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PubMed1998

Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs?

Antiepileptic drugs (AEDs), such as phenytoin (PHT), carbamazepine (CBZ), trimethadione (TMD), and phenobarbital (PB), have all been associated with a similar pattern of malformations, as well as growth retardation and developmental delay. Valproic acid (VPA) has been associated with a different pattern of malformations. Recent studies suggest that PHT's fetal adverse effect is related to its membrane stabilizing pharmacological properties (blockage of voltage-dependent ion channels). During a restricted sensitive period, this results in induction of concentration-dependent bradyarrhythmia in the embryo and episodes of hypoxia/reoxygenation. The aim of this study was to compare the potential of PHT, CBZ, PB, TMD, and dimethadione (DMD; the active metabolite of TMD) to cause bradyarrhythmias. All of these AEDs exert mainly their pharmacological effect via blockage of ion channels. VPA and vigabatrin (VGB), which are pharmacologically active mainly by other mechanisms, were also tested. C57 Bl/6J mouse embryos were cultured in vitro on gestation day 10 in vitro (in 20% rat serum). The drugs were suspended in either water or dimethylsulfoxide and administered into the culture medium in increasing concentrations up to 20 times the human therapeutic plasma concentration. A scoring system was employed in order to rank the drugs based on their potential to cause bradycardia, ventricular arrhythmia, and cardiac arrest in relation to human therapeutic concentrations. Based on this system, the drugs were ranked as follows: DMD = PHT >> PB = CBZ > TMD = VPA >> VGB (no potential). The results correlate well with the available clinical/experimental data of the tested AED's potential to induce hypoxia-related fetal adverse effects, such as oral clefts, distal limb defects, growth retardation, and developmental delay. The results support the idea that adverse fetal effects after in utero exposure to PHT, PB, CBZ, and TMD (via the active metabolite DMD) are initiated via a common pharmacological mechanism: blockage of ion channels in the developing heart in the early embryo resulting in bradyarrhythmias, hemodynamic alterations, and hypoxia/reoxygenation damage.

Abnormalities, Drug-Induced↗

PubMed1999

Pharmacokinetics of ezlopitant, a novel non-peptidic neurokinin-1 receptor antagonist in preclinical species and metabolite kinetics of the pharmacologically active metabolites.

The pharmacokinetics of ezlopitant were determined in the rat, gerbil, guinea pig, ferret, dog and monkey after intravenous and oral administration. In general, ezlopitant is marked by high clearance values that approach or exceed hepatic blood flow values, moderate to high values for steady-state volume of distribution (3. 9-28 L/kg), and terminal phase half-life values ranging from 0.6 h in the guinea pig to 7.7 h in the rat. Oral bioavailability ranged from <0.2% (guinea pig) to 28% (dog). Data from portal vein cannulated dogs suggested that 37% of an oral dose of ezlopitant enters the portal vein as an unchanged drug in this species. Ezlopitant is metabolized to two pharmacologically active metabolites, an alkene (CJ-12 458) and a benzyl alcohol (CJ-12 764). After administration of the parent compound, CJ-12 764 was found in greater abundance than CJ-12 458 in all species examined. Ezlopitant and CJ-12 458 were highly protein bound in plasma (or serum), whereas the protein binding of CJ-12 764 was somewhat lower. Measurement of the kinetics of ezlopitant, CJ-12 458 and CJ-12 764 in the cerebrospinal fluid (CSF) of dogs demonstrated that all three compounds can partition into the CSF, and thereby, be capable of contributing to centrally mediated pharmacological effects. Thus, these data suggest that the pharmacological activity exhibited by ezlopitant in preclinical species in vivo is likely a result of the parent compound plus the active metabolites. Furthermore, the contributions of ezlopitant and the active metabolites to pharmacological activity probably varies with the identity of the model species, as well as the dose and route of ezlopitant administration.

Animals↗

PubMed2004

Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome.

