Cost-effectiveness analysis of solifenacin versus oxybutynin immediate-release in the treatment of patients with overactive bladder in the United Kingdom.

OBJECTIVE: To carry out a cost-utility analysis comparing initial treatment with solifenacin 5 mg/day vs oxybutynin immediate-release (IR) 15 mg/day for the treatment of patients with overactive bladder (OAB) from the perspective of the U.K. National Health Service (NHS). METHODS: A Markov model with six health states was developed to follow a cohort of OAB patients treated with either solifenacin or oxybutynin during a 1-year period. Costs and utilities were accumulated as patients transited through the health states in the model and a drop-out state. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 8 weeks. A proportion of drop-out patients were assumed to continue treatment with tolterodine ER. Utility values were obtained from a Swedish study and pad use was based on a multinational clinical trial. Adherence rates for individual treatments were derived from a U.K. database study. For pad use and utility values, the drop-out state was split between those patients who were no longer receiving treatment and those on second-line therapy. Patients on second-line therapy who drop-out were referred for a specialist visit. Results were expressed in terms of incremental cost-utility ratios. RESULTS: Total annual costs for solifenacin and oxybutynin were £504.30 and £364.19, respectively. First-line drug use represents 49% and 4% of costs and pad use represent 23% and 40% of costs for solifenacin and oxybutynin, respectively. Differences between cumulative utilities were small but were greater for solifenacin (0.7020 vs. 0.6907). The baseline incremental cost-effectiveness ratio was £12,309/QALY. CONCLUSION: Under the baseline assumptions, solifenacin would appear to be cost-effective with an incremental cost-utility of less than £20,000/QALY. However, small differences in utility between the alternatives and the large number of drop-outs means that the results are sensitive to small adjustments in the values of utilities assigned to the drop-out state.

The effect of protein kinase C-delta knockdown on anti-free radical enzyme and neuropeptide Y gene expression in phenylpropanolamine-treated rats.

Hypothalamic neuropeptide Y (NPY) has been reported to involve in regulating behavioral response of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored if protein kinase C (PKC)-delta signaling participated in this regulation. Moreover, possible roles of anti-free radical enzyme catalase (CAT) and nitrogen oxide synthase (NOS) were also examined. Rats were treated daily with PPA for 4 days. Changes in food intake and hypothalamic NPY, PKCdelta, CAT, and NOS contents were assessed and compared. Results showed that PKCdelta and CAT increased during PPA treatment, which were concomitant with decreases in NPY content and food intake, while the change of NOS was expressed differently. Moreover, PKCdelta knockdown could modify PPA anorexia as well as NPY and CAT expression, while NOS expression remained unchanged. Furthermore, pre-treatment with NOS inhibitor could modify both PPA anorexia and NPY content. It is suggested that PKCdelta participates in the anorectic response of PPA via the modulation of NPY and CAT, while NOS contribute to this modulation via a different mechanism during PPA treatment. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the therapeutic research of PPA and other anti-obesity drugs.

Effects of rice proteins from two cultivars, Koshihikari and Shunyo, on hepatic cholesterol secretion by isolated perfused livers of rats fed cholesterol-enriched diets.

BACKGROUND/AIMS: The aim of the present study was to clarify the effect of rice proteins, with different contents of glutelin and prolamin, on the regulation of hepatic cholesterol output pathways and the development of hypocholesterolemia in rats. METHODS: Seven-week-old male Wistar rats were fed 2 types of rice protein from either the cultivar Koshihikari (RRP) or the cultivar Shunyo (SRP), or casein as a control, for 2 weeks (n = 6 for each group). Each diet was supplemented with 1% cholesterol and 0.25% sodium cholate. Using an isolated perfused liver, hepatic secretion of cholesterol into bile and the circulation was measured during a 4-hour perfusion. RESULTS: Total hepatic cholesterol secretions into the circulation were significantly reduced by both rice proteins (p < 0.05), and hepatic cholesterol secretions into very-low-density lipoproteins were also effectively decreased by RRP and SRP. In contrast, bile flow and biliary output of bile acids were significantly stimulated by RRP and SRP (p < 0.05). CONCLUSIONS: These results demonstrate that the key metabolic pathways of hepatic cholesterol are modified by both rice proteins leading to similar hypocholesterolemic effects. The increased excretion of biliary bile acids associated with a decreased output of hepatic cholesterol into the circulation suggests a functional reciprocal interrelationship between both of the hepatic cholesterol secretory pathways in the rice-protein-fed rats, regardless of rice protein type.

