Amplification of cyclic AMP generation reveals agonistic effects of certain beta-adrenergic antagonists

Some beta-adrenergic receptor (beta AR) antagonists, in addition to blocking receptor-mediated responses, possess agonistic properties or intrinsic sympathomimetic activity (ISA). In this study we describe several techniques for amplification of cAMP levels as a measure of agonistic activity, and we apply these techniques to the study of beta AR antagonists with ISA. We show that 1) a variety of beta AR antagonists with ISA, including alprenolol and cyanopindolol, enhance cyclic AMP accumulation in S49 lymphoma cells if cells are also incubated with the diterpene forskolin; 2) beta AR blockers with ISA stimulate cAMP accumulation in the presence of a water-soluble analog of forskolin but not in the presence of 9,11-dideoxyforskolin (which does not activate adenylyl cyclase); 3) the potentiation by forskolin is not unique to S49 cells but is also observed in BC3H1 smooth muscle-derived cells; 4) stimulation of cAMP accumulation by beta-blockers with ISA occurs in S49 cells in three additional settings that do not involve the use of forskolin, after pretreatment with pertussis toxin to inactivate the inhibitory guanine nucleotide binding protein, after pretreatment with [D-Trp8]-somatostatin to sensitize adenylyl cyclase, and using a radioimmunoassay to quantitate levels of cellular cAMP. We conclude that beta AR antagonists with ISA can weakly stimulate intracellular cAMP accumulation, but this stimulation is not easily detected. Elevation of cAMP levels may account for the agonistic effects of these drugs or, at least provides a measure of stimulatory guanine nucleotide-binding protein activation by these compounds.     

Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis

The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as regulators of the extravasation and migration of leukocytes may provide a novel approach for the treatment of these diseases. Moreover, the possibility of developing small-molecule antagonists offers an excellent method for the oral delivery of compounds with a short half-life.     

Drug costs developments after patent expiry of enalapril, fluoxetine and ranitidine

Background

In order to increase price competition, government regulations focus on controlling drug costs. Drug costs after patent expiry are an area of particular interest because the substitution of branded medication with generics represents an opportunity for lowering drug costs. However, drug costs may not decrease after patent expiry, because of a lack of price competition and different national pricing systems.

Aim

The aim of this study was to investigate the trends in the use of generics after patent expiry for enalapril, fluoxetine and ranitidine and the subsequent changes, if any, in the costs of these medications.

Methods

A drug-utilisation study was performed using data from a large sample of Dutch pharmacies. Both volumes (measured as defined daily doses [DDD] per 1000 population) as well as drug costs (calculated per DDD) prior to and after patent expiry were calculated. Costs per DDD were compared using trend-line analysis. In addition, the relative market shares of the different trade channels (branded, parallel imported and generic) were compared before and after patent expiry.

Results

The costs per DDD decreased for all three drugs and, as expected, these costs decrease more rapidly after patent expiry. Significant differences in the trend lines were found for enalapril and fluoxetine.

Conclusions

Despite relatively high reimbursement prices for generics in the Netherlands, this example from the Dutch pharmaceutical market demonstrates the benefit of generic substitution for containing pharmaceutical costs, which contrasts with concerns raised by the Dutch government.     

The orienting of visuospatial attention: an event-related brain potential study

This study investigated the electrophysiological correlates of shifting, maintaining, and relaxing the focus of attention, using a symbolic cuing task. Cues and imperative stimuli were presented in rapid succession, and the ADJAR procedure was used to remove the contribution of event-related potential (ERP) activity associated with the imperative stimulus from the cue-related ERP waveforms. Initial analyses, comparing left and right attention-directing cues, replicated previous findings of early directing attention negativity (EDAN) and anterior directing attention negativity (ADAN) effects. To isolate ERP activity that is common to leftward and rightward attention shifts, the combined ERP activity elicited by attention-directing cues was compared to the ERP activity elicited by non-informative cues. This analysis revealed a strong and broadly distributed early positivity followed by a sustained central negativity, possibly reflecting the controlled orienting and subsequent maintenance of attentional focus. Finally, imperative stimuli preceded by non-informative cues were characterized by an enhanced posterior P2 effect, with a scalp distribution indicative of generators in visual areas. This result suggests a relatively late (re)activation in visual areas associated with the processing of stimuli that had not been cued in advance.     