BACKGROUND: Multiple pharmacologic treatments have been studied for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). OBJECTIVES: Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS. SEARCH STRATEGY: We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to week 2, January 2004), EMBASE (1980 to week 4, 2004), CINAHL (1982 to week 2, January 2004), and HEALTHSTAR (1995 to December 2003); proceedings from four conferences (1994 to 2003); and bibliographies of review articles and included studies. SELECTION CRITERIA: Randomized controlled trials of pharmacologic treatments compared to no therapy or placebo for established ALI or ARDS in adults admitted to an intensive care unit, with measurement of early mortality (primary outcome), late mortality, duration of mechanical ventilation, ventilator-free days to day 28, or adverse events. We excluded trials of nitric oxide, partial liquid ventilation, fluid and nutritional interventions, oxygen, and trials in other populations reporting outcomes in subgroups of patients with ALI or ARDS. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts, rated studies for inclusion, extracted data and assessed methodologic quality of included studies. Disagreements were resolved by consensus in consultation with a third reviewer. For each pharmacologic therapy, we quantitatively pooled the results of studies using random effects models where permitted by the available data. We contacted study authors when clarification of the primary outcome was required. MAIN RESULTS: Thirty three trials randomizing 3272 patients met our inclusion criteria. Pooling of results showed no effect on early mortality of prostaglandin E1 (seven trials randomizing 697 patients; relative risk [RR] 0.95, 95% confidence interval [CI] 0.77 to 1.17), N-acetylcysteine (five trials randomizing 239 patients; RR 0.89, 95% CI 0.65 to 1.21), early high-dose corticosteroids (two trials randomizing 187 patients; RR 1.12, 95% CI 0.72 to 1.74), or surfactant (nine trials randomizing 1441 patients; RR 0.93, 95% CI 0.77 to 1.12). Two interventions were beneficial in single small trials; corticosteroids given for late phase ARDS reduced hospital mortality (24 patients; RR 0.20, 95% CI 0.05 to 0.81), and pentoxifylline reduced one-month mortality (RR 0.67, 95% CI 0.47 to 0.95) in 30 patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show a beneficial effect on prespecified outcomes. REVIEWERS' CONCLUSIONS: Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.

Acetylcysteine↗

PubMed2026

Pharmacological therapies for the prevention of fractures in men.

