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PubMed2000

Octopamine receptors in the honey bee and locust nervous system: pharmacological similarities between homologous receptors of distantly related species.

Honey bees are perhaps the most versatile models to study the cellular and pharmacological basis underlying behaviours ranging from learning and memory to sociobiology. For both aspects octopamine (OA) is known to play a vital role. The neuronal octopamine receptor of the honey bee shares pharmacological similarities with the neuronal octopamine receptor of the locust. Both, agonists and antagonists known to have high affinities for the locust neuronal octopamine receptor have also high affinities for the bee neuronal octopamine receptor. The distribution of receptors is more or less congruent between locusts and bees. Optic lobes and especially the mushroom bodies are areas of greatest octopamine receptor expression in both species, which mirrors the physiological significance of octopamine in the insect nervous system. The neuronal octopamine receptor of insects served as a model to study the pharmacological similarity of homologous receptors from distantly related species, because bees and locusts are separated by at least 330 million years of evolution.

Animals↗
PubMed2001

Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line.

1. The present work characterizes, from a pharmacological and biochemical point of view, adenosine receptors in the human malignant melanoma A375 cell line. 2. Adenosine receptors were detected by RT - PCR experiments. A1 receptors were characterized using [3H]-DPCPX binding with a KD of 1.9+/-0.2 nM and Bmax of 23+/-7 fmol x mg(-1) of protein. A2A receptors were studied with [3H]-SCH 58261 binding and revealed a KD of 5.1+/-0.2 nM and a Bmax of 220+/-7 fmol x mg(-1) of protein. A3 receptors were studied with the new A3 adenosine receptor antagonist [3H]-MRE 3008F20, the only A3 selective radioligand currently available. Saturation experiments revealed a single high affinity binding site with KD of 3.3+/-0.7 nM and Bmax of 291+/-50 fmol x mg(-1) of protein. 3. The pharmacological profile of radioligand binding on A375 cells was established using typical adenosine ligands which displayed a rank order of potency typical of the different adenosine receptor subtype. 4. Thermodynamic data indicated that radioligand binding to adenosine receptor subtypes in A375 cells was entropy- and enthalpy-driven. 5. In functional assays the high affinity A2A agonists HE-NECA, CGS 21680 and A2A - A2B agonist NECA were able to increase cyclic AMP accumulation in A375 cells whereas A3 agonists Cl-IB-MECA, IB-MECA and NECA were able to stimulate Ca2+ mobilization. In conclusion, all these data indicate, for the first time, that adenosine receptors with a pharmacological and biochemical profile typical of the A1, A2A, A2B and A3 receptor subtype are present on A375 melanoma cell line.

Adenosine Deaminase↗
PubMed2002

Pharmacological characterization of F-180: a selective human V(1a) vasopressin receptor agonist of high affinity.

1. The pharmacological properties of F-180, a vasopressin (VP) structural analogue, were determined on CHO cells expressing the different human vasopressin and oxytocin (OT) receptor subtypes. Binding experiments revealed that F-180 exhibited a high affinity for the human V(1a) receptor subtype (K(i)=11 nM) and was selective for this receptor subtype. 2. Functional studies performed on CHO cells expressing human V(1a) receptors indicate that similarly to AVP, F-180 can stimulate the accumulation of inositol phosphate. The activation constant (K(act)) for both F-180 and AVP was 1.7 nM. F-180 was also an agonist for the human V(2) and V(1b) receptor subtypes and an antagonist for the human OT receptor. 3. Since marked species pharmacological differences for vasopressin receptors have been described, we studied the properties of F-180 on various mammalian species. F-180 showed high affinity and good selectivity for human and bovine V(1a) receptors, but weak affinity and non selective properties for rat V(1a) receptors. 4. To assess the functional properties of F-180 on a native biological model, we performed studies on primary cultures of cells from bovine zona fasciculata (ZF). As AVP, F-180 stimulated inositol phosphate accumulation and cortisol secretion with similar efficiency. 5. In conclusion, we demonstrate that F-180 is the first selective V(1a) agonist described for human and bovine vasopressin receptors. Therefore F-180 can be used as a powerful pharmacological tool to characterize the actions of vasopressin that are mediated by V(1a) receptor subtypes.

Animals↗
PubMed2003

Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex.

