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PubMed2005

Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.

The electrocardiographic parameters relating occurrence of ventricular fibrillation (VF) episodes in patients with idiopathic VF (IVF) are still unknown. The aim of this study was to clarify efficacy of pharmacological therapy in patients with IVF with respect to repolarization dynamics. The study group consisted of 8 men (age 43.6 +/- 9.1 years) with IVF (Brugada type 5 patients, prominent J wave in the inferior leads 3 patients) who had documented spontaneous episodes of VF, 7 of whom had implantable cardioverter defibrillators. The relation between QT and RR interval was analyzed from 24-hour Holter ECG using an automatic analyzing system before and after pharmacological therapy (bepridil 5 and disopyramide 3). From QT-RR linear regression lines, QT intervals were determined at RR intervals of 0.6 second [QT(0.6)], 1.0 second [QT(1.0)], and 1.2 seconds [QT(1.2)]. Pharmacological therapy increased the slope of QT-RR regression line from 0.105 +/- 0.020 to 0.144 +/- 0.037 (P < 0.05). Accordingly, QT(1.0) and QT(1.2) became longer after drug therapy [QT(1.0), 0.382 +/- 0.016 seconds vs 0.414 +/- 0.016 seconds (P < 0.01); QT(1.2), 0.403 +/- 0.017 seconds vs 0.442 +/- 0.021 seconds (P < 0.01)]. However, QT(0.6) did not change after drug administration. Before drug therapy the average episodes of VF were 5.5 +/- 5.8 (range 1 to 17) during the observation period of 19.3 +/- 17.6 months (range 6 to 60 months). After drug therapy, 6 patients had no episode of VF for 24 to 120 months (66.0 +/- 38.5 months). Two patients had a single episode of VF for 12- and 96-month follow-ups. Pharmacological therapy decreased the frequency of VF episodes in association with prolongation of QT intervals at slower heart rates. Not only J wave and ST elevation but also shorter QT intervals at slower heart rates may represent an electrophysiological substrate for development of VF episodes in these specific IVF patients.

Adult↗
PubMed2006

Pharmacologic management of chronic insomnia.

Chronic insomnia is a common disorder that is under recognized, under diagnosed and under treated. Initial assessment should focus on identifying and treating, if present, any secondary causes of insomnia. Primary insomnia can be treated with behavioral and/or pharmacological therapy. A thorough sleep history can identify the type of insomnia present, its severity, and can consequently guide therapy. Behavioral therapy has been shown to be equivalent to or superior to pharmacologic therapy, at least in some patients. It is a reasonable initial approach, although there are barriers to its use. There are several pharmacologic agents available, some of which are more effective at reducing time to fall asleep and others for maintaining sleep. There is some evidence to indicate that combining the approaches may impair outcomes. There is little data on the long-term use of pharmacologic agents.

Humans↗
PubMedDate not supplied

Recent progress in pharmacological therapy of male subfertility--a review.

A review of pharmacological therapy in male infertility shows that apart from specific therapy with gonadotropins in hypogonadotropic hypogonadism, treatment in normogonadotropic idiopathic oligozoospermia and asthenozoospermia is still empirical and often unsuccessful. Modern therapy is based on three pharmacological groups of compounds: gonadotropins, androgens and kininogenases, the latter releasing pharmacologic active kinin peptides from kininogen. In addition, antiestrogens and gonadotropin-releasing hormones seem to be promising agents for the near future. The use of antibiotics is of great importance in the therapy of male genital tract infections which often to a reduced fertility. Several other drugs (amino acids, psychopharmaceuticals, spasmolytic agents, trijodothyronine, glucocorticoids, vitamins) seem to be suitable in individuals cases, but in greater group of patients these agents do not improve fertility. Using the mentioned hormonal and nonhormonal pharmacological agents considerable progress can be demonstrated in the therapy of male infertility. However, before initiating any therapy it is important to exclude patients whose cause of infertility is untreatable or those who require surgery. Finally, it is hoped that additional progress in treatment of male infertility will soon be made possible by further improvement of fundamental research in andrology. Especially important is the development of better criteria for selection of patients for any form of therapy in order to make more specific and less empirical approaches for treatment of male infertility available.

Anti-Infective Agents↗
PubMed1995

Functional evidence equating the pharmacologically-defined alpha 1A- and cloned alpha 1C-adrenoceptor: studies in the isolated perfused kidney of rat.