RATIONALE: Pharmacological therapies for fracture prevention usually target osteoporosis, a skeletal disorder characterised by compromised bone mass or quality (or both). As most participants in osteoporosis trials are women, a review of pharmacological therapies for fracture prevention in men was warranted. OBJECTIVES: To determine the benefits and harms of bisphosphonates, parathyroid (PTH) or parathyroid-related protein (PTHrP) analogues, denosumab, and romosozumab therapy for the prevention of fractures in men. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and WHO ICTRP) until 14 October 2025, with no restrictions on date or language of publication. ELIGIBILITY CRITERIA: We included randomised controlled trials that compared bisphosphonates, PTH or PTHrP analogues, denosumab, or romosozumab (alone or with calcium or vitamin D, or both) with placebo, other drugs, or non-pharmacological therapies in men aged 50 years or older. Our primary comparison was bisphosphonates versus placebo. OUTCOMES: Critical outcomes were incidence of hip fractures, symptomatic vertebral fractures, other (not hip or vertebral) fractures, disability, participants with adverse events, study withdrawals due to adverse events, and participants with serious adverse events. Our primary time point was the final time point reported in the trials. RISK OF BIAS: We used Cochrane's RoB 2 tool to assess risk of bias. SYNTHESIS METHODS: We used a random-effects model for meta-analysis employing the Mantel-Haenszel approach, and the DerSimonian and Laird method to estimate between-trial variance. We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: Seventeen trials (4132 participants) met our inclusion criteria. The average age of participants ranged from 52 to 73 years. Twelve trials used a placebo comparator versus bisphosphonate (7 trials, 2548 participants), PTH or PTHrP analogues (4 trials, 569 participants), denosumab (1 trial, 240 participants), and romosozumab (1 trial, 244 participants). For the other planned comparisons, a bisphosphonate was compared to vitamin D/vitamin D analogues (2 trials, 434 participants), to calcitonin (1 trial, 32 participants), to PTH or PTHrP analogues (1 trial, 19 participants), or to another bisphosphonate (1 trial, 301 participants), and one trial compared a bisphosphonate plus calcium to calcium tablets alone (46 participants). SYNTHESIS OF RESULTS: Placebo-controlled trials were largely susceptible to bias in selection of the reported result (83%), while most trials without a placebo control were also susceptible to bias arising from the randomisation process (100%) and in measurement of the outcome (80%). We are very uncertain about the effect of bisphosphonates on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures compared to placebo at the final follow-up (up to two years). We downgraded the certainty of evidence once for risk of bias, twice for imprecision (very low event rates), and once for suspected publication bias. The certainty of evidence for incidence of other fractures was further downgraded for indirectness, as it was unclear if hip fractures were also included in the outcome. At up to two years, 2/875 participants (2 per 1000) in the bisphosphonate group reported hip fractures compared with 2/760 (3 per 1000) in the placebo group (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.06 to 8.51; I² = 36%; 4 trials, 1635 participants); 5/1021 (4/1000) participants in the bisphosphonate group had a symptomatic vertebral fracture compared to 7/855 (8/1000) participants in the placebo group (RR 0.49, 95% CI 0.14 to 1.74; I² = 0%; 5 trials, 1876 participants); 25/1130 participants (16/1000) in the bisphosphonate group reported other (non-hip non-vertebral) fractures compared to 19/913 participants (21/1000) in the placebo group (RR 0.78, 95% CI 0.42 to 1.45; I² = 0%; 6 trials, 2043 participants). Bisphosphonates probably do not increase the risk of adverse events: 1024/1374 participants (746/1000) receiving bisphosphonates reported adverse events compared to 826/1174 participants (704/1000) receiving placebo (RR 1.06, 95% CI 0.93 to 1.19; I² = 75%; 7 trials, 2548 participants; moderate-certainty evidence) or serious adverse events: 329/1329 participants (272/1000) receiving bisphosphonate reported serious adverse events compared to 323/1128 participants (286/1000) receiving placebo (RR 0.95, 95% CI 0.84 to 1.08; I² = 0%; 6 trials, 2457 participants; moderate-certainty evidence). We downgraded the certainty of evidence once due to potential bias for adverse events and serious adverse events. We are very uncertain if bisphosphonates result in more withdrawals due to adverse events: 41/1374 participants (25/1000) in the bisphosphonate group withdrew due to adverse events compared with 43/1174 participants (37/1000) in the placebo group (RR 0.68, 95% CI 0.39 to 1.18; I² = 37%; 7 trials, 2548 participants; very low-certainty evidence). We downgraded the certainty of evidence once for risk of bias, once for indirectness, and once for imprecision. No trial reported disability. We are very uncertain about the effects of PTH or PTHrP analogues, denosumab, or romosozumab compared to placebo on fracture outcomes. We are very uncertain about the effects of PTH/PTHrP analogues on total adverse events, withdrawals due to adverse events, and serious adverse events. Denosumab may not increase the risk of adverse events or serious adverse events compared to placebo, while the evidence for withdrawals due to adverse events is very uncertain. Romosozumab probably does not increase the risk of adverse events and may not increase the risk of serious adverse events or result in more withdrawals due to adverse events. AUTHORS' CONCLUSIONS: We are very uncertain about the effects of bisphosphonates compared to placebo on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures in men at up to two years of use. Bisphosphonates probably do not increase the risk of adverse events or serious adverse events, and we are very uncertain if they result in more withdrawals due to adverse events. We downgraded the certainty of evidence for indirectness, imprecision (low event rate), and serious risk of bias in selection of the reported result, as it was unclear if all studies fully reported every fracture. We found similar results for PTH or PTHrP analogues, denosumab, or romosozumab versus placebo. Larger, longer placebo-controlled studies are needed to determine whether pharmacological therapies are beneficial for reducing fractures in men. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol (2021): https://doi.org/10.1002/14651858.CD014707.

Humans↗

PubMed1996

Complications of pharmacologic stress echocardiography in coronary artery disease.

In the last few years, pharmacologic stress echocardiography is emerging as a promising diagnostic tool with a favorable cost/benefit ratio. Its main clinical applications include the assessment of coronary artery disease, the identification of viable myocardium, and risk stratification before major vascular surgery. However, cardiac (arrhythmic, ischemic, or hemodynamic) as well as noncardiac complications have been reported, so that a risk/benefit analysis is advisable in view of the extensive introduction of this technique in the clinical arena. The most popular pharmacologic agents employed for stress echocardiography are dipyridamole, dobutamine, and adenosine. A comparative analysis with exercise stress testing, the classical standard a reference of all ischemia-provoking tests, confirms that in terms of safety and tolerability pharmacologic stress echocardiography may be considered a good alternative in patients unable to exercise maximally. No appreciable difference among the safety profiles of the most common pharmacologic agents has been found, but a careful evaluation of the risk/benefit ratio is advisable for any stressor in the individual patient by considering the relative importance of the expected diagnostic contribution and the pharmacodynamic impact of the test. Finally, adequate training of the operator and monitoring of the patient during stress and recovery are essential for getting optimal safety conditions.