1 The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5-hydroxytryptamine (5-HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl. 2 N/OFQ concentration-dependently inhibited K(+)-evoked [(3)H]-5-HT and [(3)H]-NE overflow with similar potency (pEC(50) approximately 7.9 and approximately 7.7, respectively) and efficacy (maximal inhibition approximately 40%). 3 N/OFQ (0.1 micro M) inhibition of [(3)H]-5-HT and [(3)H]-NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe(1)]N/OFQ(1-13)NH(2) and UFP-101; 10 and 1 microM, respectively) and non-peptide (J-113397 and JTC-801; both 0.1 microM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre-application time was necessary for J-113397 and JTC-801 to prevent N/OFQ inhibition of [(3)H]-NE overflow. 4 The NOP receptor ligand [Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2) ([F/G]N/OFQ(1-13)NH(2); 3 microM) did not affect K(+)-evoked [(3)H]-NE but inhibited K(+)-evoked [(3)H]-5-HT overflow in a UFP-101 sensitive manner. [F/G]N/OFQ(1-13)NH(2) antagonized N/OFQ actions on both neurotransmitters. 5 The time-dependency of JTC-801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin-stimulated cAMP accumulation and JTC-801, tested at different concentrations (0.1-10 microM) and pre-incubation times (0, 40 and 90 min), antagonized this effect in a time-dependent manner. The Schild-type analysis excluded a competitive type of antagonism. 6 We conclude that presynaptic NO receptors inhibiting 5-HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1-13)NH(2) and time-dependent sensitivity towards non-peptide antagonists.

Animals↗
PubMed2003

Pharmacological profile of store-operated channels in cerebral arteriolar smooth muscle cells.

1. In this study, we determined a pharmacological profile of store-operated channels (SOCs) in smooth muscle cells of rabbit pial arterioles. Ca(2+)-indicator dyes, fura-PE3 or fluo-4, were used to track [Ca(2+)](i) and 10 micro M methoxyverapamil (D600) was present in all experiments on SOCs to prevent voltage-dependent Ca(2+) entry. Store depletion was induced using thapsigargin or cyclopiazonic acid. 2. SOC-mediated Ca(2+) entry was inhibited concentration dependently by Gd(3+) (IC(50) 101 nM). It was also inhibited by 10 micro M La(3+) (70% inhibition, N=5), 100 micro M Ni(2+) (57% inhibition, N=5), 75 micro M 2-aminoethoxydiphenylborate (66% inhibition, N=4), 100 micro M capsaicin (12% inhibition, N=3) or preincubation with 10 micro M wortmannin (76% inhibition, N=4). It was completely resistant to 1 micro M nifedipine (N=5), 10 micro M SKF96365 (N=6), 10 micro M LOE908 (N=14), 10-100 micro M ruthenium red (N=1+2), 100 micro M sulindac (N=4), 0.5 mM streptomycin (N=3) or 1 : 10,000 dilution Grammostolla spatulata venom (N=4). 3. RT-PCR experiments on isolated arteriolar fragments showed expression of mRNA species for TRPC1, 3, 4, 5 and 6. 4. The pharmacological profile of SOC-mediated Ca(2+) entry in arterioles supports the hypothesis that these SOCs are distinct from tonically active background channels and several store-operated and other nonselective cation channels described in other cells. Similarities with the pharmacology of TRPC1 support the hypothesis that TRPC1 is a subunit of the arteriolar smooth muscle SOC.

Androstadienes↗
PubMed2003

Pharmacological comparison of the alternatively spliced short and long CCK2 receptors.

(1) The alternatively spliced, short and long cholecystokinin receptors (CCK2S and CCK2L) were expressed in NIH3T3 cells, and compared using radioligand-binding assays with identical buffer and incubation conditions. (2) As judged by a saturation analysis, the selective CCK2-receptor antagonist radioligand [3H]-JB93182 did not discriminate between the CCK2S or CCK2L receptors. (3) A global analysis of competition studies, using a range of structurally diverse, CCK-receptor selective ligands, provided further evidence that these receptor subtypes were pharmacologically indistinguishable. However, when analysed individually a number of small, yet significant differences were observed with some of the compounds. (4) These data are consistent with previous study that suggested a possible pharmacological difference between these isoforms, at least in terms of the CCK2-receptor antagonist, L-365,260. However, it would appear that the pharmacological profile of these compounds is not consistent with their affinity at the putative G1/G2 receptors previously described by Harper et al.