Boltushka: a homemade amphetamine-type stimulant and HIV risk in Odessa, Ukraine.

BACKGROUND: Homemade amphetamine-type stimulants (ATSs) have been reported in Russia and Eastern Europe for decades. Recipes differ geographically and over time producing differing active ingredients. Vint and jeff (active ingredients methamphetamine and methcathinone, respectively) are two such homemade ATSs originally produced from over-the-counter cold medications and household chemicals. METHODS: During a Rapid Policy Assessment and Responses (RPAR) project in Odessa, Ukraine, researchers found use of boltushka, a novel homemade ATS. Fourteen supplemental qualitative interviews were conducted, including ten interviews with boltushka injectors and four interviews with pharmacists. We report patterns of boltushka use among local injection drug users (IDUs) as well as the role of laws, regulations, and current pharmacy practices. RESULTS: Legal restrictions on over-the-counter cold medicines in Ukraine led to products containing phenylpropanolamine (PPA), which oxidised with KMnO(4) (potassium permanganate), produces a weak ATS, cathinone, called boltushka. Boltushka's ingredients are easily available in pharmacies or on the black market. IDUs reported a mean age at first use of 16 years old (range 12-21). While published data are scant, anecdotal evidence reported here include amphetamine-like effects on energy and appetite, binging patterns of use, and some reports of shaking and other neurological damage consistent with earlier reports from exposure to KMnO(4). Users reported sharing syringes and other non-sterile injection practices. No users reported specific treatment or prevention programs for boltushka users. CONCLUSIONS: Although Ukrainian government regulations have limited access to precursor chemicals, IDUs have continued to make and use boltushka. The actual extent and demographics of boltushka use are unknown. Besides risk of bloodborne disease, the health effects of injected homemade ATSs and their constituent chemicals are poorly documented. Interventions beyond available harm reduction efforts may be required. Education/treatment specific to boltushka users and screening for other physical harms are critical interventions.

Interrupting activator protein-1 signaling in conscious rats can modify neuropeptide Y gene expression and feeding behavior of phenylpropanolamine.

The mechanism for phenylpropanolamine (PPA)-induced anorexia has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an orexigenic agent abundant in the brain. However, molecular mechanisms behind this effect are not well known. In this study, we investigated whether activator protein-1 (AP-1) signaling was involved. Rats were daily treated with PPA for 4 days. Changes in hypothalamic NPY, c-fos, c-jun, superoxide dismutase (SOD)-1, and SOD-2 mRNA contents were measured and compared. Results showed that c-fos and c-jun mRNA levels were increased following PPA treatment, which were relevant to a reduction in NPY mRNA level. To further determine if c-fos/c-jun genes were involved in PPA anorexia, infusions of antisense oligonucleotide into cerebroventricle were performed before daily PPA treatment in freely moving rats. Results showed that either c-fos or c-jun knock down could block PPA anorexia and restore NPY mRNA content to normal level. It is suggested that AP-1 signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of NPY gene expression. Moreover, this modulation might be partly because of the neuroprotective effect of AP-1 since SOD gene was activated during PPA treatment.

Antimuscarinic agents exhibit local inhibitory effects on muscarinic receptors in bladder-afferent pathways.