Adenosine↗

PubMed2003

Pharmacologic treatment of binge eating disorder.

OBJECTIVE: To review the findings from pharmacologic trials of binge eating disorder (BED) and to provide guidelines for pharmacologic treatment. METHODS: The literature was searched for studies of pharmacologic treatment of BED and related conditions, such as nonpurging bulimia nervosa. RESULTS: Placebo-controlled studies of desipramine, fluvoxamine, fluoxetine, sertraline, citalopram, dexfenfluramine, sibutramine, and topiramate have demonstrated the efficacy of these agents in the treatment of BED. An open trial of venlafaxine has offered preliminary evidence for the efficacy of this medication. Guidelines for pharmacologic management of BED are provided. CONCLUSIONS: The literature offers support for the use of agents from three categories of medication (antidepressants, appetite suppressants, and anticonvulsants) in the treatment of BED.

Anticonvulsants↗

PubMed2007

Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review.

BACKGROUND: Wandering occurs in 15-60% of people with dementia. Psychosocial interventions rather than pharmacological methods are recommended, but evidence for their effectiveness is limited and there are ethical concerns associated with some non-pharmacological approaches, such as electronic tracking devices. OBJECTIVE: To determine the clinical and cost effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia. DESIGN: A systematic review to evaluate effectiveness of the interventions and to assess acceptability and ethical issues associated with their use. The search and review strategy, data extraction and analysis followed recommended guidance. Papers of relevance to effectiveness, acceptability and ethical issues were sought. RESULTS: (i) Clinical effectiveness. Eleven studies, including eight randomised controlled trials, of a variety of interventions, met the inclusion criteria. There was no robust evidence to recommend any intervention, although there was some weak evidence for exercise. No relevant studies to determine cost effectiveness met the inclusion criteria. (ii) Acceptability/ethical issues. None of the acceptability papers reported directly the views of people with dementia. Exercise and music therapy were the most acceptable interventions and raised no ethical concerns. Tracking and tagging devices were acceptable to carers but generated considerable ethical debate. Physical restraints were considered unacceptable. CONCLUSIONS: In order to reduce unsafe wandering high quality research is needed to determine the effectiveness of non-pharmacological interventions that are practically and ethically acceptable to users. It is important to establish the views of people with dementia on the acceptability of such interventions prior to evaluating their effectiveness through complex randomised controlled trials.

Aged↗

PubMed1982

Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Adult↗

PubMed1994

Pharmacologic modulation of the cutaneous vasculature in the isolated perfused porcine skin flap.

The isolated perfused porcine skin flap (IPPSF), an ex vivo model system used in cutaneous toxicology and pharmacology, is capable of assessing the percutaneous absorption of vasoactive compounds. However, the vascular responses of the IPPSF to classical pharmacologic agents have not been calibrated. The ability of acetylcholine, nitroglycerin, tolazoline, and norepinephrine to affect vasculature resistance and glucose utilization was investigated in the IPPSF. Norepinephrine infusions between 10(-7) and 10(-5) M increased vascular resistance in a dose-dependent manner; half-maximal (EC50) and maximal responses occurred at 3.18 x 10(-6) and 10(-5) M, respectively. In non-preconstricted flaps, neither acetylcholine, nitroglycerin, nor tolazoline vasodilated the IPPSF; however, acetylcholine, nitroglycerin, and tolazoline each lowered vascular resistance in a dose-dependent manner in norepinephrine-preconstricted flaps. Maximal relaxation was induced at 10(-4), 10(-6), and 5 x 10(-5) M, by tolazoline, acetylcholine, and nitroglycerin, respectively, whereas the EC50 values were 2.88 x 10(-7), 1.35 x 10(-8), and 1.72 x 10(-7) M, respectively. In flaps pretreated with norepinephrine and methylene blue (a potential blocker of edothelium-derived relaxing factor), no concentration of acetylcholine, and only the highest concentration of nitroglycerin, lowered vascular resistance. In non-preconstricted flaps, glucose utilization decreased in norepinephrine-infused flaps, increased in nitroglycerin- and tolazoline-infused flaps, and was biphasic in acetylcholine-infused flaps. These results indicate that the IPPSF responds to pharmacologic agents in a manner similar to classic in vitro and in vivo models. Thus, the IPPSF would be a relevant model for investigating the delivery and/or toxicity of pharmacologically active compounds.