Animals↗
PubMed2004

Pharmacological characterization of human S1P4 using a novel radioligand, [4,5-3H]-dihydrosphingosine-1-phosphate.

Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects a variety of cellular processes through both its actions as a second messenger and via activation of a family of G protein-coupled receptors (S1P(1-5)). The study of S1P receptor pharmacology, particularly S1P(4), has been hindered by the lack of high-affinity radioligands with good specific activity. The studies presented herein characterize [(3)H]DH-S1P as a stable, high-affinity radioligand for S1P(4) pharmacology. Using a transfected Ba/F3 cell line selected for high hS1P(4) surface expression, we compared the consequences of different cellular backgrounds and commercial sources of sphingophospholipids on S1P(4) characterization. The development and subsequent use of the assay described has enabled us to extensively and definitively characterize the pharmacology of the human S1P(4) receptor.

Animals↗
PubMed2005

Molecular and pharmacological characteristics of transient voltage-dependent K+ currents in cultured human pulmonary arterial smooth muscle cells.

The A-type voltage-dependent K(+) current (I(A)) has been identified in several types of smooth muscle cells including the pulmonary artery (PA), but little is known about the pharmacological and molecular characteristics of I(A) in human pulmonary arterial smooth muscle cells (hPASMCs). We investigated I(A) expressed in cultured PASMCs isolated from the human main pulmonary artery, using patch-clamp techniques, reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR and immunocytochemical studies. With high EGTA and ATP in the pipette, the outward currents were dominated by a transient K(+) current (I(A)), followed by a relatively small sustained outward current (I(K)). I(A) was inhibited by 4-aminopyridine (4-AP) concentration-dependently, and could be separated pharmacologically into two components by tetraethylammonium (TEA) sensitivity. A component was sensitive to TEA, and the second component was insensitive to TEA. I(A) was inhibited by blood depressing substrate (BDS)-II, a specific blocker of K(V)3.4 subunit, and phrixotoxin-II, a specific blocker of K(V)4.2 and 4.3. Flecainide inhibited I(A) concentration-dependently, but it inhibited it preferentially in the presence of TEA (TEA-insensitive I(A)). Systematic screening of expression of K(V) genes using RT-PCR showed the definite presence of transcripts of the I(A)-encoding genes for K(V)3.4, K(V)4.1, K(V)4.2 and K(V)4.3 as well as the I(K)-encoding genes for K(V)1.1, K(V)1.5 and K(V)2.1. The real-time RT-PCR analysis showed that the relative abundance of the encoding genes of I(A) alpha-subunit and K(V) channel-interacting proteins (KChIPs) was K(V)4.2 > K(V)3.4 > K(V)4.3 (long) > K(V)4.1, and KChIP3 >> KChIP2, respectively. The presence of K(V)3.4, K(V)4.2 and K(V)4.3 proteins was also demonstrated by immunocytochemical studies, and confirmed by immunohistochemical staining using intact human PA sections. These results suggest that I(A) in cultured hPASMCs consists of two kinetically and pharmacologically distinct components, probably K(V)3.4 and K(V)4 channels.

Calcium-Binding Proteins↗
PubMed2002

Development of a rat model of sexual performance anxiety: effect of behavioural and pharmacological hyperadrenergic stimulation on APO-induced erections.

As part of the multifactorial nature of erectile dysfunction, anxiety associated with sexual performance (SPA) remains a major contributing factor to its progression. In fact, the heightened sympathetic activity associated with sexual performance anxiety may be a key early component of this disruption of normal erectile responses. We are not aware that any animal models have been developed to assess this phenomenon. Using apomorphine (APO, 80 microg/kg s.c.)-induced erections in rats we characterised the effects of behavioural or pharmacological hyperadrenergic stimulation (that is, anxiety) on erections and hemodynamics. We developed an experimental SPA paradigm by exposing male rats to the stress of being observed by a larger, older male rat placed in close proximity to test rats during APO testing. In a separate group, adrenergic stress was simulated using a sympathomimetic, methoxamine (MXA) given prior to APO testing. In a third group, the changes in circulatory parameters (mean arterial pressure, heart rate) were determined following instrumentation with radiotelemetric transducers for each scenario. APO-induced erections were significantly lower in both the behavioural (1.25+/-0.8) and pharmacological (0.33+/-0.5) stressor paradigms compared to controls (2.81+/-0.9). Further, erections in MXA-treated rats were significantly lower than in the observed scenario. Despite the differences in erections hemodynamic assessments showed no differences in MAP or HR changes between the different experimental conditions. Thus, both the behavioural and pharmacological paradigms of SPA decreased erections, but did not affect the circulation. This suggests that the level of hyperadrenergic input required to induce erectile dysfunction can be subtle, and target only erectogenic pathways.

