Canadian cost-effectiveness analysis of solifenacin compared to oxybutynin immediate-release in patients with overactive bladder.

OBJECTIVE: To estimate the cost effectiveness of solifenacin 5 mg/day compared to oxybutynin immediate-release (IR) 15 mg/day in patients with overactive bladder, from the perspective of the Canadian healthcare (payer) system. RESEARCH DESIGN AND METHODS: A Markov model was adapted to estimate the incremental cost per quality-adjusted life-year (QALY) of solifenacin and oxybutynin IR over a 1-year time horizon, based on efficacy and discontinuation data from the Canadian VECTOR (VEsicare in Comparison To Oxybutynin for oveRactive bladder patients) study. In the model, patients who discontinued treatment were offered tolterodine extended release 4 mg/day as second-line. Model robustness was tested using various sensitivity analyses. Utility values were derived from published literature; incontinence pads were included in a secondary analysis. RESULTS: In the base-case analysis, total costs over 1 year were CAN$695 and CAN$550 in the solifenacin and oxybutynin IR groups, respectively. When including incontinence pad costs, there was an incremental saving of CAN$1,831 per patient with solifenacin. Solifenacin was associated with an incremental QALY gain of 0.01 over 1 year. In the base-case analysis without incontinence pads, the incremental cost-utility ratio for solifenacin was CAN$14,092. Probabilistic analyses showed no overlap in the 95% confidence intervals for total costs or QALYs with or without incontinence pads. Solifenacin was cost effective in >90% of cases, based on a willingness-to-pay threshold of CAN$50,000 per additional QALY, irrespective of whether pad costs were included in the model. The most influential variables were the discontinuation rates and the cost of incontinence pads. Limitations of the analysis relate mainly to the fact that data in the VECTOR study were collected using a direct questioning approach, which might have increased the reporting of dry mouth. CONCLUSIONS: Solifenacin 5 mg/day was a cost-effective treatment compared with oxybutynin IR 15 mg/day. TRIAL REGISTRATION: NCT00431041 (of the VECTOR study, upon which the analysis in this paper was based).

Validation studies of the Pregnancy Unique-Quantification of Emesis (PUQE) scores.

The Pregnancy-Unique Quantification of Emesis (PUQE) is a scoring system to quantify the severity of nausea and vomiting of pregnancy (NVP). Based on quantification of the 3 physical symptoms of NVP (nausea, vomiting and retching), PUQE closely correlates with the validated but much more complex Rhodes' score. We examined the ability of PUQE to predict four independent aspects of NVP: (a) pregnant women's ability to take multivitamins. (b) rates of emergency room visits and hospitalisation for NVP. (c) health cost of NVP. (d) women's self scores of well-being in NVP. Using large prospective cohorts of women for each end point, severity of NVP measured by PUQE had significant predictive value for all 4 aspects sought. PUQE has been validated through 4 independent clinical outcomes of direct importance and relevance for NVP. The simplicity of PUQE and the ease of its execution make it a practical tool for both clinical follow-up and research.

Distinct changes in peptide YY binding to, and mRNA levels of, Y1 and Y2 receptors in the rat hippocampus associated with kindling epileptogenesis.

Electrical kindling of the rat dorsal hippocampus induced significant changes in the binding of 125I-peptide YY to Y1 and Y2 subtypes of neuropeptide Y receptors and in their mRNA levels in the area dentata as assessed by quantitative receptor autoradiography and in situ hybridization histochemistry. Binding to Y1 receptor sites decreased by 50% (p < 0.05) in the molecular layer of the stimulated dentate gyrus, 2 days after preconvulsive stage 2 and 1 week or 1 month after generalized stage 5 seizures compared with sham-stimulated rats. Binding to Y2 receptor sites increased bilaterally by 36-87% (p < 0.05) in the hilus at stage 2 and 1 week or 1 month after stage 5. No significant changes were observed after one afterdischarge or in the other hippocampal subfields or in the cortex. Y1 receptor mRNA signal decreased bilaterally by 50-64% (p < 0.01) in the granule cell layer, 6 h but not 24 h after stages 2 and 5. The Y2 receptor mRNA signal was enhanced by 283% (p < 0.01) in the stimulated granule cell layer 24 h after stage 2. At 6 and 24 h after stage 5, mRNA levels were increased both ipsilaterally (283 and 360%, respectively; p < 0.01) and contralaterally (190 and 260%, respectively; p < 0.05). No significant changes in level of either mRNA was found following one afterdischarge. These modifications, and the enhanced neuropeptide Y release previously shown in the hippocampus, suggest that kindling is associated with lasting changes in neuropeptide Y-mediated neurotransmission.

Autoradiographic analysis of somatostatin SRIF1 and SRIF2 receptors in the human brain and pituitary.

