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At least 811 records · Page 45Linked to original sources
PubMed2003

Prognostic value of pharmacological stress echocardiography in diabetic patients.

Our study was undertaken to assess the prognostic significance of pharmacological stress echocardiography in 325 diabetic patients. Pharmacological stress echocardiography was performed for diagnosis of coronary artery disease in 128 patients, and for risk stratification in 197 patients. Follow-up was 34 months. Cardiac-related death and non-fatal myocardial infarction were considered hard events. During the follow-up period, there were 38 deaths and 23 acute non-fatal myocardial infarctions. By univariate analysis, a pharmacological stress echocardiography positive response for ischaemia indicated an increased risk of cardiovascular death. However, by multivariate analysis, advanced age and peak ejection fraction <40% were the only independent predictors of cardiac death. The same peak ejection fraction (EF) <40%, rest wall motion score index and previous myocardial infarction were independent predictors of hard events. After dividing the population into two subgroups on the basis of EF at rest, only a peak EF <40% and a pharmacological stress echocardiography positive test were powerful independent predictors of cardiovascular mortality.

Adrenergic beta-Agonists↗
PubMed2002

Molecular and pharmacological diversity of the kinin B1 receptor.

The pharmacological properties of the kinin B1 receptor in binding the endogenous kinin peptides are known to differ across species. Molecular cloning has revealed that these pharmacological differences arise from the diversity within the BDKRB gene. In this report, the molecular diversity of the human BDKRB1 gene is expanded by the identification of eight single nucleotide polymorphisms (SNPs) in the coding sequence of the receptor, three of which change the amino acid sequence of the receptor. The molecular cloning and pharmacological characterization of two primate B1 receptors, rhesus and African Green monkey, reveals that they exhibit the same high degree of selectivity for des-Arg10 kallidin (Lys-bradykinin) relative to des-Arg9 bradykinin that is observed with the human kinin B1 receptor. Previous mutagenesis studies of the human B1 receptor have implicated extracellular domain (EC) IV in conferring this selectivity for des-Arg10 kallidin, by interacting with the N-terminal Lys residue of the peptide. The pharmacological analysis of chimeric B1 receptors, in which EC-IV of the human B1 receptor is replaced with the corresponding domain of either rat or dog, supports the proposal that EC-IV is an important determinant in conferring ligand selectivity.

Amino Acid Sequence↗
PubMed2006

Neurotoxicity and other pharmacological activities of the snake venom phospholipase A2 OS2: the N-terminal region is more important than enzymatic activity.

Several snake venom secreted phospholipases A2 (sPLA2s) including OS2 exert a variety of pharmacological effects ranging from central neurotoxicity to anti-HIV activity by mechanisms that are not yet fully understood. To conclusively address the role of enzymatic activity and map the key structural elements of OS2 responsible for its pharmacological properties, we have prepared single point OS2 mutants at the catalytic site and large chimeras between OS2 and OS1, a homologous but nontoxic sPLA2. Most importantly, we found that the enzymatic activity of the active site mutant H48Q is 500-fold lower than that of the wild-type protein, while central neurotoxicity is only 16-fold lower, providing convincing evidence that catalytic activity is at most a minor factor that determines central neurotoxicity. The chimera approach has identified the N-terminal region (residues 1-22) of OS2, but not the central one (residues 58-89), as crucial for both enzymatic activity and pharmacological effects. The C-terminal region of OS2 (residues 102-119) was found to be critical for enzymatic activity, but not for central neurotoxicity and anti-HIV activity, allowing us to further dissociate enzymatic activity and pharmacological effects. Finally, direct binding studies with the C-terminal chimera, which poorly binds to phospholipids while it is still neurotoxic, led to the identification of a subset of brain N-type receptors which may be directly involved in central neurotoxicity.

Amino Acid Sequence↗
PubMed1990

Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10-substituted cannabidiol and 11- or 12-substituted delta 8-tetrahydrocannabinol.