Animals↗
PubMed1999

Pharmacological treatment of obesity: present status.

OBJECTIVE: Obesity poses a serious health hazard and its treatment is often disappointing. This review describes the present status of pharmacological treatment of obesity in man. DESIGN: Obesity treatment may include drugs that reduce food intake, drugs that increase energy expenditure and drugs that affect nutrient partitioning or metabolism. The mode of action, efficacy and safety of each approach will be briefly discussed. RESULTS: All of the pharmacological possibilities have potential activities, but also serious limitations. While current anti-obesity pharmacotherapy essentially uses centrally-acting anorectic drugs, severe side-effects (more particularly pulmonary hypertension and valvular heart disease) have been reported, leading to the withdrawal of licensed fenfluramine and d-fenfluramine. New approaches have been recently proposed, such as sibutramine, an amine reuptake inhibitor which decreases food intake, and orlistat, an intestinal lipase inhibitor which decreases fat absorption. Obesity is a chronic disease and should be treated as such with reasonable expectations. Large-scale one-year placebo-controlled studies demonstrated that d-fenfluramine, sibutramine and orlistat significantly increased body weight loss by an average of 2-4 kg when compared to placebo and, more interestingly, multiplied by 2-3 the number of patients who succeeded in obtaining and maintaining a reduction of more than 10% of initial body weight. Interestingly, some of these compounds may also exert favourable effects on other vascular risk factors, independently of weight loss. CONCLUSIONS: Even if all anti-obesity pharmacological approaches can be helpful, they also have important limitations so that other strategies including either combined therapies or new drugs (peptides) are currently under investigation.

Anti-Obesity Agents↗
PubMed2003

A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells.

It is now well established that the reduced capacity of tumor cells of undergoing cell death through apoptosis plays a key role both in the pathogenesis of cancer and in therapeutic treatment failure. Indeed, tumor cells frequently display multiple alterations in signal transduction pathways leading to either cell survival or apoptosis. In mammals, the pathway based on phosphoinositide 3-kinase (PI3K)/Akt conveys survival signals of extreme importance and its downregulation, by means of pharmacological inhibitors of PI3K, considerably lowers resistance to various types of therapy in solid tumors. We recently described an HL60 leukemia cell clone (HL60AR cells) with a constitutively active PI3K/Akt pathway. These cells were resistant to multiple chemotherapeutic drugs, all-trans-retinoic acid (ATRA), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatment with two pharmacological inhibitors of PI3K, wortmannin and Ly294002, restored sensitivity of HL60AR cells to the aforementioned treatments. However, these inhibitors have some drawbacks that may severely limit or impede their clinical use. Here, we have tested whether or not a new selective Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate (Akt inhibitor), was as effective as Ly294002 in lowering the sensitivity threshold of HL60 cells to chemotherapeutic drugs, TRAIL, ATRA, and ionizing radiation. Our findings demonstrate that, at a concentration which does not affect PI3K activity, the Akt inhibitor markedly reduced resistance of HL60AR cells to etoposide, cytarabine, TRAIL, ATRA, and ionizing radiation. This effect was likely achieved through downregulation of expression of antiapoptotic proteins such as c-IAP1, c-IAP2, cFLIP(L), and of Bad phosphorylation on Ser 136. The Akt inhibitor did not influence PTEN activity. At variance with Ly294002, the Akt inhibitor did not negatively affect phosphorylation of protein kinase C-zeta and it was less effective in downregulating p70S6 kinase (p70S6K) activity. The Akt inhibitor increased sensitivity to apoptotic inducers of K562 and U937, but not of MOLT-4, leukemia cells. Overall, our results indicate that selective Akt pharmacological inhibitors might be used in the future for enhancing the sensitivity of leukemia cells to therapeutic treatments that induce apoptosis or for overcoming resistance to these treatments.

