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Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake ( BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume ( VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

Background/Aims Recent data show great benefit from beta adrenergic blocking drug (β-blocker) use in heart failure and has resulted in increased use of these established agents. Older data caution against their use in patients with reversible airways disease because of risks of bronchoconstriction. Anecdotally, we noted a difference in willingness to prescribe β-blockers by cardiologists and respiratory physicians, especially for patients with coexisting airways disease. We sought to test this difference. Methods Nine clinical scenarios were created, tested and emailed to all members of the Cardiac and Thoracic societies of Australasia. Scenarios combined varying degrees of benefit and risk (bronchoconstriction). An inducement to return questionnaires was applied. Results Cardiologists and respiratory physicians were similarly willing to prescribe β-blockers for patients at little risk of bronchoconstriction, irrespective of potential benefit. Cardiologists were more willing to prescribe β-blockers than respiratory physicians for patients at greater risk of bronchoconstriction, particularly when the potential therapeutic benefit was greater. Conclusions Our perception that cardiologists were more willing to prescribe β-blockers than respiratory physicians was confirmed. This probably results from a difference in focus (namely focus on benefit by cardiologists vs focus on risk by respiratory physicians), although other factors including awareness of limitations of pulmonary function testing by respiratory physicians may have been involved. Until better tests are available (that discriminate between patients who are likely to suffer bronchoconstriction from those who are not), it is likely that this difference between the specialties will remain.

The conformational structure of propranolol, a β-adrenergic blocking drug, has been investigated by pcilo calculations and 270-MHz proton nuclear magnetic resonance in D 2 O solution. The molecules coexist in at least two conformational states in solution with a low energy barrier. Both preferred conformations have extended structures which allow a three-point drug-receptor binding involving the aromatic moiety, the β-hydroxyl group, and -NH + 2 groups of propranolol. The previously postulated "rigid" bicyclic structure does not exist to an appreciable extent in D 2 O solution.

The rapid component of the delayed rectifying potassium ion current (IKr), plays an important role in cardiac repolarization. In rats, potent IKr channel blocking drugs cause similar stage-specific malformations (such as orofacial clefts and digital reductions) on gestational days (GDs) 10-14 as after periods of embryonic oxygen deprivation (hypoxia). The idea of a hypoxia-related teratogenic mechanism is supported by studies using rat embryos cultured in vitro. These studies show that the embryonic heart reacts with concentration-dependent bradycardia, arrhythmia, and cardiac arrest when exposed to IKr blockers on GDs 10-14. The main purpose of this study was to investigate whether previously shown teratogenic doses on GD 11 and 13 of the selective IKr blocker almokalant (ALM) induce hypoxia in rat embryos in vivo by using the hypoxia marker pimonidazole hydrochloride (PIM). Rats were orally dosed with almokalant or tap water on GD 11 (150 micromol/kg), 13 (50 micromol/kg), or 16 (800 micromol/kg), followed by PIM intravenously 30 min later. Two hours after the PIM dose, the embryonic heart activity was videotaped and analysed, and the embryos were fixed, sectioned, and immunostained. Computer-assisted image analysis showed a two- and threefold increase in hypoxia staining in embryos exposed to teratogenic doses of ALM on GDs 11 and 13. Embryonic arrhythmia was observed in almokalant groups on these GDs, but not in controls. In contrast, dosing on GD 16, with a much higher dose (800 micromol/kg), caused neither hypoxia nor any effects on heart rhythm. The results support the IKr-related arrhythmia-hypoxia hypothesis, by showing that the potent IKr-blocking drug, almokalant, (1) causes severe embryonic hypoxia and arrhythmia at stages (GDs 11 and 13) when developmental toxicity could be induced and IKr is functional and (2) does not cause hypoxia or affect heart rhythm at a developmental stage when IKr is suppressed (GD 16) and potent IKr blockers do not induce developmental toxicity.