The synthesis of a variety of novel 10-substituted cannabidiol (CBD) and 11- or 12-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino functional group is described, as well as their pharmacological evaluation in mice. These analogues, which possess only a portion of the full pharmacological spectrum of activity of delta 9-THC, indicate that cannabinoid-mediated reduction of spontaneous locomotor activity, hypothermia, antinociception, and/or catalepsy need not be produced simultaneously, possibly suggesting the existence of more than one mechanism of action. The 10-substituted CBD analogues 3, 4, and 5 with an ethylamino, propylamino, or azido functional group, respectively, proved to be largely inactive, except for the production of central nervous system (CNS) depression concomitant with toxicity. Toxicity and CNS depression may be related phenomena in these nitrogenous compounds since 12-amino and 12-ethylamino analogues (8 and 11) of delta 8-THC also proved to be very toxic. Antinociceptive and hypothermic responses (without reduction of motor activity) were observed at a dose of 10 mg/kg of the 11-ethylamino analogue (9) of delta 8-THC, while a dose of 50 mg/kg of the nitrogen mustard 11-[N,N-bis(2-chloroethyl)amino]-delta 8-THC (12) was necessary to produce any observable pharmacological effect. When selected analogues were evaluated for antagonistic properties, they failed to attenuate the effects of delta 9-THC. Some nitrogen mustard analogues were capable of producing minimal pharmacological effects after either peripheral or direct CNS administration; however, these analogues also failed to attenuate the effects of delta 9-THC either immediately after administration or 24-48 h later.

Analgesics↗
PubMed1988

Crystal structures and pharmacologic activities of 1,4-dihydropyridine calcium channel antagonists of the isobutyl methyl 2,6-dimethyl-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nisoldipine) series.

A series of isobutyl methyl 2,6-dimethyl-4-(X-substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, 4-F, 2-CF3, 3-CF3, and 4-Cl) related to and including nisoldipine (X = 2-NO2) has been synthesized, their solid-state structures determined by X-ray analysis (X = H, 2-NO2, 3-NO2, 3-CN, 3-MeO, and 4-F), and their pharmacologic activities determined, as the racemic compounds, against [3H]nitrendipine binding and K+-depolarization-induced tension responses in intestinal smooth muscle as measures of Ca2+ channel antagonist activity. Comparisons of structure are presented to previously analyzed 1,4-dihydropyridines. The degree of 1,4-dihydropyridine ring puckering is dependent on the nature and position of the phenyl ring substituent and the adopted interring conformation. Different ester substituents affect 1,4-dihydropyridine ring puckering to a small extent in most cases. Pharmacologic and radioligand binding activities for the nine compounds studied show a parallel dependence on phenyl ring substituent, but the compounds are approximately 10-fold more active in the radioligand binding assay than in the pharmacologic assay. Consistent with a previous report for the nifedipine series (Fossheim et al. J. Med. Chem. 1982, 25, 126), pharmacologic activity increases with increasing 1,4-dihydropyridine ring planarity.

Animals↗
PubMed2003

Orally active analogues of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: synthesis and pharmacological activity.

A series of analogues of 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (6), an enone prodrug of the mixed DA D(1)/D(2) agonist 5,6-diOH-DPAT (2), was synthesized. The pharmacological profiles of these new enones and their in vivo pharmacological activities were investigated in the Ungerstedt rat rotation model for Parkinson's disease. At 0.1 mg kg(-1) po, the N-methyl-N-n-propyl (12) and the N-ethyl-N-propyl (13) analogues induced pronounced and long lasting pharmacological effects. The pharmacological profile of enone 12 was found to be similar to that of 6, while enone 13 was significantly more potent than 6 (p < 0.01). Analyses of rat brains after the administration of (-)-6 and 13 indicated the presence of hydroxylated metabolites of the parent enones. It is speculated that such metabolites are alpha'-hydroxylated enones that may constitute the first step in the formation of the corresponding catechols.