Antineoplastic Agents↗
PubMed2002

Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite.

Cytochrome P450 (P450) is a superfamily of enzymes which mediates metabolism of xenobiotics including drugs. Alprazolam, an anti-anxiety agent, is metabolized in rat and human liver by P4503A1 and P4503A4 respectively, to 4-hydroxy alprazolam (4-OHALP, pharmacologically less active) and alpha-hydroxy alprazolam (alpha-OHALP, pharmacologically more active). We examined P450 mediated metabolism of alprazolam by rat and human brain microsomes and observed that the relative amount of alpha-OHALP formed in brain was higher than liver. This biotransformation was mediated by a P450 isoform belonging to P4503A subfamily, which is constitutively expressed in neuronal cells in rat and human brain. The formation of larger amounts of alpha-OHALP in neurons points to local modulation of pharmacological activity in brain, at the site of action of the anti-anxiety drug. Since hydroxy metabolites of alprazolam are hydrophilic and not easily cleared through blood-CSF barrier, alpha-OHALP would potentially have a longer half-life in brain.

Adult↗
PubMed2006

Stuttering treatment research 1970-2005: II. Systematic review incorporating trial quality assessment of pharmacological approaches.

PURPOSE: To complete a systematic review, incorporating trial quality assessment, of published research about pharmacological treatments for stuttering. Goals included the identification of treatment recommendations and research needs based on the available high-quality evidence. METHOD: Multiple readers reviewed 31 articles published between 1970 and 2005, using a written data extraction instrument developed as a synthesis of existing standards and recommendations. Articles were then assessed using 5 methodological criteria and 4 outcomes criteria, also developed from previously published recommendations. RESULTS: None of the 31 articles met more than 3 of the 5 methodological criteria (M = 1.74). Four articles provided data to support a claim of short-term improvement in social, emotional, or cognitive variables. One article provided data to show that stuttering frequency was reduced to less than 5%, and 4 additional articles provided data to show that stuttering may have been reduced by at least half. Among the articles that met the trial quality inclusion criterion for the second stage of this review, none provided uncomplicated positive reports. CONCLUSIONS: None of the pharmacological agents tested for stuttering have been shown in methodologically sound reports to improve stuttering frequency to below 5%, to reduce stuttering by at least half, or to improve relevant social, emotional, or cognitive variables. These findings raise questions about the logic supporting the continued use of current pharmacological agents for stuttering.

Anticonvulsants↗
PubMed2001

The pharmacology of the internal anal sphincter and new treatments of ano-rectal disorders.

Surgical options for faecal incontinence in the presence of intact sphincters are limited. Furthermore, in patients with fissures, lateral sphincterotomy reduces anal sphincter hypertonia but there has been concern about complications. A greater understanding of the basic pharmacology of the internal anal sphincter has led to the development of novel treatments for both these disorders. A Medline review was undertaken for internal anal sphincter pharmacology, anal fissures and faecal incontinence. This review is based on these articles and those found by further cross-referencing. Nitric oxide released from non-adrenergic non-cholinergic nerves is the main inhibitory agent in the internal anal sphincter. Relaxations are also mediated through beta-adrenoceptors and muscarinic receptors. Stimulation of alpha-receptors results in contraction. Calcium and its entry through L-type calcium channels is important for the maintenance of tone. Nitric oxide donors produce reductions in resting anal tone and heal fissures but are associated with side-effects. Muscarinic agents and calcium channel antagonists show promise as low side-effect alternatives. Botulinum toxin appears more efficacious than other agents in healing fissures. To date, alpha-receptor agonists have been disappointing at improving incontinence. Further understanding of the pharmacology of the internal anal sphincter may permit the development of new agents to selectively target the tissue with greater efficacy and fewer side-effects.

