Preliminary evaluation of a new controlled-release oxybutynin in urinary incontinence

OBJECTIVE: To conduct a preliminary evaluation of a new oral formulation of controlled-release (CR) oxybutynin tablet taken once-daily in patients with urinary urge incontinence. RESEARCH DESIGN AND METHODS: A single-centre, open-label, 8-week study was conducted. Patients with urodynamically-confirmed detrusor instability, micturition frequency (>/= 8 voids/day) and/or urinary incontinence (>/= 2 incontinence periods/day) were enrolled. The study duration was 8 weeks: patients received IR oxybutynin (2.5-5 mg bid) for 2 weeks, followed by a 2-week washout/baseline period to avoid carryover effects, and oral CR oxybutynin (15 mg OD) for 4 weeks. Daily void frequency, fluid intake, urinary incontinence episodes, and spontaneously reported adverse events were recorded in a daily diary for five consecutive days in each treatment period. RESULTS: Of 12 enrolled patients, 9 patients efficacy; all patients were evaluable for safety. completed the study and were evaluable for Compared to baseline/washout, CR oxybutynin reduced UI episodes/day by 45% (p = 0.13) and micturitions/day by 15% (p = 0.07). Treatment with IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day) reduced UI episodes/day from baseline by 7% (p = 0.58) and voids/day by 6% (p = 0.29). Fluid intake remained consistent at approximately 2 litres/day during all study periods. The most common adverse event was dry mouth. CONCLUSIONS: Based on the reductions in daily frequency of incontinence and micturition following 4-weeks treatment, CR oxybutynin (15 mg OD) was at least as effective as the patients' previous dose of IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day). These improvements were achieved without restriction of fluid intake. Initial 15 mg doses of CR oxybutynin appear to be well tolerated.     

Oxybutynin extended-release: a review of its use in the management of overactive bladder

The OROS-based oxybutynin extended-release (ER) formulation (Lyrinel XL; Ditropan XL) represents a new form of oral delivery for oxybutynin, a muscarinic receptor antagonist used in the treatment of overactive bladder (OAB). The release of oxybutynin from oxybutynin ER occurs in a sustained manner, resulting in a smoother plasma concentration-time profile and a lower maximum plasma concentration than those seen with oxybutynin immediate-release (IR). The ER formulation has been developed with the aim of improving the tolerability of oxybutynin therapy and facilitating once-daily administration. Moreover, oxybutynin ER offers greater flexibility in dosage (5-30 mg/day) than the other available treatment options. At dosages of 5-30 mg once daily, oxybutynin ER produced significant decreases from baseline in weekly urinary urge incontinence in patients with OAB. In addition, there were significant decreases in weekly total incontinence episodes and micturition frequency. In two randomised, double-blind studies in patients with OAB, the improvement in all the symptoms with once-daily oxybutynin ER 5-30 mg/day was similar to that produced by oxybutynin IR 5-20 mg/day given one to four times daily. Once-daily oxybutynin ER 10 mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations. Oxybutynin ER was well tolerated in all the trials, with adverse events usually being mild to moderate and transient. In direct comparisons, the overall tolerability profile of oxybutynin ER was better than that of oxybutynin IR. Oxybutynin ER was similar to tolterodine (IR and ER) with respect to the incidence of clinically important dry mouth. A large 12-month tolerability study demonstrated no significant risks associated with the long-term use of oxybutynin ER. A few noncomparative studies have shown promising results with oxybutynin ER in the treatment of adult and paediatric patients with neurogenic bladder dysfunction secondary to neuronal injury. Long- and short-term studies have reported significant improvements in health-related quality of life with oxybutynin ER therapy. In addition, pharmacoeconomic studies have suggested that oxybutynin ER is more cost effective than oxybutynin IR and at least as cost effective as tolterodine IR. In conclusion, oxybutynin ER shows excellent efficacy in the treatment of symptoms associated with OAB in adults and the elderly with a good tolerability profile over a prolonged period of use (12 months). The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability profile and dosage flexibility, oxybutynin ER provides an excellent treatment option in the first-line pharmacotherapy of OAB.     

Treatment of Overactive Bladder with Once-daily Extended-release Tolterodine or Oxybutynin: The Antimuscarinic Clinical Effectiveness Trial (ACET)

Summary

Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2?mg or 4?mg of once-daily extended-release tolterodine (TER), and in the other to 5?mg or 10?mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2?mg, n?=?333; TER 4?mg, n?=?336) and 620 in the oxybutynin trial (OER 5?mg, n?=?313; OER 10?mg, n?=?307). Fewer patients prematurely withdrew from the trial in the TER 4?mg group (12%) than either the OER 5?mg (19%; p?=?0.01) or OER 10?mg groups (21%; p?=?0.002). More patients in the OER 10?mg group than the TER 4?mg group withdrew because of poor tolerability (13% vs 6%; p?=?0.001). After 8 weeks, 70% of patients in the TER 4?mg group perceived an improved bladder condition, compared with 60% in the TER 2?mg group, 59% in the OER 5?mg group and 60% in the OER 10?mg group (all p?<?0.01 vs TER 4?mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4?mg 77% vs OER 10?mg 65%; p?<?0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5?mg vs OER 10?mg; p?=?0.05). Patients treated with TER 4?mg reported a significantly lower severity of dry mouth compared with OER 10?mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4?mg suggests improved clinical effectiveness compared with oxybutynin ER 10?mg.     