The hormone blocking drug abiraterone extended life in men with prostate cancer when used first line at the start of standard treatment, two studies have found. Abiraterone is usually used in men whose prostate cancer has spread and has stopped responding to standard hormone therapy. But the two studies, published in the New England Journal of Medicine ,12 suggest that it could benefit all men at the start of treatment, whether they have metastatic prostate cancer or prostate cancer that has not spread. In the first study,1 part of the Systemic Therapy in …

For decades, surgeons and pathologists have likened pancreatic tumors to rocks. That’s because a dense, fibrotic mass called the stroma surrounds the cancer cells in the tumor. Such stroma, consisting of connective tissue, fibroblasts, leukocytes, and blood vessels, accompanies most solid tumors, but its extent and compactness are exceptional in pancreatic cancer. And since pancreatic cancer is exceptional also in its deadliness, researchers have wondered whether the stroma is at least partly responsible. Some recent studies now make that case. They argue for the idea that the stroma is blocking drug penetration and contributing to tumor survival, and that drugs that punch holes in the stromal barrier can be effective. “It’s hard to get drug into a rock,” said Robert Wolff, M.D., an oncologist at the University of Texas M. D. Anderson Cancer Center in Houston. “If you can soften up the rock, you may be able to get a better therapeutic index.” Skeptics remain, but several combination therapies are now in clinical trials to test this “stromal depletion hypothesis.” And some oncologists, including Wolff, are already giving certain patients a stromatargeted drug in an off-label indication, outside clinical trials.

The distribution of gingival overgrowth was investigated in a cohort of organ transplant patients, who were medicated with cyclosporin or the combination of cyclosporin and a calcium channel blocking drug. Gingival overgrowth scores were significantly higher at buccal sites than lingual-palatally (p0.0001). There was no significant difference between upper and lower overgrowth scores (p = 0.88). The most severe overgrowth was seen in the canine region. Overgrowth between the central incisors was significantly less than in the canine region (por = 0.044) and was similar to that in the molar and premolar region. Although raised overgrowth scores were associated with increased levels of plaque and gingival inflammation, the distribution could not be explained by this observation.

Three chiral stationary phases were evaluated for their usefulness in determinations of optical purity and separations of β-blocking drug substances. The phases were a modified cellulose phase (Chiralcel OD), an immobilized protein (AGP) and a β-cyclodextrin phase (Cyclobond I). These phases were evaluated concerning their practical analytical use for the determination of the enantiomeric purity of non-racemic β-blocking substances. The best phase proved to be Chiralcel OD, which provided excellent separations of almost all β-blocking substances tested and rugged determinations performed with satisfactorily low detection limits. Similar results could be obtained with AGP, but this did not seem to be sufficiently rugged for routine analysis. The β-cyclodextrin phase resulted in poor chiral separations of most β-blocking substances and the usefulness of this phase for analytical purposes seems limited.

Sudden, unexpected death due to cocaine in young otherwise healthy individuals occurs in an idiosyncratic manner and is commonly felt to be arrhythmogenic in nature, although the exact cause of death is rarely documented. In addition to indirect sympathomimetic actions, cocaine is a potent sodium channel blocking drug and, in this regard, most closely resembles agents such as flecainide. We suggest that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmic drugs.

Patients with diabetes mellitus and symptomatic coronary artery disease are also likely to be hypertensive and, overall, are at very high cardiovascular (CV) risk. This paper reports the findings of a posthoc analysis of the 1113 patients with diabetes mellitus in the ACTION trial: ACTION itself showed that outcomes in patients with stable angina and hypertension were significantly improved when a long-acting calcium channel blocking drug (nifedipine GITS) was added to their treatment regimens. This further analysis of the ACTION database in those patients with diabetes has identified a number of practical therapeutic issues which are still relevant because of potential outcome benefits, particularly in relation to BP control. For example, despite background CV treatment and, specifically, despite the widespread use of ACE Inhibitor drugs, the addition of nifedipine GITS was associated with significant benefits: improvement in BP control by an average of 6/3 mmHg and significant improvements in outcome. In summary, this retrospective analysis has identified that the addition of nifedipine GITS resulted in improved BP control and significant outcome benefits in patients with diabetes who were at high CV risk. There is evidence to suggest that these findings are of direct relevance to current therapeutic practice.

Metipranolol is a non-cardioselective beta adrenergic blocking drug used in the treatment of glaucoma. 56 patients with intraocular pressure between 30-49 mm hg were randomised to one of six treatment regimens for a 12 week period. Each patient received each concentration for 4 weeks and intraocular pressures were checked every two weeks. Using a worst and an average eye approach, mean initial intra-ocular pressures were 35.8 and 35.0 mm hg respectively. The mean fall in intra-ocular pressure after 4 weeks treatment ranged from 12.8 (0.1%) to 14.1 mm hg (0.6%) for average eyes (n = 56), and from 13.4 to 16.7 mm hg for worst eyes. These differences were not statistically significant (p greater than 0.05-p greater than 0.5). Increasing the concentration had no significant effect on pressure. Reducing the concentration had no effect except in patients who changed from 0.6% to 0.1%, when there was a mean rise of approximately 2 mm hg, p less than 0.02. The incidence of stinging varied from 19% of attendances on 0.1%, to 63% on 0.6%. We recommend the use of the 0.1% strength since all three significantly lower intra-ocular pressure but the higher concentrations are more expensive, cause more stinging, and are no better at lowering intra-ocular pressure.