Adrenergic alpha-Agonists↗
PubMed2001

Review article: the pharmacological treatment of acute colonic pseudo-obstruction.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) can be defined as a clinical condition with symptoms, signs and radiological appearance of acute large bowel obstruction unrelated to any mechanical cause. Recent reports of the efficacy of cholinesterase inhibitors in relieving acute colonic pseudo-obstruction have fuelled interest in the pharmacological treatment of this condition. The aim of the present review is to outline current perspectives in the pharmacological treatment of patients with acute colonic pseudo-obstruction. The best documented pharmacological treatment of Ogilvie's syndrome is intravenous neostigmine (2-2.5 mg), which leads to quick decompression in a significant proportion of patients after a single infusion. However, the search for new colokinetic agents for the treatment of lower gut motor disorders has made available a number of drugs that may also be therapeutic options for Ogilvie's syndrome. Among these agents, the potential of 5-hydroxytryptamine-4 receptor agonists and motilin receptor agonists is discussed.

Acute Disease↗
PubMed1999

alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role.

Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.

Adjuvants, Anesthesia↗
PubMed2002

Pharmacological agents as cerebral protectants during deep hypothermic circulatory arrest in adult thoracic aortic surgery. A survey of current practice.

A postal survey was sent to members of the Association of Cardiothoracic Anaesthetists to ascertain current practice in the use of pharmacological agents as cerebral protectants during deep hypothermic circulatory arrest. The response rate was 60%. Eighty-three per cent of respondents used some form of pharmacological agent specifically for cerebral protection. Fifty-nine per cent of respondents used thiopental, 29% used propofol and 48% used a variety of other agents, the most common of these being a steroid. There were variations in the dose and timing of administration of drugs. Few respondents believed that there was a body of evidence to support this use of pharmacological agents. Only 35% of respondents believed there to be sufficient evidence to support the use of thiopental. Similarly, only 11% of respondents believe that there is evidence supporting the use of propofol, and 16% the use of steroids. The above findings demonstrate that it would not be possible to create a "best practice" set of guidelines at present. A national database of all cases of adult thoracic surgery involving deep hypothermic cardiac arrest, with methodology and outcome, could probably establish such guidelines, evidence based.

Adult↗
PubMed2003

Angiotensin II dose-effect curves and Schild regression plots for characterization of different angiotensin II AT1 receptor antagonists in clinical pharmacology.

The 'Schild regression' method is based on the principle of assessing the rightward shift of agonist dose-effect curves in the presence of different doses/concentrations of the respective receptor antagonist and presenting their relationship in a double log plot (i.e. the 'Schild plot'). The original method was developed to quantitatively characterize antagonistic drugs in experimental pharmacology. The method was adopted for evaluation of various AT1 antagonists in humans utilizing (human) angiotensin II as the agonist. Angiotensin II (Ang II) in continuous intravenous dose-incremental administration resulted in a clearly dose-dependent increase in blood pressure. All AT1 antagonists tested after oral administration yielded concentration-dependent rightward shifts of those Ang II dose-effect curves that were quantified as dose ratio (DR). DR minus 1 (DR-1) enabled the assessment of antagonist time kinetics in humans and a quantitatively precise determination of the half-life of antagonism in vivo. Schild plots allowed for assessment of apparent Ki doses indicative of a twofold rightward shift of the Ang II effect, thus providing the means for a rational comparison of the pharmacological potency of many of these compounds, where the Ki doses obtained at 24 h after administration were in the range of 'therapeutic' doses. Schild plots of a variety of substances showed linear relations independent of whether the blockade was deemed surmountable or not. It is therefore assumed that this property does not play a role at clinical doses/concentrations. Slopes slightly below 1 in the Schild plots of all tested antagonists point to a second 'counterregulatory' vasodilatory mechanism of action of Ang II which becomes apparent with AT1 blockade in conditions of high doses/concentrations of Ang II. Concentration vs. effect relationships indicate that if assessed at the same degree of direct vascular antagonism, other effects, such as increase in plasma renin activity, may be present to a varying degree with different antagonists. Thus for irbesartan, the potency to stimulate renin release was found to be at least twice that of candesartan. These observations should stimulate further research into the relevance of these dynamic differences between the various compounds. Thus, methodologies relying on fundamental principles of experimental pharmacology can provide the clinical pharmacologist with powerful tools to measure accurately degree of antagonism and time kinetics and to investigate the nature of receptor antagonism in humans.

Angiotensin I↗