Acetylcholine↗

PubMed1990

New pharmacologic approaches to obsessive compulsive disorder.

Although obsessive compulsive disorder (OCD) traditionally has been considered a treatment-refractory syndrome, rigorous treatment studies over the past decade have demonstrated that most OCD patients respond to specific behavioral or pharmacologic therapies. In terms of the pharmacologic treatment of OCD, a relatively small group of antidepressant drugs (clomipramine, fluvoxamine, and fluoxetine) have been demonstrated to be antiobsessional. Several related antidepressants (desipramine, nortriptyline) appear to be ineffective for OCD. Clinical response requires prolonged treatment (greater than 6 weeks) with antiobsessional drugs and efficacy is not limited to depressed OCD patients. The few drugs that have been demonstrated to be antiobsessional share a high potency for the blockade of serotonin reuptake, suggesting a serotonergic mechanism for antiobsessional drug action. This suggestion has been further strengthened by studies demonstrating a high correlation between clinical response and changes in serotonergic markers with clomipramine treatment. Moreover, a serotonin antagonist, metergoline, appears to partly reverse the improvement observed following chronic clomipramine treatment. Overall, only about 50% of OCD patients appear to respond in any given pharmacologic treatment trial. Adjunctive treatments, such as lithium or L-tryptophan, have been reported to help in some cases. In addition, the use of neuroleptics either alone or in combination with antiobsessional drugs may be useful for OCD patients with psychotic features or tics. Pharmacologic treatments should be considered only one element of the therapeutic approach to be integrated with behavioral techniques as well as psychosocial interventions for the relief of this very intriguing syndrome.

Behavior Therapy↗

PubMed1994

Comparison of cloned and pharmacologically defined rat tissue alpha 1-adrenoceptor subtypes.

Multiple alpha 1-adrenoceptor subtypes have been defined by pharmacological and receptor cloning techniques, but the precise alignment of cloned and pharmacologically-defined subtypes is still unclear. We have compared the affinities of 8 subtype-selective compounds at three cloned alpha 1-adrenoceptor subtypes (rat alpha 1B, bovine alpha 1C, rat alpha 1A/D) with those previously determined by the same methods in rat spleen, cerebral cortex, and kidney (Naunyn-Schmiedeberg's Arch. Pharmacol. 348: 385-395, 1993). Among all compounds tested to date at cloned alpha 1-adrenoceptor subtypes (+)-tamsulosin appears to be the most selective with a rank order of potency alpha 1C > alpha 1A/D > or = alpha 1B. Affinities for the alpha 1A-selective 5-methyl-urapidil, methoxamine, oxymetazoline, phentolamine and (-)- and (+)-tamsulosin and for noradrenaline and SDZ NVI-085 at the splenic alpha 1B-adrenoceptors and at their low affinity sites in cerebral cortex and kidney correlated best with those at the cloned alpha 1B-adrenoceptor. Affinities of these drugs at their high affinity sites in cerebral cortex (pharmacologically-defined alpha 1A-adrenoceptor) were matched best by those at the cloned alpha 1C-adrenoceptor. Rat kidney appears to contain two chloroethylclonidine-resistant alpha 1-adrenoceptor subtypes one of which is similar to the cloned alpha 1C- and one to the cloned alpha 1A/D-adrenoceptor. We conclude that the cloned alpha 1B-adrenoceptor is the genetic correlate of the pharmacologically-defined alpha 1B-adrenoceptor. An alpha 1-adrenoceptor subtype corresponding to the cloned alpha 1A/D-adrenoceptor appears to exist in rat kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Can a pharmacological pain analysis in patients with chronic low back pain predict the outcome of lumbar fusion? Preliminary report.