The distribution of somatostatin (SRIF) receptor sites was studied by in vitro receptor autoradiography in the human brain and pituitary using the SRIF1 (sst2) receptor selective [125I]Tyr3-octreotide, the non-subtype selective [125I]LTT-SRIF-28 ([Leu8,D-Trp22, 125I-Tyr25]SRIF-28) and the SRIF2-receptor selective [125I]CGP 23996 (c[Asu- Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) in buffer containing 120 mM Na+. SRIF receptor autoradiography was compared with mRNA expression of somatostatin receptors sst1-5 as studied by in situ hybridisation in human brain. High levels of [125I]LTT-SRIF-28 and [125I]Tyr3-octreotide recognition sites were found in the deep layers of cerebral cortex and molecular layer of cerebellum of the human brain. The hypothalamus, choroid plexus, most areas of the brainstem and dentate nucleus were associated with low levels of binding. In contrast to [125I]LTT-SRIF-28 and [125I]Tyr3-octreotide, no difference was observed for [125I]CGP 23996 labelling in the various layers of cerebral cortex. The choroid plexus, substantia nigra and molecular layer of the cerebellum presented high densities of [125I]CGP 23996 binding sites whereas no binding was observed in the hypothalamus and locus coeruleus using this radioligand. Both lobes of the human pituitary displayed low levels of [125I]LTT-SRIF-28 and [125I]Tyr3-octreotide binding. By contrast, the anterior lobe of the pituitary displayed very high levels of [125I]CGP 23996 labelled sites whereas intermediate levels were found in the posterior lobe. There was a partial overlap between sst2 receptor mRNA and [125I]Tyr3-octreotide binding, although the distribution of the binding sites was much wider than that of receptor mRNA. The same observation was made for sst1 and/or sst4 receptor mRNA and [125I]CGP 23996 labelled sites. The present data show that SRIF1 and SRIF2 receptors are present in the human brain with different distributions, especially in the cerebral cortex and the pituitary. The very similar distribution of sites labelled with [125I]LTT-SRIF-28 and [125I]Tyr3-octreotide suggests (i) that sst2 receptors are predominant within the SRIF1 family in the human brain and (ii) that [125I]LTT-SRIF-28 under the conditions used in the present study, does not significnatly label SRIF2 sites.

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.

The elusive nature of cerebellar somatostatin receptors: studies in rat, monkey and human cerebellum.

The pharmacological profile and localization of somatostatin (SRIF) receptors were determined in rat, monkey and human cerebellum. In rat cerebellar cortex, low sst1/sst4, intermediate sst2 and very high sst3 receptor mRNA levels were found. sst1 mRNA was also expressed in the deep cerebellar nuclei. [125I]Tyr3-octreotide binding sites in cerebellar membranes correlated with recombinant sst2, but not with sst5 or sst3 receptors and were found in the molecular layer of the cerebellum. [125I]CGP 23996 (in Na(+)-buffer) binding in rat cerebellum correlated with sst1 or sst4, but not with sst2, sst3 or sst5 receptor binding. Similar data were obtained in rhesus monkey cerebellum. mRNAs for all five receptors were found in the granule cell layer of the human cerebellum and/or in the dentate nucleus. [125I]Tyr3-octreotide binding was strong in the molecular layer and correlated with that of recombinant sst2 receptors, but not with sst3 or sst5 receptors. [125I]CGP 23996 (in Mg(++)-buffer) binding was heterogeneous (about 75%, to sst2 and 25% to sst1 and/or sst4 receptors). The molecular and granular layers were equally and the dentate nucleus strongly labeled. Thus, SRIF receptors of the sst2, sst1 and/or sst4 subtype are presnt in the rat, monkey and human cerebellum. In the latter two species, the sst2 type appears to be predominant. Surprisingly, the high expression of sst3 receptor mRNA is not supported by radioligand binding data in any of the species studied. The reason for this discrepancy remains to be elucidated.

Status of somatostatin receptor messenger RNAs and binding sites in rat brain during kindling epileptogenesis.