2-Naphthylamine↗
PubMed2007

Isofagomine- and 2,5-anhydro-2,5-imino-D-glucitol-based glucocerebrosidase pharmacological chaperones for Gaucher disease intervention.

Gaucher disease, resulting from deficient lysosomal glucocerebrosidase (GC) activity, is the most common lysosomal storage disorder. Clinically important GC mutant enzymes typically have reduced specific activity and reduced lysosomal concentration, the latter due to compromised folding and trafficking. We and others have demonstrated that pharmacological chaperones assist variant GC folding by binding to the active site, stabilizing the native conformation of GC in the neutral pH environment of the endoplasmic reticulum (ER), enabling its trafficking from the ER to the Golgi and on to the lysosome. The mutated GC fold is generally stable in the lysosome after pharmacological chaperone dissociation, owing to the low pH environment for which the fold was evolutionarily optimized and the high substrate concentration, enabling GC to hydrolyze glucosylceramide to glucose and ceramide. The hypothesis of this study was that we could combine GC pharmacological chaperone structure-activity relationships from distinct chemical series to afford potent novel chaperones comprising a carbohydrate-like substructure that binds in the active site with a hydrophobic substructure that binds in a nearby pocket. We combined isofagomine and 2,5-anhydro-2,5-imino-D-glucitol active site binding substructures with hydrophobic alkyl adamantyl amides to afford novel small molecules with enhanced ability to increase GC activity in patient-derived fibroblasts. The cellular activity of N370S and G202R GC in fibroblasts is increased by 2.5- and 7.2-fold with isofagmine-based pharmacological chaperones N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)-butanamide (3) and N-adamantanyl-4-((3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-1-yl)pentanamide (4), respectively, the best enhancements observed to date.

Adamantane↗
PubMedDate not supplied

Stereochemical considerations in relation to the pharmacological activity of Pterotaberna alkaloids.

Five 2-acylindole alkaloids, isolated from the leaves of Pterotaberna inconspicua, were pharmacologically investigated. The major alkaloids methuenine and 16-epimethuenine showed some interesting pharmacological features, whereas the minor alkaloids including 6-oxomethuenine and methuenine N-oxide were almost devoid of these pharmacological properties. Methuenine, being the most potent, was characterized as a non competitive antagonist against acetylcholine (pD'2=5.10 +/- 0.11) and histamine (pD'2 = 5.13 +/- 0.14) in guinea-pig ileum. Its potency was comparable to that of papaverine. 16-Epimethuenine behaved as a weak antihistaminic (pA2 = 6.55 +/- 0.08). The stereochemistry of both components is discussed in relation to their pharmacological activity.

Alkaloids↗
PubMed2002

Pharmacologic reperfusion therapy for acute myocardial infarction.

Acute myocardial infarction (MI) remains a significant problem in terms of morbidity, mortality and healthcare costs. Pharmacologic reperfusion therapies for MI are becoming increasingly complex. This review therefore places contemporary pharmacologic MI developments into perspective. An historical overview of pharmacologic reperfusion therapy for MI is provided, followed by an analysis of current limitations, treatment options, and present and likely future pharmacologic therapies. Adjunctive percutaneous and other treatments are also discussed, to clarify what is becoming a rapidly changing field.

Animals↗
PubMed2003

The enteric nervous system III: a target for pharmacological treatment.

The past decade has seen major advances in the pharmacological understanding of the nervous system of the gastrointestinal tract, the enteric nervous system, and its importance for gut functions in several states of disease. Indeed, the enteric nervous system has become a promising target in the treatment of many gastrointestinal symptoms and disorders. Some of these new therapeutic concepts, such as botulinum toxin for achalasia and serotonergic drugs for functional bowel diseases, are already in clinical use. This paper is part 3 of three Minireviews in Pharmacology & Toxicology, and presents the neurogastrointestinal pharmacological therapeutic options in gastrointestinal pain, functional gastrointestinal disorders, inflammatory bowel diseases, cancer and related conditions with focus on future drug targets. The diagnosis of gastrointestinal neuropathy, the role of serotonin and related neuroendocrine transmitters, serotonergic drugs, and neurotrophic factors in neurogastrointestinal pharmacology will be addressed in this context.