Chronic low back pain patients chosen for lumbar fusion surgery were entered into a prospective study with the aim of evaluating whether pre-operative pharmacological pain classification correlated with the outcome of surgical treatment. Twenty consecutive patients (mean age 39 years, range 29-50 years) with a mean pain duration of 4.6 years (range 1-8 years) participated. The patients' pain, disability and work situation were evaluated pre- and post-operatively. According to the results of pharmacological pain testing the patients were classified into five pain groups: (1) those with nociceptive pain, (2) those with neuropathic pain, (3) placebo responders, (4) non-responders and (5) unclassified. This classification was based on the following approaches: intravenous morphine, intravenous lidocaine, epidurally administered fentanyl and a local anaesthetic. Surgical treatment consisted of posterolateral fusion of the lower two functional lumbosacral spinal units combined, if necessary with appropriate decompression. The results of the pharmacological pain assessment were not disclosed until the end of the follow-up period and outcome was evaluated by an unbiased observer. The distribution of patients between pain groups was as follows; nine had nociceptive pain, two suffered neuropathic pain, there were no placebo responders and seven were non-responders. Two patients could not be classified into any of these groups. Outcome was rated at 6, 12 and 24 months as excellent/good in eight out of nine patients with nociceptive pain. In the group with non-responding pain surgical outcome was significantly poorer (P < 0.01), and was ranked as excellent/good in only one out of seven patients. There was a significant improvement (P < 0.05) concerning both pain and disability in the nociceptive group, but not in the non-responding group. Pre-operative pharmacological pain testing may be useful as a predictor of surgical outcome and we suggest that it can be employed as a means to identify patients with non-responding pain and poor surgical prognosis.

Adult↗

PubMed1985

The functional consequences of inhibition of monoamine oxidase type B: comparison of the pharmacological properties of L-deprenyl and MDL 72145.

The pharmacological properties of two selective inhibitors of monoamine oxidase (MAO) type B, L-deprenyl and MDL 72145 [(E)-2-(3,4-dimethoxyphenyl)-3-fluoroallylamine, HCl], have been investigated in rats and mice in relation to their effects on MAO. Selective inhibition of MAO B achieved following 18 h pretreatment with L-deprenyl and/or MDL 72145 did not per se lead to prominent pharmacological activity; no effects were seen in the mouse "Behavioural Despair" test, hypothermia induced by reserpine in mice was neither prevented nor reversed and there was no change in the cardiovascular responsiveness of the pithed rat to tyramine, noradrenaline or stimulation of the spinal sympathetic outflow. L-Deprenyl differed from MDL 72145 in that short term treatment with this drug caused positive effects in the "Behavioural Despair" test, reversal of reserpine hypothermia, indirect sympathomimetic stimulation of blood pressure and heart rate in the pithed rat and ipsilateral rotation in rats with unilateral nigro-striatal lesions. Qualitatively similar effects were seen with dexamphetamine. The marked difference between the pharmacological effects of MDL 72145 and L-deprenyl despite equivalent inhibition of MAO B suggests that many of the pharmacological actions of L-deprenyl result from its amphetamine-like sympathomimetic properties. MDL 72145 can, therefore, be considered a more reliable tool with which to explore the functional importance of MAO B inhibition in experimental animals and man.

Allylamine↗

PubMed1988

Improved efficacy of intra-aortic balloon pumping by pharmacological myocardial protection for postoperative pump failure after coronary revascularization.

Fifty patients took part in a randomized and prospective study to define the effect of pharmacological myocardial protection when using IABP in patients with postoperative pump failure, following coronary revascularization under cardiopulmonary bypass employing moderate hypothermia and cardioplegia. Pharmacological protection was given to 23 patients, administering coenzyme Q, 5 mg/kg, and aprotinin, 10,000 KIU/kg, intravenously, every 12 hours, following surgery. A single dose of each drug was also given intraoperatively. The postoperative haemodynamics, serum enzyme levels and success of weaning from IABP, were compared between the group of patients who received pharmacological protection (the treated group) and the control group which comprised 27 patients who were treated only with IABP. Among the surviving patients, no significant differences were seen in the hemodynamics or cardiac enzyme levels between the two groups. The rate of successful weaning from IABP however, was 95 per cent in the treated group as compared with only 74 per cent in the control group, p = 0.02. These results suggest that pharmacological myocardial protection, using coenzyme Q and aprotinin in both the intra- and post-operative periods, improves the efficacy of IABP in the treatment of post-operative pump failure following coronary revascularization.

Aprotinin↗

PubMed1998

The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes.