1. The present study characterizes and classifies alpha 1-adrenoceptor-mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in cloned alpha 1-adrenoceptor subtypes, native alpha 1A-adrenoceptors in submaxillary gland of rat, and alpha 1A-adrenoceptors in several other tissues of rat). 2. Concentration-effect curves to noradrenaline in the presence of 5-methyl-urapidil were biphasic, indicating alpha 1-adrenoceptor heterogeneity. The alpha 1-adrenoceptor subtype mediating the first phase (low affinity for 5-methyl-urapidil) could not be 'isolated' for detailed pharmacological characterization but was defined by a sensitivity to inhibition by chloroethylclonidine and an inability of methoxamine to activate the site. Additionally, vasoconstriction mediated by this alpha 1-adrenoceptor subtype or subtypes was abolished by nitrendipine (1 microM), thereby allowing characterization of the second, high affinity site for 5-methyl-urapidil. 3. The following antagonists interacted competitively with noradrenaline at the alpha 1-adrenoceptor for which 5-methyl-urapidil exhibits high affinity (pKB value): WB 4101 (10.3) > prazosin (9.5) approximately HV 723 (9.3) approximately 5-methyl-urapidil (9.2) > phenotolamine (8.6) > spiperone (pA2 = 8.1) approximately oxymetazoline (7.9). In contrast, insurmountable antagonism was seen with S(+)- and R(-)-niguldipine, the S(+)-isomer being approximately 30 fold more potent than the R(-)-isomer. Receptor protection experiments indicated that S(+)-niguldipine interacted directly with alpha 1-adrenoceptors. Dehydroniguldipine acted as a competitive antagonist (pKB = 9.0). Thus, the results with antagonists define the alpha 1-adrenoceptor as an alpha 1A-adrenoceptor. 4. An agonist 'fingerprint' was constructed in the presence of nitrendipine to define further the alpha 1A-adrenoceptor. The following order and relativity of agonist potency was obtained: cirazoline (1) approximately adrenaline (2) > noradrenaline (5) > phenylephrine (23) approximately amidephrine (31) > methoxamine (71) >> isoprenaline (1456) approximately dopamine (2210). 5. A high correlative association was shown between the affinity of antagonists obtained functionally in the isolated perfused kidney of rat and pKi values obtained from binding experiments with the cloned bovine alpha 1C-adrenoceptor (R2 = 0.85), native alpha 1A-adrenoceptors in submaxillary gland of rat (R2 = 0.79), and alpha 1A-adrenoceptors from several other tissues of rat (values taken from the literature, R2 = 0.89). 6. The present study demonstrates that the alpha 1A-adrenoceptor is the predominant alpha 1-adrenoceptor subtype mediating vasoconstrictor responses to exogenously administered noradrenaline in the isolated perfused kidney of rat. More importantly, alpha 1A-adrenoceptors mediating vasoconstrictor responses to noradrenaline exhibited a pharmacological equivalency to the cloned bovine alpha 1 c-adrenoceptor. Thus,definitive functional pharmacological data are provided for equating the two receptors and support results derived recently from molecular and radioligand binding studies.

Adrenergic alpha-Agonists↗
PubMed1996

Agonist pharmacology of two Drosophila GABA receptor splice variants.

1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of certain native insect GABA receptors which distinguish them from vertebrate GABA receptors. The high potency and efficacy of isoguvacine and ZAPA distinguishes RDLac homo-oligomers from bicuculline-insensitive vertebrate GABAC receptors, while the low potency of SR95531 and 3-APS distinguishes them from GABAA receptors. The differences in the potency of agonists on RDLac and DRC 17-1-2 homo-oligomers observed in the present study may assist in identification of further molecular determinants of GABA receptor function.

Animals↗
PubMed2004

The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile.

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets. Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8-10 mg/day) and that it exhibits minimal drug-drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo-controlled, active comparator-controlled and open-label uncontrolled studies in both short-term and long-term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short- or long-term placebo-controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active-controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side-effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.

Adrenergic Uptake Inhibitors↗
PubMed1999

Pharmacologic treatment of hypersexuality and paraphilias in nursing home residents.