OBJECTIVES: To investigate the potential of antimuscarinic agents for sensory mechanisms in overactive bladder using intravesical instillation. METHODS: Antimuscarinic agents were instilled intravesically in rats using two protocols. In the high-dose protocol, 5 mg atropine, oxybutynin, and dimethindene (M2-selective muscarinic receptor antagonist) were instilled into the bladder, and cystometric parameters, such as bladder capacity, intercontraction interval, pressure threshold, and maximal voiding pressure were monitored. In the low-dose protocol, 0.1 and 0.5 mug/mL oxybutynin, trospium, tolterodine, and dimethindene were continuously infused into the bladder. The doses chosen were based on the calculated urine-excreted concentrations of trospium typically achieved from human oral treatment of 40 mg/day. The effect of carbachol with and without the low-dose agents was then assessed. RESULTS: With the high-dose protocol, bladder capacity, intercontraction interval, and pressure threshold were increased when atropine and oxybutynin were instilled, but not when dimethindene was used. The maximal voiding pressure was not affected by any of the agents tested. In the low-dose protocol, none of the cystometric parameters were altered with antimuscarinic agents alone. The intercontraction interval decreased with intravesical carbachol (65% +/- 0.1% compared with baseline), but this was prevented with concomitant antimuscarinic agents. CONCLUSIONS: We have separated the local inhibitory effects of antimuscarinic agents during the storage phase from a decrease in voiding pressure. Intravesical instillation of antimuscarinic agents at clinically meaningful concentrations also suppressed carbachol-induced bladder overactivity. Antimuscarinic agents may be effective in treating overactive bladder, not only by suppression of muscarinic receptor-mediated detrusor muscle contractions, but also by blocking muscarinic receptors in bladder-afferent pathways.

Influence of a combination of herbs on appetite suppression and weight loss in rats.

AIM: We evaluated the ability of a Chinese herbal formulation previously associated with weight loss to influence appetite and weight loss in a carefully controlled laboratory study performed on rats. As a secondary gain, results with this herbal formulation were compared with those from a commonly available phenylpropanolamine (PPA) compound. DESIGN: Eight rats were placed in each arm of a three-arm study, a total of 24 rats. All rats were gavaged with a 2-ml fluid volume containing no addition (control) or the two test substances (combined herbs or PPA) for the first 4 days of the week over 6 consecutive weeks; no gavages were given over weekends. Rats in the two-test groups were given a relatively low dose of the test substance for 3 weeks, followed by a higher dose over the next 3-week periods. Food and water intake were measured for 24-h periods over the ensuing week days. The average daily values for food and water intake for an individual rat were calculated on the basis of collected data over each 3-week period. The mean values for each rat obtained over the low- and high-dose periods comprised results from averaging at least 10 measurements. RESULTS: Average daily food intake was decreased only with the herbal formulation, not the PPA compound at the low and high doses. Both the PPA compound and the herbal formulation lowered water intake significantly at the low and high doses. Rats ingesting the herbal formulation at the lower dose had statistically significant lower daily body weight changes over the 3 weeks than those ingesting the PPA compound. At the higher dose, body weight changes for both agents were significantly less than the control, but not significantly different from each other. No evidence of toxicity was seen in the blood chemistries or after histopathological examination. CONCLUSIONS: Data collected on rats suggest that the herbal formulation examined might be a useful and safe combination to overcome the overweight state and obesity.

Phenylpropanolamine inhibits feeding, but not drinking, induced by hypothalamic stimulation.

In rats bearing lateral hypothalamic electrodes that elicited both feeding and drinking, intraperitoneal injection of the appetite suppressant drug phenylpropanolamine (Propadrine) inhibited only feeding. This occurred whether feeding and drinking were tested simultaneously or separately. Selective inhibition of lateral hypothalamic feeding also followed injection of this drug through lateral, but not medial, hypothalamic electrode cannulas. We conclude that hypothalamically induced feeding is under some of the same pharmacological controls as spontaneous feeding, that this control may be exerted, in part, in or near the lateral hypothalamus, and that the neural systems which induce feeding and drinking during hypothalamic stimulation can be pharmacologically separated.