Acetylcholine↗
PubMed2002

Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.

1: The pharmacology of the stable cell line expressing human alpha(4)beta(3)delta GABA(A) receptor was investigated using whole-cell patch-clamp techniques. 2: alpha(4)beta(3)delta receptors exhibited increased sensitivity to GABA when compared to alpha(4)beta(3)gamma(2) receptors, with EC(50)'s of 0.50 (0.46, 0.53) microM and 2.6 (2.5, 2.6) microM respectively. Additionally, the GABA partial agonists piperidine-4-sulphonate (P4S) and 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP) displayed markedly higher efficacy at alpha(4)beta(3)delta receptors, indeed THIP demonstrated greater efficacy than GABA at these receptors. 3: The delta subunit conferred slow desensitization to GABA, with rate constants of 4.8+/-0.5 s for alpha(4)beta(3)delta and 2.5+/-0.2 s for alpha(4)beta(3)gamma(2). However, both P4S and THIP demonstrated similar levels of desensitization on both receptor subtypes suggesting this effect is agonist specific. 4: alpha(4)beta(3)delta and alpha(4)beta(3)gamma(2) demonstrated equal sensitivity to inhibition by the cation zinc (2-3 microM IC(50)). However, alpha(4)beta(3)delta receptors demonstrated greater sensitivity to inhibition by lanthanum. The IC(50) for GABA antagonists SR-95531 and picrotoxin, was similar for alpha(4)beta(3)delta and alpha(4)beta(3)gamma(2). Likewise, inhibition was observed on both subtypes at high and low pH. 5: alpha(4)beta(3)delta receptors were insensitive to modulation by benzodiazepine ligands. In contrast Ro15-4513 and bretazenil potentiated GABA responses on alpha(4)beta(3)gamma(2) cells, and the inverse agonist DMCM showed allosteric inhibition of alpha(4)beta(3)gamma(2) receptors. 6: The efficacy of neurosteroids at alpha(4)beta(3)delta receptors was greatly enhanced over that observed at alpha(4)beta(3)gamma(2) receptors. The greatest effect was observed using THDOC with 524+/-71.6% potentiation at alpha(4)beta(3)delta and 297.9+/-49.7% at alpha(4)beta(3)gamma(2) receptors. Inhibition by the steroid pregnenolone sulphate however, showed no subtype selectivity. The efficacy of both pentobarbitone and propofol was slightly augmented and etomidate greatly enhanced at alpha(4)beta(3)delta receptors versus alpha(4)beta(3)gamma(2) receptors. 7: We show that the alpha(4)beta(3)delta receptor has a distinct pharmacology and kinetic profile. With its restricted distribution within the brain and unique pharmacology this receptor may play an important role in the action of neurosteroids and anaesthetics. British Journal of Pharmacology (2002) 136, 965-974

Allosteric Regulation↗
PubMed2003

Pharmacological characterization of the homomeric and heteromeric UNC-49 GABA receptors in C. elegans.