Onset of efficacy of tolterodine extended release in patients with overactive bladder*

ABSTRACT

Objective: To assess the onset of efficacy of tolterodine extended release (ER) in patients with overactive bladder (OAB).

Research design and methods: A post hoc analysis was conducted using 3-day bladder diary data from a 12?week, multicenter, prospective, open-label study of tolterodine ER (4?mg qd) in patients (aged ≥ 18 years) with urinary frequency (≥ 8 micturitions/24?h) and urgency (strong and sudden desire to urinate) with or without urgency urinary incontinence (UUI).

Main outcome measures: Changes in micturition frequency, urgency, and UUI episodes/24?h were evaluated for treatment Days 5, 6, and 7. The percentages of patients who achieved normal micturition frequency (< 8/day) and 50%, 70%, 90%, and 100% reductions in urgency and UUI episodes (i.e., responders) were determined at Days 5, 6, and 7. Week 12 data are presented as a referent for the magnitude of treatment efficacy during Week 1.

Results: This analysis included 698 patients. On Day 5, there were significant reductions in all three diary variables (all p < 0.0001), and improvements continued on Days 6 and 7. More than half of the patients reported ≥ 50% reductions in urgency or UUI episodes on Day 5. Responder rates for all three symptoms increased through Week 12.

Conclusions: Patients with OAB experienced significant reductions in OAB symptoms as early as Day 5 of treatment with tolterodine ER. These data extend the findings of a previous analysis, in which all 3 days of the bladder diary were pooled, that demonstrated improvements in micturition frequency, urgency episodes, and UUI episodes in patients with OAB after 1 week of treatment with tolterodine ER. Limitations are that efficacy was not assessed before Day 5, this was a post hoc analysis, and the study was not placebo-controlled.     

An evaluation of patient and physician satisfaction with controlled-release oxybutynin 15 mg as a one-step daily dose in elderly and non-elderly patients with overactive bladder: results of the STOP study

Abstract Objective: Evaluate patient and physician satisfaction with a novel formulation of a once-daily controlled-release (CR) oxybutynin (Uromax * *Uromax is a registered trade-mark of Purdue Pharma, Pickering, Ontario, Canada ) 15-mg tablet as both the initial and maintenance dose in elderly and non-elderly patients with overactive bladder (OAB). Methods: Patients not on anticholinergic treatment for OAB and experiencing urinary incontinence (≥1 episode/week) and micturition frequency (≥8 episodes/day) or urgency (≥1 episode/week) were enrolled in this 4-week, open-label study. Satisfaction, efficacy, mental status and adverse events were evaluated by urologists, gynecologists, urogynecologists and family practitioners. The analyses compared the outcomes in patients <65 and ≥65 years. Clinical trial registration: ISRCTN 19242032. Results: A total of 240 patients enrolled; 111 (46%) were ≥65 years of age. Completion rate was 76.0% (<65) and 62.2% (≥65) (p?=?0.0204). Medication was rated as tolerable by 75.2% of patients <65 and 58.6% of patients ≥65 (p?=?0.0099). Based on overall satisfaction scores 64.2% (patient scores) and 57.1% (physician scores) of patients were considered 'successfully treated' (p?=?0.0001 & p?=?0.0451). There was a significant reduction in incontinence (64.3%; p?=?0.0001), nocturia (38.6%; p?=?0.0001) and night-time incontinence (39.7%; p?=?0.0436) with no difference between age groups. Total continence was achieved by 29.8% and 47.5% of patients <65 and ≥65, respectively (p?=?0.0077). No patients clinically experienced confusion or delirium and only six patients ≥65 had a decrease in MMSE score of ≥3 units, which was not statistically different from patients <65 (p?=?0.3112). Dry mouth was the most common adverse event reported by 24.8% of patients <65 and 36.0% of patients ≥65 (p?=?0.0584). Limitations of the study include a fixed dosing, no control group and 4-week trial. Conclusion: Patients and physicians were satisfied with CR oxybutynin 15?mg once-daily. Patients tolerated the CR oxybutynin 15?mg as both the initial and maintenance dose and provided significant reductions in incontinence, nocturia and night-time incontinence without a significant change in cognitive status. Total continence rates were significantly superior in patients ≥65 and there was no difference in dry mouth, cognitive status or efficacy in patients <65 and ≥65.     