A comparison of the ability of a 4:1 ketogenic diet and a 6.3:1 ketogenic diet to elevate seizure thresholds in adult and young rats

PURPOSE: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically. METHODS: Ninety adult rats and 75 young rats were placed on one of five experimental diets: (a) a 4:1 KD, (b) a control diet balanced to the 4:1 KD, (c) a 6.3:1 KD, (d) a standard control diet, or (e) an ad libitum standard control diet. All subjects were seizure tested by using the PTZ infusion test. Blood glucose and beta-hydroxybutyrate (beta-OHB) levels were measured. RESULTS: Neither KD elevated absolute "latencies to seizure" in young or adult rats. Similarly, neither KD elevated "threshold doses" in adult rats. In young rats, the 6.3:1 KD, but not the 4:1 KD, significantly elevated threshold doses. The 6.3:1 KD group showed poorer weight gain than the 4:1 KD group when compared with respective controls. The most dramatic discrepancies were seen in young rats. CONCLUSIONS: "Threshold doses" and "latency to seizure" data provided conflicting measures of seizure threshold. This was likely due to the inflation of threshold doses calculated by using the much smaller body weights found in the 6.3:1 KD group. Ultimately, the PTZ infusion test in rats may not be a good preparation to model the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups.     

A 15-year follow-up of neuromuscular function in patients with prior poliomyelitis

A population-based cohort of poliomyelitis survivors was established and followed for 15 years (mean time since poliomyelitis was 40 years). Over time, the cohort demonstrated only a modest decline in function as measured by strength measurements, electrophysiologic assessments, and timed functional tasks. There was no association between symptoms of late deterioration and magnitude of decline. Rather, the presence of these symptoms was associated with the magnitude of the residual deficits.     

Mechanism of change in cognitive-behavioral treatment of panic disorder: evidence for the fear of fear mediational hypothesis

Numerous clinical trials have demonstrated the efficacy of cognitive-behavioral treatment (CBT) for panic disorder. However, studies investigating the mechanisms responsible for improvement with CBT are lacking. The authors used regression analyses outlined by R. M. Baron and D. A. Kenny (1986) to test whether a reduction in fear of fear (FOF) underlies improvement resulting from CBT. Pre- and posttreatment measures were collected from 90 CBT-treated patients and 40 wait-list control participants. Overall, treatment accounted for 31% of the variance in symptom reduction. The potency of FOF as a mediator varied as a function of symptom facet, as full mediation was observed for the change in global disability, whereas the effects of CBT on agoraphobia, anxiety, and panic frequency were partially accounted for by reductions in FOF. Clinical implications and future research directions are discussed.     

Evaluation of donor site function and morbidity of the fasciocutaneous radial forearm flap

OBJECTIVE: To assess the results of the use of the free radial forearm flap in terms of objective morbidity and subjective patient response. STUDY DESIGN: The donor sites were examined from 37 patients who underwent reconstruction with a free fasciocutaneous radial forearm flap in the head and neck after ablative tumor surgery. METHODS: Patients were asked to fill in a written questionnaire. The following additional tests were performed: resting skin temperature of digits I and V, temperature after submersion in iced water, grip and pinch tests, and goniometry. RESULTS: Resting skin temperature was slightly decreased for donor hands 0.69 degrees C (P < .001) and 0.31 degrees C (P = .048) for digits I and V, respectively, but recovery after submersion in iced water showed no differences. The strength tests and goniometry revealed no statistically significant findings between donor and control sides. On the questionnaire, 9 patients (24%) reported slightly impaired function, 14 (38%) could not wear their watch or bracelet, 17 (46%) reported numbness, 5 (14%) reported soreness, 5 (14%) reported itching, 6 (16%) reported cold intolerance, 5 (14%) reported bad cosmetic appearance, and 9 (24%) expressed the opinion that they were insufficiently counseled. CONCLUSION: There is a negligible objective morbidity of a free radial forearm flap harvest procedure, but a number of patients have subjective complaints when asked. Elaborate presurgical counseling can probably reduce these complaints.