(1) UNC-49B and UNC-49C are gamma-aminobutyric acid (GABA) receptor subunits encoded by the Caenorhabditis elegans unc-49 gene. UNC-49B forms a homomeric GABA receptor, or can co-assemble with UNC-49C to form a heteromeric receptor. The pharmacological properties of UNC-49B homomers and UNC-49B/C heteromers were investigated in Xenopus oocytes. (2) The UNC-49 subunits are most closely related to the bicuculline- and benzodiazepine-insensitive RDL GABA receptors of insects. Consistent with this classification, bicuculline (10 micro M) did not inhibit, nor did diazepam (10 micro M) enhance UNC-49B homomeric or UNC-49B/C heteromeric receptors. (3) The UNC-49C subunit strongly affects the pharmacology of UNC-49B/C heteromeric receptors. UNC-49B homomers were much more picrotoxin sensitive than UNC-49B/C heteromers (IC(50)=0.9+/-0.2 micro M and 166+/-42 micro M, respectively). Pentobarbitone enhancement was greater for UNC-49B homomers compared to UNC-49B/C heteromers. Propofol (50 micro M) slightly enhanced UNC-49B homomers but slightly inhibited UNC-49B/C heteromers. Penicillin G (10 mM) inhibited UNC-49B homomers less strongly than UNC-49B/C heteromers (30% compared to 53% inhibition, respectively). (4) Several aspects of UNC-49 pharmacology were unusual. Picrotoxin sensitivity strongly correlates with dieldrin sensitivity, yet UNC-49B homomers were highly dieldrin resistant. The enhancing neurosteroid pregnanolone (5beta-pregnan-3alpha-ol-20-one; 10 micro M) strongly inhibited both UNC-49 receptors. Alphaxalone (10 micro M), another enhancing neurosteroid, did not affect UNC-49B homomers, but slightly inhibited UNC-49B/C heteromers. (5) UNC-49 subunits and mammalian GABA(A) receptor alpha, beta, and gamma subunit classes all share roughly the same degree of sequence similarity. Thus, although they are most similar to other invertebrate GABA receptors, the UNC-49 receptors share significant structural and pharmacological overlap with mammalian GABA(A) receptors.

Amino Acid Sequence↗
PubMed2005

Molecular cloning, expression and pharmacological characterization of the canine cholecystokinin 1 receptor.

1 The full-length, canine cholecystokinin 1 (CCK1) receptor was cloned from gallbladder tissue using RT-PCR with a combination of primers designed to interact with conserved regions of the human and rat CCK1 receptor, which also shared homology with the canine genomic sequence. 2 Analysis of the sequence of the canine CCK1 receptor revealed a 1287 base pair product, which encoded a 429 amino-acid protein. This protein was 89% identical to the human and 85% identical to the rat CCK1 receptor. 3 The canine CCK1 receptor was expressed in CHO-K cells for pharmacological characterization. In competition studies, using [(125)I]BH-CCK-8S as radioligand, the affinity values estimated for CCK receptor-selective compounds were not significantly different between the canine and human CCK1 receptors (pK(I)+/-s.e.m. at canine CCK1 receptor; L-364,718=8.82+/-0.08, L-365,260=6.61+/-0.05, YF476=7.91+/-0.15, YM022=8.28+/-0.06 and dexloxiglumide=7.53+/-0.11). Furthermore, the selectivity of these compounds between canine CCK1 and CCK2 receptors was consistent with the selectivity between the human CCK1 and CCK2 receptors. 4 Two additional forms of the canine CCK1 receptor were identified during the cloning procedure. These had three (variant #1) and six (variant #2) amino-acid differences from the wild-type canine CCK1 receptor. Variant #1 bound [(125)I]BH-CCK-8S and displayed an identical pharmacological profile to the wild-type receptor using the ligands described above. No significant binding was measured with variant #2. 5 In conclusion, we have cloned and pharmacologically characterized the canine CCK1 receptor. The data obtained will facilitate the interpretation of numerous pharmacological experiments that have been performed using canine tissue to elucidate the actions of CCK and gastrin.

Amino Acid Sequence↗
PubMed2006

In vivo pharmacological resultant analysis reveals noncompetitive interactions between opioid antagonists in the rat tail-withdrawal assay.