The effects of the second generation calcium channel blocking drug nisoldipine on subjective and objective measurements of exercise performance were studied in 19 patients with moderate to severe heart failure (9 New York Heart Association functional class 2, 9 class 3 and 1 class 4) due to fixed ventricular dysfunction following myocardial infarction. Nisoldipine (10 mg 3 times daily) or placebo were administered for 8 weeks in a double-blind parallel study, assessing exercise performance by symptom-limited treadmill exercise testing using a modified Naughton protocol. Nisoldipine was well-tolerated and produced a small increase in peak estimated workload performed (6.2 +/- 2.9 to 8.2 +/- 3.0 METs, p = 0.06). The rate of perceived exertion (Borg scale) increased from 17.5 +/- 2.2 to 18.8 +/- 1.2 (p less than 0.02). The higher workload was performed at a lower peak systolic blood pressure (p = 0.03), higher peak heart rate (p = 0.06) and identical double product (NS). There was no change in resting and peak heart rate and blood pressure or in exercise performance in patients receiving placebo. Resting left ventricular ejection fraction, measured by radionuclide ventriculography, was unchanged after 8 weeks both in the placebo (21 +/- 9 to 20 +/- 9%) and nisoldipine (34 +/- 17 to 36 +/- 19%) groups.

Receptor occupancy (RO) PET is a non-invasive way to determine drug on target. Given the complexity of procedures, long acquisition times, and high cost, ligand displacement imaging trials often have a limited size and produce sparse RO results over the time course of the blocking drug. To take the best advantage of the available data, we propose a Bayesian hierarchical model to analyze RO as a function of the displacing drug. The model has three components: the first estimates RO using brain regional time-radioactivity concentrations, the second shapes the pharmacokinetic profile of the blocking drug, and the last relates PK to RO. Compared to standard 2-steps RO estimation methods, our Bayesian approach quantifies the variability of the individual RO measures. The model has also useful prediction capabilities: to quantify brain RO for dosage regimens of the drug that were not tested in the experiment. This permits the optimal dose selection of neuroscience drugs at a limited cost. We illustrate the method in the prediction of RO after multiple dosing from a single-dose trial.

Objective—To determine survival times in dogs with severe subvalvular aortic stenosis (SAS) treated by means of balloon valvuloplasty or with atenolol, a β-adrenoceptor blocking drug. Design—Prospective study. Animals—38 dogs < 24 months old with severe SAS (peak systolic pressure gradient ≥ 80 mm Hg). Procedure—10 dogs underwent balloon valvuloplasty and were reexamined 6 weeks later to determine the feasibility of the procedure. The remaining 28 dogs were randomly assigned to undergo balloon valvuloplasty (n = 15) or to be treated with atenolol long term (13) and were reexamined annually for 9 years or until the time of death. Results—For the first 10 dogs, mean pressure gradient 6 weeks after balloon valvuloplasty (mean ± SD, 119 ± 32.6 mm Hg) was significantly decreased, compared with mean baseline pressure gradient (167 ± 40.1 mm Hg). Median survival time for dogs that underwent balloon valvuloplasty (55 months) was not significantly different from median survival time for dogs treated with atenolol (56 months). Conclusions and Clinical Relevance—Results suggest that balloon valvuloplasty can result in a significant decrease in the peak systolic pressure gradient in dogs with severe SAS, at least for the short term. No clear benefit in survival times was seen for dogs that underwent balloon valvuloplasty versus dogs that were treated with atenolol. (J Am Vet Med Assoc 2005;227:420–424)

Nifedipine, a calcium-channel blocking drug was analysed in dog plasma after oral dosing with two different formulations. Sample preparation was automated with a laboratory robot. Quantitative determination of the drug was performed on a reversed-phase HPLC system with electrochemical detection (ED) using an internal standard. Validation of the analytical method showed that the system is well suited for pharmacokinetic studies on dogs. The assay was linear in the range 1-50 ng/ml. Inter-day and intra-day variability were between 6.43-18.15% C.V. and 1.57-5.53% C.V., respectively.

