to human post mortem cortical membranes and (2) the M1 mAChR-mediated increase in neuronal firing in human neocortical slices. NDMC displayed intrinsic activities of 46±9%, compared to oxo-M, at the human recombinant M1 receptor, in FLIPR studies and 35±4% at rat native M1 receptors in [35S]-GTPγS-Gq/11α binding studies. In [35S]-GTPγS-Gq/11α binding studies in human cortex, oxo-M stimulated binding by 240±26% above basal with a pEC50 of 6.56±0.05. In contrast, NDMC did not stimulate [35S]-GTPγS-Gq/11α binding to human cortical membranes but antagonised the response to oxo-M (2μM) showing a pKB of 6.8, comparable to its human recombinant M1 mAChR affinity (pKi=6.9) derived from [3H]-NMS binding studies. In human, contrary to the rat neocortical slices, NDMC did not elicit a significant increase in M1 mAChR-mediated neuronal firing, and attenuated a carbachol-induced increase in neuronal firing when pre-applied. These data indicate that, whereas NDMC displays moderate to low levels of partial agonism at the human recombinant and rat native M1 mAChR, respectively, it acts as an antagonist at the M1 mAChR in human cortex.

Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.

Using a selective Galpha(q/11) protein antibody capture guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding approach, it has been possible to perform a quantitative pharmacological examination of the functional activity of the M(1) muscarinic acetylcholine receptor (mAChR) in membranes prepared from human postmortem cerebral cortex. Oxotremorine-M caused a > or = 2-fold increase in [35S]GTPgammaS-Galpha(q/11) binding with a pEC(50) of 6.06 +/- 0.16 in Brodmann's areas 23 and 25 that was almost completely inhibited by preincubation of membranes with the M(1) mAChR subtype-selective antagonist muscarinic toxin-7. In addition, the orthosteric and allosteric agonists, xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] and AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), increased [35S]-GTPgammaS-Galpha(q/11) binding, but with reduced intrinsic activities, inducing maximal responses that were 42 +/- 1 and 44 +/- 2% of the oxotremorine-M-induced response, respectively. These data indicate that the M(1) receptor is the predominant mAChR subtype coupling to the Galpha(q/11) G protein in these brain regions and that it is possible to quantify the potency and intrinsic activity of full and partial M(1) mAChR receptor agonists in postmortem human brain using a selective Galpha(q/11) protein antibody capture [35S]GTPgammaS binding assay.

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The 5-ht5A receptor is enigmatic among 5-HT receptors since, although the human receptor was cloned in 1994, until recently, very little has been learnt about the function of the receptor in native tissues. Findings from 5-ht5A receptor mRNA localisation and immunolabelling studies have revealed widespread expression in the CNS, and have provided pointers to the potential functional role(s) of the receptor. The expression of the 5-ht5A receptor in raphe nuclei and in higher brain areas, such as the cerebral cortex and hippocampus, suggests a potential autoreceptor function whilst localisation in the suprachiasmatic nucleus (SCN) suggests a role in circadian rhythm control. Additionally, 5-ht5A receptor knockout mouse phenotyping studies support a role in the control of exploratory behaviour. The lack of understanding of the role of the receptor has been, in part, due to the lack of available selective 5-ht5A receptor ligands. However, a selective 5-ht5A receptor antagonist, 3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride (SB-699551-A), has recently been identified which appears to be a useful tool with which to elucidate the physiological function of the receptor. Brain localisation and functional studies to date potentially implicate the receptor in the control of circadian rhythms, mood and cognitive function, whilst gene association studies implicate the receptor in the aetiology of schizophrenia. Although much is still to be learnt about the function of the 5-ht5A receptor, on the basis of these findings, it can be speculated that 5-ht5A receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.

This study utilised the selective 5-ht(5A) receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPgammaS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA2 8.1+/-0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT(1A/B/D), 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 microM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.

High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-ht5A receptor. The structure-activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-ht5A receptor antagonist.