BACKGROUND AND PURPOSE: Pharmacological resultant analysis is a technique that can detect secondary effects of competitive antagonists in vitro. The utility of pharmacological resultant analysis as a potential tool for the investigation of antagonist interactions in vivo was examined in the present study using two opioid antagonists, naltrexone and CTAP. EXPERIMENTAL APPROACH: Using the experimental design of pharmacological resultant analysis, the well-characterized opioid antagonist naltrexone was examined in the presence of multiple doses of CTAP to block the antinociceptive effects of morphine in the rat warm-water (55(o)C), tail-withdrawal assay. KEY RESULTS: Alone, all doses of naltrexone, CTAP, and CTOP examined blocked the antinociceptive effects of morphine. In the presence of fixed doses of 1 or 10 microg CTAP, increasing doses of naltrexone produced dose-dependent shifts to the right in the morphine dose-response curve. However, a lower dose of naltrexone in combination with 1 or 10 mug CTAP failed to alter the morphine dose-response curve. In the presence of a fixed dose of 0.1 mg kg(-1) naltrexone, CTAP doses produced irregular shifts to the right in the morphine dose-response curves. CONCLUSIONS AND IMPLICATIONS: Resultant analysis was applied and an apparent pK(C) value for CTAP was found to be one log unit higher than the apparent pA(2) value for CTAP, evidence that CTAP may have secondary actions or that a signal transducer function may be altered by the combinations of these antagonists. Taken together, these data suggest pharmacological resultant analysis can reveal novel interactions between antagonists in vivo.

Algorithms↗
PubMed2005

The influence of pharmacological mydriasis on biomicroscopic evaluation of the glaucomatous optic nerve head.

AIMS: To investigate whether pharmacological mydriasis influences interobserver agreement or within-observer agreement (comparing estimates made before and after dilation) in the evaluation of the optic nerve head (ONH) of the glaucoma suspect or patient. METHODS: Monoscopic disc photographs of the ONH were assessed by each observer on two separate occasions in order to establish baseline intra- and inter-observer agreement. Then the ONH of 53 eyes of 53 patients was examined by each observer on two separate occasions, the pupil being pharmacologically dilated on only one of these visits. Each observer commented on the vertical and horizontal cup-to-disc (C/D) ratio, and the presence of the following ONH parameters: laminar dots; disc haemorrhage; disc saucering; disc notching, and peripapillary atrophy (PPA). RESULTS: Intersessional variability of C/D ratio estimates, based on photographs of the ONH, was similar for the two observers. The mean (+/-standard deviation) age of the 53 patients was 70 (+/-15) years, and the male : female ratio was 28 : 25. Intraobserver agreement of C/D ratio estimation performed through a dilated pupil on one occasion and an undilated pupil on the other occasion was not statistically different between observers. Interobserver agreement of C/D ratio estimates were not adversely affected in a statistically meaningful way if ONH evaluation was performed by each observer under conditions of nonmydriasis or by each observer under conditions of pharmacological mydriasis. Within-observer (before and after dilation) and interobserver agreement with respect to the presence of laminar dots (kappa=0.41-0.69), PPA (kappa=0.36-0.54), and pathological cupping (kappa=0.46-0.68) was typically moderate to good across the two visits where the pupil was dilated on one occasion only, but less reliable for saucering, disc notching and disc margin haemorrhage. CONCLUSION: Routine pharmacological mydriasis is not essential for reproducible evaluation of the ONH for patients in whom a satisfactory view of the optic disc can be achieved through the undilated pupil.

Adult↗
PubMed1998

Integrating clinical pharmacology teaching with general practice.

AIMS: To make Clinical Pharmacology teaching relevant and introduce students to therapeutic problems relevant to general practice. METHODS: Six topics in the 'core curriculum' for Clinical Pharmacology were taught jointly by a Clinical Pharmacologist and General Practitioners (GPs). Formal teaching was reduced by issuing handouts containing copies of the overheads used. At least half the time was spent on interactive discussion of case histories. RESULTS: Students rated the sessions more highly than other Clinical Pharmacology teaching and were not disadvantaged in examinations. All participants enjoyed and learnt from the experience and the GPs gained confidence in their ability to teach. CONCLUSIONS: This simple method is ideal for teaching Clinical Pharmacology and Therapeutics.

Curriculum↗
PubMed2001

Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants.