The amino acid gamma-aminobutyric-acid (GABA) prevails in the CNS as an inhibitory neurotransmitter that mediates most of its effects through fast GABA-gated Cl(-)-channels (GABAAR). Molecular biology uncovered the complex subunit architecture of this receptor channel, in which a pentameric assembly derived from five of at least 17 mammalian subunits, grouped in the six classes alpha, beta, gamma, delta, sigma and epsilon, permits a vast number of putative receptor isoforms. The subunit composition of a particular receptor determines the specific effects of allosterical modulators of the GABAARs like benzodiazepines (BZs), barbiturates, steroids, some convulsants, polyvalent cations, and ethanol. To understand the physiology and diversity of GABAARs, the native isoforms have to be identified by their localization in the brain and by their pharmacology. In heterologous expression systems, channels require the presence of alpha, beta, and gamma subunits in order to mimic the full repertoire of native receptor responses to drugs, with the BZ pharmacology being determined by the particular alpha and gamma subunit variants. Little is known about the functional properties of the beta, delta, and epsilon subunit classes and only a few receptor subtype-specific substances like loreclezole and furosemide are known that enable the identification of defined receptor subtypes. We will summarize the pharmacology of putative receptor isoforms and emphasize the characteristics of functional channels. Knowledge of the complex pharmacology of GABAARs might eventually enable site-directed drug design to further our understanding of GABA-related disorders and of the complex interaction of excitatory and inhibitory mechanisms in neuronal processing.

Anesthetics↗

PubMed1997

Behavioral issues in the efficacy versus effectiveness of pharmacologic agents in the prevention of cardiovascular disease.

A number of pharmacologic interventions are now recommended for the prevention of cardiovascular disease, based on the results of randomized controlled trials. These include antihypertensive drugs, lipid-lowering agents, antiplatelet and anticoagulant drugs, estrogen replacement therapy, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors. It is likely that additional pharmacologic interactions will soon be proven efficacious. Despite the strength of this evidence and the development of clinical guidelines incorporating their use, a surprisingly low proportion of patients are actively treated with these agents. There may be a variety of explanations for this, including barriers at the level of the patient, health care provider, and health care institution. Finally, a number of questions remain as to the optimal combination of interventions, both behavioral and pharmacologic, which will yield maximal reduction in risk. The description of factors which reduce the effectiveness of pharmacologic interventions below the efficacy demonstrated in randomized clinical trials should be a fertile area for epidemiologic and behavioral research.

Cardiovascular Agents↗

PubMed1997

Pharmacological characterisation of human cerebral cortex somatostatin SRIF1 and SRIF2 receptors.

Radioligand binding studies were performed in membranes of human cerebral cortex using [125I]Tyr3-octreotide in the presence of 5 mM MgCl2, [125I]SRIF-14 ([125I]Tyr11-SRIF-14) and [125I]CGP 23996 ([125I]c[Asu- Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) both in the presence of 120 mM NaCl, to characterise the nature of the somatostatin (SRIF) receptors. The pharmacological profile of human brain SRIF recognition sites was compared with that of recombinant human SRIF1 (sst2-sst3-sst5) or SRIF2 receptors (sst1-sst4) and with that of native rat sst1, sst2, and sst4 receptors. [125I]Tyr3-octreotide labelled binding sites in human cerebral cortex: Bmax = 238 +/- 36 fmol/mg protein and pKd = 9.73 +/- 0.08. The pharmacological profile of [125I]Tyr3-octreotide labelled sites correlated very significantly with that of recombinant human sst2 receptors (r = 0.98) and much less with those of recombinant human sst3 (r = 0.65) or sst5 receptors (r = 0.72). The correlation between [125I]Tyr3-octreotide binding to native sst2 receptors in human and rat cerebral cortex was also highly significant (r = 0.97). [125I]SRIF-14 and [125I]CGP 23996 binding (performed in the presence of 120 mM NaCl) in the human cerebral cortex identified very similar populations of sites Bmax = 44 +/- 7 and 36 +/- 5 fmol/mg protein and pKd = 9.44 +/- 0.08 and 9.48 +/- 0.10, respectively. The pharmacological profiles of the sites labelled with [125I]SRIF-14 and [125I]CGP 23996 correlated highly significantly with those of recombinant human sst1 (r = 0.97-0.99) or sst4 receptors (r = 0.91-0.94). Similarly, the correlations between [125I]SRIF-14 or [125I]CGP 23996 binding in human cortex and [125I]SRIF-14 binding to native sst1 sites in rat cerebral cortex were also highly significant (r = 0.97 and 0.94, respectively). Finally, the pharmacological profile of native rat lung sst4 sites determined with [125I]LTT-SRIF-28 ([Leu8,D-Trp22, 125I-Tyr25]SRIF-28) correlated with [125I]SRIF-14 and [125I]CGP 23996 binding in human cortex; r = 0.91 and 0.87, respectively. The present data show that in human cerebral cortex, [125I]Tyr3-octreotide labels SRIF1 receptor sites which are best characterised as of the sst2 type, whereas [125I]SRIF-14 and [125I]CGP 23996 (both in the presence of 120 mM NaCl), label sites which fit almost equally well with sst1 or sst4 receptors and therefore are best described as of the SRIF2 type. Under the conditions used, there was no evidence that either of these ligands would label sst3 or sst5 receptors in human cerebral cortex.