OBJECTIVETo measure expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in the prostates of men after transurethral resection of the prostate (TURP) following 2 weeks of treatment with finasteride.PATIENTS AND METHODSSixty-four men scheduled to undergo TURP were randomized to receive 5 mg of finasteride or placebo daily for 2 weeks before surgery. Sections of prostatic urothelium were stained for VEGF expression and for CD31 to assess MVD. Ten consecutive, non-overlapping high-power fields were analysed in a blinded fashion.RESULTSIn all, 31 men received finasteride and 33 placebo; the groups were similar in patient age, resected prostate weight, preoperative catheterization, prostate-specific antigen level, aspirin use, spinal anaesthesia and postoperative diagnosis of prostate cancer. The mean (95% confidence interval) MVD was significantly lower in the finasteride group (60, 55-65) than in the placebo group (71, 64-78; P < 0.01). Similarly, the mean expression of VEGF was significantly lower in the finasteride group (47, 43-52 vs 61, 54-67; P < 0.001)CONCLUSIONFinasteride inhibits angiogenic growth factors leading to reduced vascularity, and this is the basis of its action in reducing haematuria of prostatic origin. The present study shows that finasteride influences the prostatic microvasculature after only 2 weeks exposure.

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT1A receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT1A/1B/1D receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pKi 8.2). This compound also had good oral bioavailability and brain penetration in the rat.

You have accessJournal of UrologyDiscussed Poster, Wednesday, May 25, 2005, 8:00 am - 12:00 pm1 Apr 20051449: Finasteride Rapidly Reduces Prostatic Vascularity: A Randomized Placebo Controlled Study John F. Donohue, Dickon Hayne, Neil J. Barber, Uttara Karnig, David R. Thomas, and Michael C. Foster John F. DonohueJohn F. Donohue More articles by this author , Dickon HayneDickon Hayne More articles by this author , Neil J. BarberNeil J. Barber More articles by this author , Uttara KarnigUttara Karnig More articles by this author , David R. ThomasDavid R. Thomas More articles by this author , and Michael C. FosterMichael C. Foster More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)35583-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1449: Finasteride Rapidly Reduces Prostatic Vascularity: A Randomized Placebo Controlled Study." The Journal of Urology, 173(4S), pp. 392–393 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 392-393 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information John F. Donohue More articles by this author Dickon Hayne More articles by this author Neil J. Barber More articles by this author Uttara Karnig More articles by this author David R. Thomas More articles by this author Michael C. Foster More articles by this author Expand All Advertisement PDF downloadLoading ...

Following the cloning of the 5-HT7 receptor in 1993, studies to investigate 5-HT7 receptor function in native tissues focused on identifying functional correlates that matched the pharmacological profile determined for the cloned receptor. Studies in peripheral tissues established that the 5-HT7 receptor mediates the relaxation of smooth muscle, including the gastrointestinal tract and cardiovascular systems. Although a number of studies provided preliminary evidence for a role for the 5-HT7 receptor in the circadian pacemaker function of the suprachiasmatic nucleus (SCN), additional studies to investigate 5-HT7 receptor function in other brain regions have, until recently, been hindered by the absence of 5-HT7 receptor-selective ligands. More recently, a number of 5-HT7 receptor-selective antagonists including, SB-269970-A and SB-656104-A have been developed. Studies utilising these compounds suggest that the 5-HT7 receptor modulates neuronal function in a number of brain areas including the hippocampus and thalamus. In turn, these findings suggest that 5-HT7 receptor-selective ligands might prove therapeutically useful for the treatment of psychiatric disorders. In this respect there is increasing evidence to suggest that the 5-HT7 receptor plays a role in the control of both circadian rhythms and sleep and might therefore represent a therapeutic target for the treatment of those disorders in which disturbances in circadian rhythms and sleep architecture are thought to be contributory factors. Furthermore, there is evidence to suggest that the receptor may play a role in other CNS disorders including, anxiety, cognitive disturbances and also migraine probably via both peripheral and central mechanisms. Although further studies are required to confirm the potential role of the receptor in such disorders, findings to date suggest there are exciting opportunities for the development of novel therapeutic agents acting either selectively at the 5-HT7 receptor or whose profile of action includes an interaction with this receptor.