PURPOSE: To discuss the pharmacologic options for treatment of hypersexuality or paraphilias in nursing home residents. DATA SOURCES: A MEDLINE search was conducted for English-language articles published over the past 20 years and was supplemented by a search of bibliographies of relevant articles. STUDY SELECTION: Case reports of pharmacologic treatment of hypersexual or paraphilic behavior were selected only if the patient receiving treatment was an older person and/or cognitively impaired. DATA EXTRACTION: Case reports were grouped according to the class of the pharmacologic agent used (antiandrogens, estrogens, GnRH analogues, or serotonergic drugs). Each case report was evaluated for pharmacologic agent administered, route of administration, duration of therapy, therapeutic response, and incidence of side effects. CONCLUSIONS: Nursing home residents who display hypersexual or paraphilic behavior are extremely difficult to manage. Before initiating pharmacotherapy to control unwanted sexual behaviors, the current drug regimen should be evaluated carefully for drugs that may be causing or exacerbating the behavior. Case reports suggest that antiandrogens, estrogens, GnRH analogues, and serotonergic medications may be useful when other methods have failed. Controlled comparative trials of these agents are needed to establish their efficacy clearly.

Aged↗
PubMed1998

Rhythm management in atrial fibrillation--with a primary emphasis on pharmacological therapy: Part 2.

Atrial fibrillation (AF) is the most common, sustained, symptomatic tachyarrhythmia that clinicians are called upon to manage. Management strategies include ventricular rate control coupled with anticoagulation, versus restoration and maintenance of sinus rhythm. Rate control may be achieved pharmacologically, with agents that impair AV nodal conduction directly and/or by increasing parasympathetic/sympathetic balance, or by modifying or ablating the AV nodal region anatomically. Rhythm control may be achieved by electrical or pharmacological conversion followed by maintenance of sinus rhythm by pharmacological (or occasionally ablative) therapies. This article will present current approaches to rate and rhythm control issues in AF. Part 1, published previously, dealt with rate control. Part 2, the current article, details approaches to the restoration of sinus rhythm by electrical and pharmacological means. The former may use transthoracic or catheter-based energy delivery systems. The latter may use intravenous or oral drug approaches. Part 3, to be published in a subsequent edition of PACE will deal with the maintenance of sinus rhythm.

Anti-Arrhythmia Agents↗
PubMed1998

Effects of pharmacological autonomic blockade on dual atrioventricular nodal pathways physiology in patients with slow-fast atrioventricular nodal reentrant tachycardia.

The purpose of this study was to investigate the atrioventricular AV nodal physiology and the inducibility of AV nodal reentrant tachycardia (AVNRT) under pharmacological autonomic blockade (AB). Seventeen consecutive patients (6 men and 11 women, mean age 39 +/- 17 years) with clinical recurrent slow-fast AVNRT received electrophysiological study before and after pharmacological AB with atropine (0.04 mg/kg) and propranolol (0.2 mg/kg). In baseline, all 17 patients could be induced with AVNRT, 5 were isoproterenol-dependent. After pharmacological AB, 12 (71%) of 17 patients still demonstrated AV nodal duality. AVNRT became noninducible in 7 of 12 nonisoproterenol dependent patients and remained noninducible in all 5 isoproterenol dependent patients. The sinus cycle length (801 +/- 105 ms vs 630 +/- 80 ms, P < 0.005) and AV blocking cycle length (365 +/- 64 ms vs 338 +/- 61 ms, P < 0.005) became shorter after AB. The antegrade effective refractory period and functional refractory period of the fast pathway (369 +/- 67 ms vs 305 +/- 73 ms, P < 0.005; 408 +/- 56 ms vs 350 +/- 62 ms, P < 0.005) and the slow pathway (271 +/- 30 ms vs 258 +/- 27 ms, P < 0.01; 344 +/- 60 ms vs 295 +/- 50 ms, P < 0.005) likewise became significantly shortened. However, the ventriculoatrial blocking cycle length (349 +/- 94 ms vs 326 +/- 89 ms, NS) and effective refractory period of retrograde fast pathway (228 +/- 38 ms vs 240 +/- 80 ms, NS) remained unchanged after autonomic blockade. Pharmacological AB unveiling the intrinsic AV nodal physiology could result in the masking of AV nodal duality and the decreased inducibility of clinical AVNRT.

Adrenergic beta-Agonists↗
PubMed2005

Pharmacological characterization of human and murine neuropeptide s receptor variants.