Animals↗

PubMed1997

Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor.

We have identified subtype selective agonists, partial agonists and antagonists, which distinguish the human recombinant Mel1a and Mel1b melatonin receptors expressed in COS-7 cells. Melatonin receptor agonists showed higher affinity for competition of 2-[125I]-iodomelatonin binding for the Mel1b than the Mel1a melatonin receptor. The dissociation constants (Ki) of 16 agonists determined on the recombinant human Mel1a and Mel1b melatonin receptor subtypes showed a significant correlation (r2 = 0.85, slope = 0.97, P < 0.0001, n = 16). However, six agonists showed 10 to 60 fold higher affinity for the Mel1b melatonin receptor as indicated by the affinity selectivity ratios (Mel1a/Mel1b) [8-methoxy-2-acetamidotetraline (11); S20098 (14); 8-methoxy-2-propionamidotetraline (20); 6, 7 di-chloro-2-methylmelatonin (21); 6-chloromelatonin (57); 6-methoxymelatonin (59)]. Dissociation constants for competition of 11 partial agonists and antagonist for 2-[125I]-iodomelatonin binding were between 15.5 (luzindole, pKi: 7.7) to 362 (4-phenyl-2-chloroacetamidotetraline, pKi: 9.1) fold higher for the Mel1b than for the Mel1a melatonin receptor. The lack of correlation between the pKi values (r2 = 0.23, P > 0.1, n = 11) strongly suggest that the two human melatonin receptor subtypes can be distinguished pharmacologically. The partial agonist: 5-methoxyluzindole (pKi: 9.6) and the competitive melatonin receptor antagonists: GR128107 (pKi: 9.6), 4-phenyl-2-chloroacetamidotetraline (pKi: 9.1), 4-phenyl-2-acetamidotetraline (pKi: 8.9) and 4-phenyl-2-propionamidotetraline (pKi: 8.8) are selective Mel1b melatonin receptor analogues as their affinity selectivity ratios (Mel1a/Mel1b) are bigger than 100. We conclude that the 40% overall amino acid difference in the sequence of the human recombinant Mel1a and Mel1b melatonin receptors is reflected in distinct pharmacological profiles for the subtypes. We compared the pharmacological profile of the presynaptic ML1 melatonin heteroreceptor of rabbit retina mediating inhibition of the calcium-dependent release of dopamine to that of the recombinant Mel1a and Mel1b melatonin receptors. Melatonin inhibited [3H]dopamine release by 50% (1C50) at 20 pM with a maximal inhibitory effect (80%) at 1 nM. The partial agonists, i.e., N-acetyltryptamine (1C50 5.6, maximal inhibition 55%) and 5-methoxyluzindole (1C50: 1.3, maximal inhibition 40%) showed various degrees of efficacy while none of the competitive melatonin receptor antagonists did inhibit [3H]dopamine release on their own. The potency (1C50) of full melatonin receptor agonists significantly correlated with their affinity to compete for 2-[125I]-iodomelatonin binding to either the Mel1a (r2 = 0.76, slope = 0.77, P < 0.0001, n = 17) or Mel1b (r2 = 0.63, slope = 0.75, P < 0.001, n = 17) human melatonin receptors. By contrast, the apparent dissociation constants (KB) for partial agonists and antagonists to antagonize the inhibition of [3H]dopamine release mediated by activation of the ML1 heteroreceptor by melatonin, significantly correlated with the affinity constants (Ki) for 2-[125I]-iodomelatonin binding determined of the Mel1b (r2 = 0.77, slope = 0.55, P < 0.001; n = 11) but not the Mel1a (r2 = 0.27, P < 0.1, n = 11) subtype. Together these results demonstrate that the pharmacological profile of the human recombinant Mel1b melatonin receptor is similar to that of the functional presynaptic melatonin heteroreceptor of rabbit retina, which we referred as an ML1B subtype. We conclude that the selective Mel1b melatonin partial agonists and antagonists described here can be used to identify melatonin receptor subtypes in native tissues and to search for subtype selective analogues with therapeutic potential.

Animals↗