The guinea pig 5-hydroxytryptamine5A (gp5-ht5A) receptor was cloned from guinea pig brain using degenerate polymerase chain reaction (PCR) and shows 88%, 85% and 84% amino acid sequence identity versus the human, rat and mouse 5-ht5A receptors, respectively. The receptor was transiently expressed in human embryonic kidney (HEK) 293 cells. [3H]-Lysergic acid diethylamide (LSD) bound saturably to gp5-ht5A/HEK293 membranes with a Kd of 2.3±0.1 nM and Bmax of 15.7±3.4 pmol/mg protein. The receptor binding profile, determined by competition with [3H]LSD, correlated well with that for the human 5-ht5A receptor. 5-HT stimulated [35S]GTPγS binding to gp5-ht5A/HEK293 membranes (pEC50 8.1±0.2), and the response was surmountably antagonised by methiothepin and ritanserin, giving apparent pKB values of 8.0 and 7.2, respectively. The 5-HT response was absent using membranes prepared from gp5-ht5A/HEK293 cells pretreated with pertussis toxin (PTX). These data suggest that the gp5-ht5A receptor couples to Gi-proteins in this expression system and shows a similar pharmacological profile to that for the human 5-ht5A receptor.

The indications for transfusing fresh‐frozen plasma (FFP), cryoprecipitate and cryosupernatant plasma are very limited. When transfused they can have unpredictable adverse effects. The risks of transmitting infection are similar to those of other blood components unless a pathogen‐reduced plasma (PRP) is used. Of particular concern are allergic reactions and anaphylaxis, transfusion‐related acute lung injury, and haemolysis from transfused antibodies to blood group antigens, especially A and B. FFP is not indicated in disseminated intravascular coagulation without bleeding, is only recommended as a plasma exchange medium for thrombotic thrombocytopenic purpura (for which cryosupernatant is a possible alternative), should never be used to reverse warfarin anticoagulation in the absence of severe bleeding, and has only a very limited place in prophylaxis prior to liver biopsy. When used for surgical or traumatic bleeding, FFP and cryoprecipitate doses should be guided by coagulation studies, which may include near‐patient testing. FFP is not indicated to reverse vitamin K deficiency for neonates or patients in intensive care units. PRP may be used as an alternative to FFP. In the UK, PRP from countries with a low bovine spongiform encephalopathy incidence is recommended by the Departments of Health for children born after 1 January 1996. Arrangements for limited supplies of single donor PRP of non‐UK origin are expected to be completed in 2004. Batched pooled commercially prepared PRP from donors in the USA (Octaplas) is licensed and available in the UK. FFP must be thawed using a technique that avoids risk of bacterial contamination. Plastic packs containing any of these plasma products are brittle in the frozen state and must be handled with care.

5-HT(7) receptor mRNA and protein are localised in the dorsal raphe nucleus (DRN) on non-serotonergic neurones. The effect of 5-HT(7) receptor antagonism on 5-HT efflux was measured from guinea-pig DRN slices, using the technique of fast cyclic voltammetry. The 5-HT(7) receptor antagonist, SB-269970-A, significantly inhibited 5-HT efflux. The GABA(A) receptor agonist, muscimol, significantly inhibited 5-HT efflux, to a similar degree as SB-269970-A. In contrast, the GABA(A) receptor antagonist, bicuculline, significantly increased 5-HT efflux and attenuated the muscimol-induced inhibition. The muscimol and SB-269970-A effects were not additive and in the presence of bicuculline the SB-269970-A-induced inhibition of 5-HT efflux was attenuated. These data suggest that 5-HT(7) receptor antagonist-induced inhibition of 5-HT efflux occurs indirectly via activation of GABA(A) receptors. That is, 5-HT(7) receptors may be located on GABA interneurones and when activated decrease GABA release and hence decrease the inhibitory tone on 5-HT neurones, increasing 5-HT efflux in the DRN. Therefore, in the presence of GABAergic tone 5-HT(7) receptor antagonists would decrease 5-HT release from the DRN.