BACKGROUND: Implantation of testosterone pellets under the lateral abdominal wall skin is an old but popular and effective form of androgen replacement therapy. Extrusion of one or more pellets remains the most frequent adverse event. OBJECTIVE: To determine whether an alternative implantation site (hip) and/or track geometry (two vs. four tracks) would reduce extrusion rates compared with the standard of a four-track abdominal site. Additionally, the study aimed to evaluate the effects of site and track geometry on other adverse effects (bruising, infection) and the pharmacology of testosterone release from the implants. DESIGN: A prospective, parallel-group unmasked study design in a single centre. The primary objective was to evaluate sites, with evaluation of track geometry a subordinate objective made necessary by anatomical differences. Accordingly, androgen deficient men requiring testosterone implantation with the standard dose (four 200 mg pellets) were randomized into one of three groups (ratio 1 : 1 : 2): a four-track abdomen site (standard), a two-track abdomen site or a two-track hip site. The pharmacological substudy was to evaluate the impact of site and track geometry on testosterone implant pharmacology by monthly hormone assays following implantation. PATIENTS: Two hundred and forty-six implantation procedures involving 96 androgen deficient men. MEASUREMENTS: The primary end-point, extrusion rate per procedure, and secondary end-points (bruising or infection post procedure) were evaluated prospectively by self-report from the participants, and verified when they returned next for implantation. The pharmacology substudy involved monthly blood sampling for hormone (total and free testosterone, LH, FSH) measurements. RESULTS: The extrusion rate was significantly higher [odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-7.1] for the hip site (15/125, 12%) compared with the abdominal site (6/121, 5%). Track geometry made no significant difference (OR = 1.05, 95% CI 0.2-5.4) to the extrusion rate. No secondary end-points (bruising, infection) were significantly different according to either site or track geometry. One operator who performed the implant procedures had significantly less primary and secondary adverse events than the other operators (P = 0.006). Neither implantation site, nor track geometry influenced pharmacokinetics [peak plasma total and free testosterone concentrations and net hormone release (area-under-curve, AUC)] or pharmacodynamics [nadir plasma LH and FSH and net suppression (AUC) in men with hypergonadotrophic hypogonadism]. CONCLUSIONS: We conclude that the hip site has a higher extrusion rate than the standard abdominal wall site but that track geometry does not increase the risk of extrusion. Neither implantation site, nor track geometry influenced either other adverse effects or the pharmacokinetics or pharmacodynamics of testosterone pellet implants.

Abdomen↗
PubMed1995

Pharmacological characterization of heterodimeric NMDA receptors composed of NR 1a and 2B subunits: differences with receptors formed from NR 1a and 2A.

Pharmacological and molecular biological evidence indicates the existence of multiple types of NMDA receptors within the CNS. We have characterized pharmacological properties of receptors assembled from the combination of NR 1a and NR 2B subunits (NR 1a/2B) expressed in transfected cells using both 125I-MK-801 binding assays and electrophysiological measures. Binding of 125I-MK-801 to cells transfected with NR 1a/2B is saturable with a KD of 440 pM. The binding is potently inhibited by ketamine, dextromethorphan, phencyclidine, and MK-801 and is stimulated by low concentrations of magnesium. These properties resemble those of native receptors and receptors produced by NR 1a/2A. However, 125I-MK-801 binding to membranes from cells transfected with NR 1a/2B is inhibited with high affinity by ifenprodil and is stimulated by spermidine, unlike receptors assembled from NR 1a/2A. NMDA-induced currents measured in cells transfected with either NR 1a/2A or NR 1a/2B have pharmacological properties that correlate well with the binding studies. Currents in cells transfected with NR 1a/2B are potentiated by spermidine and blocked with high affinity by ifenprodil, whereas currents in cells transfected with NR 1a/2A are not enhanced by spermidine and are weakly inhibited by ifenprodil. These data suggest that pharmacological heterogeneity in native NMDA receptors may be explained by combinations of different subunits.

Animals↗