We have recently shown that Neuropeptide S (NPS) can promote arousal and induce anxiolytic-like effects after central administration in rodents. Another study reported a number of natural polymorphisms in the human NPS receptor gene. Some of these polymorphisms were associated with increased risk of asthma and possibly other forms of atopic diseases, but the physiological consequences of the mutations remain unclear. One of the polymorphisms produces an Asn-Ile exchange in the first extracellular loop of the receptor protein, and a C-terminal splice variant of the NPS receptor was found overexpressed in human asthmatic airway tissue. We sought to study the pharmacology of the human receptor variants in comparison with the murine receptor protein. Here, we report that the N107I polymorphism in the human NPS receptor results in a gain-of-function characterized by an increase in agonist potency without changing binding affinity in NPSR Ile107. In contrast, the C-terminal splice variant of the human NPS receptor shows a pharmacological profile similar to NPSR Asn107. The mouse NPS receptor, which also carries an Ile residue at position 107, displays an intermediate pharmacological profile. Structure-activity relationship studies show that the amino terminus of NPS is critical for receptor activation. The altered pharmacology of the Ile107 isoform of the human NPS receptor implies a mechanism of enhanced NPS signaling that might have physiological significance for brain function as well as peripheral tissues that express NPS receptors.

Amino Acid Sequence↗
PubMed2002

The emergence of behavioral pharmacology.

Beginning over five decades ago, a pioneering series of studies was conducted that had a profound impact on the field of pharmacology. The impact of those studies was so forceful and sweeping that the discipline of pharmacology was modified in scope and practice by the emergence of a new discipline-behavioral pharmacology. The studies initiating this cascade of events stemmed from the Psychobiology Laboratory at Harvard Medical School and were associated with research conducted by Peter B. Dews, Roger T. Kelleher, and William H. Morse. These individuals shaped the conceptual framework, the experimental direction, as well as the principal focus, that defined and dominated the field of behavioral pharmacology for decades following their initial work in the 1950s. This article will highlight some of the main themes and implications of the work initiated by Dews, Kelleher, and Morse. In particular, I will focus on: i) schedule-controlled behavior and response rate; ii) schedules using noxious stimuli; and iii) the use of second-order schedules.

Animals↗
PubMed2005

Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8.

Members of the transient receptor potential (TRP) superfamily of ion channels have now been defined as molecular transducers capable of reproducing the spectrum of temperature sensation exhibited by mammals. Because of their pivotal role in sensory transduction, many of these channels represent good targets for drug discovery. With a view to gaining further insight into the functional and pharmacological properties of these channels, we have used the whole-cell patch-clamp technique to study the human cold-sensitive menthol receptor transient receptor potential melastatin 8 (TRPM8) and compared its behavior with that of its distant relative, the heat-sensitive capsaicin-gated transient receptor potential vanilloid 1 (TRPV1). It is remarkable to find that TRPM8, in addition to its behavior as an outwardly rectifying, nonselective cation channel, shares many functional and pharmacological properties with TRPV1. TRPM8 exhibits prominent time- and voltage-dependent behavior, a property that may underlie the conserved rectification or gating mechanisms exhibited by these channels. We also show that TRPM8 is modulated by ethanol but unlike TRPV1 is insensitive to extracellular acidification. There is also significant overlap in the antagonist pharmacology of these channels with many TRPV1 antagonists such as capsazepine, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (BCTC), (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide (CTPC), and N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}-urea (SB-452533) exhibiting similar activity at TRPM8. Overall, the degree of pharmacological overlap between TRPV1 and TRPM8 has implications for the interpretation of studies conducted with these ligands to date and highlights a clear challenge for the design of selective TRP channel antagonists. Our finding that N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), at least, represents an apparently selective antagonist for TRPV1 suggests that this goal is attainable.

Capsaicin↗
PubMed2006

Pharmacology and signaling properties of epidermal growth factor receptor isoforms studied by bioluminescence resonance energy transfer.

We have developed a new assay for measuring epidermal growth factor receptor (EGFR) activation using the bioluminescence resonance energy transfer (BRET) technology, which directly measures the recruitment of signaling proteins to activated EGFR. Our results demonstrate that EGFR BRET assays precisely measure the pharmacology and signaling properties of EGFR expressed in human embryonic kidney 293T cells. EGFR BRET assays are highly sensitive to known EGFR ligands [pEC50 of epidermal growth factor (EGF)=10.1+/-0.09], consistent with previous pharmacological methods for measuring EGFR activation. We applied EGFR BRET assays to study the characteristics of somatic EGFR mutations that were recently identified in lung cancer. In agreement with recent reports, we detected constitutively active mutant EGFR isoforms, which predominantly signal through the phosphatidylinositol-3-kinase/Akt pathway. The EGFR inhibitors Iressa or Tarceva are severalfold more potent in inhibiting constitutive activity of mutant EGFR isoforms compared with wild-type EGFR. Notable, our results reveal that most of the mutant EGFR isoforms tested were significantly impaired in their response to EGF. The highest level of constitutive activity and nearly complete loss of epidermal growth factor responsiveness was detected in isoforms that carry the activating mutation L858R and the secondary resistance mutation T790M. In summary, our study reveals that somatic mutations in EGFR quantitatively differ in pharmacology and signaling properties, which suggest the possibility of differential clinical responsiveness to treatment with EGFR inhibitors. Furthermore, we demonstrate that the EGFR BRET assays are a useful tool to study the pharmacology of ligand-induced interaction between EGFR and signaling pathway-specifying adapter proteins.

