In vivo and in vitro pharmacological characterization of SVT-40776, a novel M3 muscarinic receptor antagonist,for the treatment of overactive bladder

Background and purpose:

Highly selective M₃ muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non-selective antimuscarinics have been associated with activity at M₂ receptors as these receptors are mainly responsible for muscarinic receptor-dependent bradycardia. We have investigated a novel antimuscarinic, SVT-40776, highly selective for M₃ over M₂ receptors (Ki = 0.19 nmol·L⁻¹ for M₃ receptor affinity). This study reports the functional activity of SVT-40776 in the bladder, relative to its activity in atria.

Experimental approach:

In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT-40776. The in vivo efficacy of SVT-40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.

Key results:

SVT-40776 was the most potent in inhibiting carbachol-induced bladder contractions of the anti-cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT-40776 exhibited the highest urinary versus cardiac selectivity (199-fold). In the guinea pig in vivo model, SVT-40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 µg·kg⁻¹ i.v), without affecting arterial blood pressure.

Conclusions and implications:

SVT-40776 is a potent inhibitor of M₃ receptor-related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT-40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.British Journal of Pharmacology (2009) doi:10.1111/j.1476-5381.2008.00082.x     

A 'short walk' is longer before radiotherapy than afterwards: a qualitative study questioning the baseline and follow-up design

Background  

Numerous studies have indirectly demonstrated changes in the content of respondents' QoL appraisal process over time by revealing response-shift effects. This is the first known study to qualitatively examine the assumption of consistency in the content of the cognitive processes underlying QoL appraisal over time. Specific objectives are to examine whether the content of each distinct cognitive process underlying QoL appraisal is (dis)similar over time and whether patterns of (dis)similarity can be discerned across and within patients and/or items.     

Asthma at the interface: bridging the gap between general practice and a district general hospital

A clinic supervised by a nurse, using principles originally developed in general practice, was established in the paediatric department of a district general hospital. A randomised controlled study was conducted comparing children admitted with asthma or attending outpatients who were given a patient education programme and self management plan (intervention group) with a control group. The study comprised 91 patients aged 3-14 years admitted for asthma or attending a hospital outpatient department from November 1989 to November 1990. Seventy seven patients completed the study and kept diaries for a median of 283 days. Patients in the intervention group had significantly less restriction of activity (95% confidence interval (CI) -0.27 to -0.01) and fewer episodes of peak flow below 30% of best (95% CI 0.03 to 1.17). Patients in the intervention group were more likely to make the correct response to an acute exacerbation of their asthma than the control group (71% v 47%, 95% CI 9.51 to 39.1). The intervention group had fewer school absences and fewer home visits by a general practitioner. There was an increase in the readmission rate for the intervention group. A subgroup of patients who self managed by doubling their use of inhaled steroids during an exacerbation performed better than those patients who only increased their bronchodilator or were managed on salbutamol or sodium cromoglycate alone. Improvements in patient follow up and the structure of the self management plans used, particularly changing the peak flow level at which inhaled steroids are doubled, may further improve the outcome of patients attending the asthma clinic.     

Truncal site and detoxifying enzyme polymorphisms significantly reduce time to presentation of further primary cutaneous basal cell carcinoma

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians. Its incidence is rising and many patients develop multiple primary tumours at separate sites. Factors determining time between first primary tumour presentation and the next new primary lesion are unclear. We used Cox's proportional hazards model to study, in 856 Caucasians, the influence of tumour site, individual characteristics and polymorphism in glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) loci on time to next primary tumour presentation. More than one tumour at first presentation (P <0.0001, hazard ratio 2.72) and GSTT1 null (P = 0.028, hazard ratio 1.74) were associated with decreased time to next primary tumour presentation. Significant two- factor interactions, corrected for number of tumours at presentation, were identified between a truncal tumour at first presentation and each of male gender, GSTM1 null and CYP2D6 EM (P <0.003, hazard ratios 3.09- 3.82). In each of these cases, all patients with the risk combination demonstrated further separate tumours within 5 years of first presentation. Thus, patients with a truncal tumour at first presentation, especially males and those presenting with more than one lesion have a significantly decreased time to presentation of further tumours and should receive more meticulous follow-up. Polymorphism in GSTM1 and CYP2D6 also influences the rate of new primary tumour accrual giving insights into the link between ultraviolet exposure and multiple tumour development.      

Long-term follow up to determine the prognostic value of imaging after urinary tract infections. Part 1: Reflux

In 3646 children with at least one confirmed urinary tract infection the prevalence of vesicoureteric reflux at presentation was correlated with progressive renal damage during follow up of not less than two and up to 16 years. Reflux was not demonstrated either at presentation or at any subsequent time in almost one half of the children who suffered progressive renal damage and was not a risk factor for progressive renal damage in boys under 1 year. It was an important risk factor in boys over 1 year and in girls of any age. The risk of progressive renal damage in children in whom micturating cystourethrography (MCU) did not reveal vesicoureteric reflux was substantially greater than in those who indirect isotope voiding study (IVS) did not show reflux. The risk of deterioration for those in whom reflux was demonstrated was similar for both techniques. This discrepancy indicates an appreciably higher false negative rate for the MCU than the IVS. Dilatation of the renal pelvis detected by ultrasound was associated with a significantly increased risk of progressive damage only when associated with reflux, but most children with progressive damage did not have a dilated collecting system at presentation.     

Role of gastro-oesophageal reflux in infant irritability

Gastro-oesophageal reflux (GOR) disease may cause excessive crying in infants. The role of GOR was evaluated in infant irritability and an attempt was made to define clinical predictors of pathological reflux. Seventy consecutively admitted infants with irritability and presumptive GOR were retrospectively reviewed. All had undergone prolonged oesophageal pH monitoring. Pathological GOR was defined as a fractional reflux time of > or = 10% and was significantly less common in infants under 3 months (one of 24; 4.2%) than in older infants (10 of 46; 21.7%). All infants with pathological GOR presented with frequent vomiting, and 'silent' pathological reflux did not occur. Poor weight gain, feeding refusal, backarching, and sleep disturbance were not significantly associated with pathological GOR. The results suggest that pathological GOR is an unlikely cause of infant irritability under the age of 3 months.