In situ hybridization histochemistry with somatostatin sst1-sst5 receptor messenger RNA-selective oligoprobes and quantitative receptor autoradiographic binding studies using [125I]Tyr3-octreotide, [Leu2,D-Trp22,125I-Tyr25]somatostatin-28 and [125I]CGP 23996 ([125I]c[Asn-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) were performed to determine the level of expression of somatostatin receptor messenger RNA and receptor binding sites in the hippocampal formation, limbic system and cerebral cortex of adult rats electrically kindled in the dorsal hippocampus. In control rats (implanted with electrodes but not electrically stimulated), the somatostatin-1 receptor-selective [125I]Tyr3-octreotide and the non-subtype-selective [Leu3,D-Trp22,125I-Tyr25]somatostatin-28 preferentially labelled the strata oriens and radiatum of the CA1 subfield of the hippocampus, the molecular layer of the dentate gyrus, the subiculum and presubiculum of the hippocampal formation, the inner layer of the frontal cortex, and the lateral and basolateral nuclei of the amygdala. The non-subtype-selective radioligand [125I]CGP 23996 (in 5 mM Mg2+ buffer) preferentially labelled the strata oriens and radiatum of the CA1 subfield of the hippocampus, the subiculum and the basolateral nucleus of the amygdala. Under conditions where primarily somatostatin-2 receptors were labelled, [125I]CGP 23996 (in 120 mM Na+ buffer) showed strong binding in the strata oriens and radiatum of the CA1 subfield of the hippocampus and the frontal cortex, whereas the dentate gyrus, subiculum and amygdala showed only weak signals. During and after kindling, no significant differences were observed between the ipsi- and contralateral sides of the hippocampus. A significant decrease (about 40%) of somatostatin receptor binding sites was observed in the molecular layer of the dentate gyrus with all radioligands (except [125I]CGP 23996 in Na+ buffer, which did not label this area) at stage 2 (pre-convulsive stage) and one week, but not one month, after stage 5 (generalized motor seizures). In contrast to somatostatin receptor binding, no alterations of the messenger RNA levels for sst1-sst5 receptors were found either at stage 2 or at stage 5. Similarly, no changes in receptor binding or messenger RNA levels were observed in the brain of rats which experienced a single afterdischarge. The present study shows a significant and selective decrease of somatostatin-1 receptor binding sites in the dentate gyrus of kindled rats. This is part of the plastic changes induced by kindling and may contribute to the increased sensitivity for the induction of generalized seizures during kindling.

Localization and pharmacological characterization of somatostatin recognition sites in the human cerebellum.

Radioligand binding studies were performed in membranes of human cerebellum using [125I][Tyr3]octreotide also known as [125I]204-090, [125I]LTT-SRIF-28 ([Leu8, D-Trp22, 125I-Tyr25]SRIF-28) and [125I]CGP 23996 ([125I]c[Asu-Lys-Asn-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) to characterize the nature of cerebellar somatostatin receptors. Saturation experiments performed with [125I]204-090 suggest the presence of a single class of binding sites with high affinity: Bmax = 55.7 +/- 9.7 fmol/mg protein, pKd = 9.57 +/- 0.04. The pharmacological profile of [125I]204-090 and [125I]LTT-SRIF-28 labelled sites in human cerebellar membranes was overlapping (correlation coefficient r = 0.998) and correlated very significantly with that of recombinant human sst2 receptors (r = 0.987). By contrast, there was very little correlation with those of recombinant human sst3 (r = 0.208) or human sst5 receptors (r = 0.547). In contrast to [125I]204-090 or [125I]LTT-SRIF-28 binding, [125I]CGP 23996 binding (in 5 mM MgCl2 buffer) in cerebellar membranes was heterogeneous as indicated by biphasic competition curves produced by sst2 receptor selective ligands such as seglitide or octreotide. The pharmacological profile of the major component was closely correlated with that of human sst2 receptors (r = 0.989), whereas the minor component correlated equally well with human sst1 or sst4 receptors (r = 0.902 and 0.941, respectively). In vitro autoradiographic studies performed in cerebellar slices using [125I]204-090 and [125I]LTT-SRIF-28 demonstrated the presence of binding sites predominantly in the molecular layer, whereas weaker labelling was detected in the granular layer. The distribution of sites labelled by both radioligands was very similar. Using [125I]CGP 23996 (in 120 mM NaCl buffer), no clear difference between labeling of the molecular and granular layers was detectable; the dentate nucleus demonstrated binding sites for [125I]CGP 23996, in contrast to the very low level of binding observed with both, [125I]204-090 and [125I]LTT-SRIF-28. Together, the present data demonstrate the presence of SRIF receptors in the adult human cerebellar cortex which are, for the major population, best characterized as sst2. The SRIF receptors in the minor populations of the cerebellar cortex and the dentate nucleus most probably represent sst1 and/or sst4 sites.

Somatostatin receptors in the rhesus monkey brain: localization and pharmacological characterization.