Cell Line↗
PubMed2003

Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling.

There is increasing evidence for a role of 5-hydroxytrypta-mine-6 (5-HT6) receptors in cognitive function. In the rat and human brain, 5-HT6 receptors are widely expressed and highly enriched in the basal ganglia. However, in the mouse brain, only very low levels of 5-HT6 receptor mRNA and receptor protein, measured by TaqMan reverse transcriptase-polymerase chain reaction and selective radioligand binding, could be detected, with no evidence of enrichment in the basal ganglia. The mouse receptor was cloned and transiently expressed in human embryonic kidney 293 cells to characterize its pharmacological profile. Despite significant sequence homology between human, rat, and mouse 5-HT6 receptors, the pharmacological profile of the mouse receptor was significantly different from the rat and human receptors. Four amino acid residues, conserved in rat and human and divergent in mouse receptors, were identified, and various mutant receptors were generated and their pharmacologies studied. Residues 188 (tyrosine in mouse, phenylalanine in rat and human) in transmembrane region 5 and 290 (serine in mouse, asparagine in rat and human) in transmembrane region 6 were identified as key amino acids responsible for the different pharmacological profiles. Molecular modeling of the receptor and docking of selective and nonselective compounds was undertaken to elucidate the ligand receptor interactions. The binding pocket was predicted to be different in the mouse compared with rat and human 5-HT6 receptors, and the models were in excellent agreement with the observed mutation results and have been used extensively in the design of further selective 5-HT6 antagonists.

Aged↗
PubMed2006

Functional pharmacology in human brain.

Most neurological and psychiatric disorders involve selective or preferential impairments of neurotransmitter systems. Therefore, studies of functional transmitter pathophysiology in human brain are of unique importance in view of the development of effective, mechanism-based, therapeutic modalities. It is well known that central nervous system functional proteins, including receptors, transporters, ion channels, and enzymes, can exhibit high heterogeneity in terms of structure, function, and pharmacological profile. If the existence of types and subtypes of functional proteins amplifies the possibility of developing selective drugs, such heterogeneity certainly increases the likelihood of interspecies differences. It is therefore essential, before choosing animal models to be used in preclinical pharmacology experimentation, to establish whether functionally corresponding proteins in men and animals also display identical pharmacological profiles. Because of evidence that scaffolding proteins, trafficking between plasma membrane and intracellular pools, phosphorylation and allosteric modulators can affect the function of receptors and transporters, experiments with human clones expressed in host cells where the environment of native receptors is rarely reproduced should be interpreted with caution. Thus, the use of neurosurgically removed fresh human brain tissue samples in which receptors, transporters, ion channels, and enzymes essentially retain their natural environment represents a unique experimental approach to enlarge our understanding of human brain processes and to help in the choice of appropriate animal models. Using this experimental approach, many human brain functional proteins, in particular transmitter receptors, have been characterized in terms of localization, function, and pharmacological properties.

Acetylcholine↗
PubMed1995

Pharmacology of kinin receptors: recent developments.

Fifteen years after the classification of kinin receptors into B1 and B2, both receptors have been shown to differ between species. New receptor types have been proposed and named B3, B4, and B5. However, it is not established whether different pharmacologic profiles describing B2 receptors in various species are indicative of different receptor types or of different subtypes (species dependent) subserving the same biological functions. To answer these questions, a systematic search of new pharmacologic tools was undertaken to find monoreceptor systems (isolated organs whose responses are contributed by a single receptor) as well as new selective agonists and competitive or noncompetitive antagonists. Classical pharmacologic experiments were performed in isolated organs for quantifying agonist activities in terms of pD2 and antagonist affinities in terms of pA2. Competitivity of antagonists was established from Schild plots. Results obtained in tissues from rabbits or guinea pigs indicate the existence of two different pharmacological entities, well characterized by selective agonists and competitive antagonists. In vivo experiments performed on anesthetized rabbits and guinea pigs have confirmed the B2 receptor heterogeneity between the two species. Correlations have been established between data obtained in rabbit and guinea pig tissues (biological assays) and in human receptors raised by genic transfection in Chinese hamster ovary (CHO) cells. A good correlation has been found between the IC50 values of kinins and derivatives to displace [3H]bradykinin from the membranes of CHO cells containing the human receptor and the pD2 or pA4 values of the same compounds in the rabbit jugular vein.