1 A descriptive case study of calcium channel-blocking drug (CCB) overdoses in the Hunter Region of NSW was performed to analyse the in-hospital morbidity and mortality of CCB drug overdoses in an Australian population.2 The patients were admitted to major hospitals within the Hunter Region and treated initially with gastrointestinal decontamination, including the use of oral activated charcoal. Further management was required in most cases and included intravenous calcium, atropine and inotropic support.3 Of the 15 CCB overdoses, four patients died. Non-cardiogenic pulmonary oedema occurred in two other cases. Cardiac conduction defects occurred in 11 cases.4 Atropine was found to be effective only after intravenous calcium had been administered.5 Overdose with slow-release verapamil required prolonged treatment with intravenous calcium salts.6 Overdose with verapamil or diltiazem in doses greater than 300 mg carries a significant risk of death and potentially life threatening arrhythmias occur with lower doses.7 Recommended initial management includes early, effective gastrointestinal decontamination. High dose intravenous calcium salts should be given to reverse hypotension and bradycardia. Atropine and inotropic support are frequently required.

Forty patients with end-stage carcinoma of the head and neck were admitted to a randomized double blind trial with cisplatinum in one arm and cisplatinum + nifedipine in the other. Nifedipine, a calcium channel blocking drug, inhibits the effect of acquired multidrug resistance in animal models. In the present study the addition of this agent had no effect on either response rate or survival in end-stage carcinoma of the head and neck. It is concluded that adding nifedipine to cisplatinum serves no useful purpose in the treatment of end-stage carcinoma of the head and neck.

The authors report a new case of retroperitoneal fibrosis due to a beta-adrenoreceptor blocking drug (atenolol) treatment. 15 well-documented cases have been described in the literature. However, the responsability of the beta-adrenoreceptor blocking drug in the occurrence of retroperitoneal fibrosis is not confirmed. Clinical cases similar to ours need to be published.

1 The inotropic effect of penbutolol, a new beta-adrenergic receptor blocking drug, has been compared with that of propranolol in two similar groups of six subjects each. 2 Inotropic changes were assessed from changes in myocardial contractility index [LV dp-dt/11 T] as well as the slope of the regression line relating LV dp/dt to LVED during incremental pacing. 3 Penbutolol was found to have a significant negative inotropic effect of an order similar to that of propranolol in the respective doses studied.

The beta-adrenergic blocking drug, timolol, was combined with bendrofluazide in a comparative trial between once and twice daily dosage, conducted on 51 patients suffering from hypertension seen in general practice. During the initial control period seven of these patients became normotensive, leaving 44 who entered the trial. Using a cross-over design, treatment was continued for a total period of up to 16 weeks. With both dose regimes, systolic and diastolic pressures were rendered normotensive in over three-quarters of the patients, significant reductions occurring within the first two to four weeks of treatment.

The long fibrillae, or hairs, on the antennae of male mosquitoes are essential for the detection of the female flight sound, the sole sexual attractant. In Anopheles stephensi, as in many other genera and species, these long hairs are recumbent on the shaft of antenna during the daytime and become briefly erect at dusk, coincident with swarming and mating activity. Evidence is presented that erection of the antennal hairs is under direct nervous control. Isolated antennae can be induced to erect their hairs only in the presence of α-adrenergic agonists, and this response is blocked in the presence of the α-adrenergic blocking drug, phentolamine. Thus, a cell surface receptor, resembling the vertebrate α-adrenergic receptor, probably mediates the response to the natural neurotransmitter. The action of α-adrenergic drugs is mimicked by cyclic nucleotides and also by theophylline.

Hydrochlorothiazide, administered at 1, 3 and 9 mg/kg/day p.o. for 4 days, produced a dose-dependent lowering of plasma potassium and an elevation in plasma renin activity in unanesthetized dogs. When plasma renin activity was suppressed in diuretic-treated dogs by the potent β-adrenergic receptor-blocking drug, timolol (0.5, 2 mg/kg/day p.o. for 4 days), the hypokalemia and hyperreninemia were significantly less pronounced. The data suggest that β-adrenergic blocking drugs can be used to antagonize these side effects of diuretics.