To characterize the nature and distribution of somatostatin (SRIF) receptors, radioligand binding studies and in vitro receptor autoradiography were performed in Rhesus monkey brain using either [125I]LTT-SRIF-28 ([Leu8, D-Trp22, 125I-Tyr25]SRIF-28) alone or in the presence of 3 nM seglitide (to block sst2 sites), [125I]Tyr3-octreotide or [125I]CGP 23996 (c[Asu-Lys-Asn-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) in buffer containing either 120 mM Na+ or 5 mM Mg2+. [125I]Tyr3 -octreotide labelled an apparently homogeneous population of sites in cerebral and cerebellar cortex (Bmax = 27.3 +/- 2.8 fmol/mg protein and 52.6 +/- 8.6 fmol/mg protein, PKd = 9.46 +/- 0.03 and] 9.93 +/- 0.03, respectively). The pharmacological profile of these sites correlated highly significantly with that of human recombinant sst2 receptors (r = 0.996), but not or much less with that of human recombinant sst3 and sst5 receptors (r = 0.12 and 0.45, respectively). [125I]CGP 23996 (in Na(+)-buffer) also labelled an apparently homogeneous population of sites in Rhesus monkey cerebral cortex membranes (Bmax = 3.1 +/- 0.3 fmol/mg protein, pKd = 10.57 +/- 0.08), the pharmacological profile of which was highly significantly correlated with the profiles of human recombinant sst1 and sst4 receptors (r = 0.98 and 0.96, respectively). Using receptor autoradiography, high levels of [125I]LTT-SRIF-28 and [125I]Tyr3 -octreotide recognition sites were found in basal ganglia, molecular and granular layers of the cerebellum and layers III, V and VI of entorhinal cortex. In these regions, the addition of 3 nM seglitide produced a marked decrease of [125I]LTT-SRIF-28 binding. Low levels of [125I]LTT-SRIF-28 binding were observed in subiculum, pituitary and choroid plexus. By contrast, [125I]CGP 23996 labelling in the presence of Mg2+ as well as Na+ ions was highest in pituitary and choroid plexus. However, [125I]CGP 23996 binding was diversely affected by these ionic conditions in several regions of hippocampus and cerebral cortex. Displacement of [125I]CGP 23996 (in Mg(2+)-buffer) with seglitide in the molecular layer of the cerebellum, deep layers of the entorhinal cortex, layers I, II and V of the insular cortex and frontal pole yielded complex competition curves suggesting the presence of two populations of SRIF receptors. By contrast, [125I]CGP 23996 binding (in Mg(2+)-buffer) in the choroid plexus, hilus of the dentate gyrus and stratum oriens and radiatum of the CA3 field of hippocampus was not affected by seglitide up to 10 microM, suggesting only sst1 and/or sst4 sites which have a negligible affinity for seglitide to be present in these structures. Taken together, these results suggest that [125I]CGP 23996 (in the presence of Na+) labels exclusively SRIF-2 receptors (sst1 and/or sst4), whereas in the presence of Mg2+ ions, [125I]CGP 23996 labels both SRIF-2 and SRIF-1 receptors (sst2, sst3 and sst5). The present study also demonstrates the presence and differential distribution of sst2 and sst1/sst4 receptors in the Rhesus monkey brain.

Localization and pharmacological characterization of somatostatin sst2 sites in the rat cerebellum.

Radioligand binding studies were performed in membranes of rat cerebellum using [125I]-[Tyr3]octreotide ([125I]204-090) to characterize the nature of cerebellar somatostatin receptors. Saturation experiments suggest the presence of a single class of binding sites with high affinity, pKd = 9.53 +/- 0.11, but low receptor density, Bmax = 12.7 +/- 1.0 fmol/mg protein. The pharmacological profile of [125I]204-090 sites in cerebellar membranes was established using a range of ligands known to interact with SSTR-2 (now called sst2) and other somatostatin (SRIF) receptors. SRIF analogues such as octreotide (SMS 201-995), seglitide (MK 678) and somatuline (BIM 23014) displayed very high affinity for cerebellar [125I]204-090 binding sites. The data were compared to results obtained using the same ligand in rat cerebral cortex membranes known to represent sst2 binding. The pharmacological characteristics of the cerebellar sites were in close correlation with those of the cerebral cortex (r = 0.976, n = 19, p < 0.001) and CHO-cells expressing human recombinant sst2 receptor (r = 0.977, n = 19, p < 0.001). By contrast, there was very little correlation between cerebellar binding and published affinities for rat sst5 receptors (r = 0.465), for which octreotide has also high affinity. In vitro autoradiographic studies performed in cerebellar slices using [125I]204-090 demonstrated the presence of binding sites in the molecular layer of the rat cerebellum. In situ hybridization studies using sst2 receptor mRNA selective oligoprobes confirmed the presence of sst2 receptor mRNA in the rat cerebellum. Together, the present data demonstrate the presence of a low density of SRIF receptors in the molecular layer of the adult rat cerebellum which are best characterized as sst2. This is the first pharmacological characterization and localization of sst2 receptors in the adult rat cerebellum.