Animals↗
PubMed1990

Pharmacological responsiveness of dissociated native and cultured eccrine secretory coil cells.

Methacholine (MCh)- and isoproterenol (Iso)-stimulated 14CO2 production was compared between freshly dissociated rhesus sweat secretory coil cells (mainly clear cells) and cultured cells (grown on a collagen-coated plastic plate) derived from native cells. 14CO2 production was enhanced by MCh and by Iso in native coil cells (but not in ductal cells) in a pharmacologically specific and dose-dependent manner. 14CO2 production in subcultured coil cells (19-45 days in culture) was only one-third to one-fifth that of native cells. MCh-stimulated 14CO2 production was inhibited by ouabain and furosemide in both native and cultured coil cells. A decrease in 14CO2 production, of about one-half, was already evident in primary cells cultured for less than 1 wk. The decreased pharmacological responsiveness of the cultured coil cells was seen, although the cultured cells showed the typical epithelioid appearance, abundant mitochondria, the occasional presence of intercellular lacunae resembling intercellular canaliculi, and the persistence of immunoreactive keratin. We conclude that 1) a primary culture of sweat gland cells can be initiated from dissociated cells; 2) cultured sweat secretory coil cells qualitatively, but not quantitatively, retain the pharmacological responsiveness and transport activity of the native cells as determined by 14CO2 production; 3) collagenase-dissociated cells represent an excellent in vitro system for the study of glandular function at the cellular level; and 4) the decrease in pharmacological responsiveness is not simply due to trypsin treatment during harvesting of cultured cells, because that of organ-cultured, intact, secretory coils also declines with time of culture.

Animals↗
PubMed1999

Somatostatin for upper gastrointestinal hemorrhage and pancreatic surgery. A review of its pharmacology and safety.

Somatostatin, a naturally occurring peptide, displays a wide range of biological actions, mainly inhibitory ones, that can make it an appropriate drug for the treatment of a variety of digestive diseases. The marked effect of the peptide on splanchnic hemodynamics together with its inhibitory action on acid-peptic and pancreatic exocrine secretions represent the rationale for the use in upper gastrointestinal (GI) bleeding and surgical conditions of the pancreas. Besides the hemodynamic effects, other pharmacological actions of somatostatin may contribute to its therapeutic efficacy in active variceal bleeding. The peptide indeed increases lower esophageal sphincter pressure (LESP), thereby reducing the inflow of blood into the submucous venous plexus of the esophagus and hence into the esophageal varices. Through its inhibitory action on acid-peptic secretion, somatostatin may also inhibit peptic digestion of the clot at the site of hemostasis on the varix itself. In addition, the natural peptide was shown to enhance human platelet aggregation in vitro, whose stimulation can activate the hemostatic process. Since its short half-life makes continuous intravenous infusion mandatory, several long-acting analogs have been synthesized. Amongst the hundreds of cyclic peptides synthesised, octreotide (which binds mainly to SSTR-2 and SSTR-5 receptor subtypes) has been the most extensively investigated. A thorough analysis of the pharmacological activities and therapeutic efficacy of the native somatostatin and the synthetic analogs reveals that the biological actions of these peptides are not always identical. These differences appear to be related to the different affinities of the natural hormone and synthetic derivatives for the different receptor subtypes. The fading of the pharmacological effect, which has yet been observed only with analogs, has never been reported with the natural peptide and may be due to down-regulation of specific receptor subtypes. The safety profile of both natural somatostatin and synthetic analogs is today well established. Most adverse reactions to these peptides are merely a consequence of their pharmacological activity and consist mainly of gastrointestinal complaints and effects on glucose metabolism. They are often of little clinical relevance, especially in the short term. Native somatostatin and its synthetic analogs are therefore safe and effective drugs for the treatment of a variety of GI disorders. While the native peptide is the drug of choice in the acute hospital setting, the synthetic derivatives are better indicated, on outpatient basis, for the long-term management of chronic conditions.

Gastrointestinal Hemorrhage↗