Impact of solifenacin on resource utilization,work productivity and health utility in overactive bladder patients switching from tolterodine ER

ABSTRACT

Objective: Assess changes in resource utilization, work and activity impairment, and health utility among OAB patients continuing to have urgency symptoms with tolterodine ER 4?mg and willing to try solifenacin 5/10?mg.

Research design and methods: This was an open-label, non-comparative, flexible-dosing, multicenter, 12-week study assessing the efficacy and safety of solifenacin 5/10?mg/day. Patients receiving tolterodine ER 4?mg/day for ≥4 weeks but continuing to experience residual urgency symptoms (≥3 urgency episodes/24?h) were enrolled into the study. After a 14-day washout, patients began treatment with solifenacin 5?mg/day with dosing adjustments allowed at Weeks 4 and 8.

Main outcome measures: Outcomes were assessed using the Work Productivity and Activity Impairment Questionnaire?–?Specific Health Problem (WPAI-SHP), Health Utilities Index (HUI), and a resource utilization questionnaire administered at Pre-Washout and Week 12.

Results: Patients (n?=?440) reported significantly fewer physician office visits (p?<?0.0001), UTIs (p?<?0.0001), and pads/diapers (p?=?0.0009) during the study period while receiving solifenacin 5/10?mg/day, compared with the Pre-Washout period when receiving tolterodine ER 4?mg/day. After 12 weeks of treatment with solifenacin 5/10?mg/day, patients reported a reduction in work time missed (p?=?0.0017), less impairment while working (p?<?0.0001), less overall work impairment (p?<?0.0001) and a reduction in activity impairment (p?<?0.0001) compared to Pre-Washout. There was no significant difference in health utility scores. Treatment-emergent adverse events were mostly anticholinergic in nature, and were mild to moderate in severity.

Conclusion: Overall, solifenacin 5/10?mg/day improved work productivity, activity participation, and reduced medical care use in OAB patients who continued to have urgency symptoms with tolterodine ER 4?mg/day and wished to switch to solifenacin 5/10?mg. This was an open-label, non-comparative study; therefore, further research is needed to confirm these results.     

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms

Objective: To assess the characteristics of tolterodine extended-release (ER) 4?mg responders and suboptimal responders (≤50% decrease in UUI episodes/24?h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8?mg in tolterodine suboptimal responders.

Methods: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24?h at week ?2 received open-label tolterodine ER 4?mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4?mg for 1 week, 8?mg for weeks 2–12) or placebo once daily. Post-hoc analyses compared the percentage change from week ?2 to week 0 in UUI episodes/24?h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8?mg among tolterodine suboptimal responders.

Results: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24?h at week ?2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24?h after tolterodine treatment at week 0 (80.0% versus 15.3%; p?p?=?.0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response.

Conclusions: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8?mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.     

Overactive bladder in women: symptom impact and treatment expectations

ABSTRACT

Objective: The objectives of this survey were to understand (1) the effects of overactive bladder (OAB) and urinary incontinence (UI) on women's lives and to understand (2) women's needs and expectations of health care providers and treatment related to these disorders.

Methods: Women (N = 1046) with self-reported symptoms of UI completed a survey via electronic mail about the impact of urinary symptoms, health care provider interactions, treatment practices and expectations, and co-morbid conditions.

Results: The majority of women rated urinary symptoms such as frequency (61%), urgency (80%), nocturia (72%), and UI (69%–88% by type of incontinence) as moderately or extremely bothersome. Over half of women with UI (55%) had not sought medical treatment, but instead used a variety of non-medical coping mechanisms for symptom management. More than one third of women (37%) would prefer that their health care provider initiate discussion about urinary symptoms. Approximately half of the women with UI in this survey desired a greater than 70% reduction in incontinence episodes in order to consider treatment effective.

Conclusion: Women are making an effort to cope with disruptive symptoms of OAB. However, a communication gap between health care providers and patients with urinary symptoms may be a barrier to appropriate medical therapy. Health care providers should routinely query patients about urinary symptoms. In addition to choosing a medical treatment that can produce a meaningful reduction in symptoms, health care providers should set expectations for patients and monitor patient satisfaction with the prescribed treatment regimen.     

Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5 mg

ABSTRACT

Background: Overactive bladder (OAB) is a highly prevalent symptom complex that may be extremely distressing to the patient, and can be associated with co-morbidities and reduced quality of life (QoL). One of the major pathophysiological causes of OAB is overactivity of the detrusor muscle, mediated via muscarinic receptors in the bladder. Urgency is the defining symptom of OAB, yet a significant proportion of patients also suffer from incontinence, which is the most distressing symptom to the patient. As such, restoration of continence should be a primary treatment goal. However, effective treatments should also impact on the other key symptoms of OAB, such as micturition frequency and urgency. Non-pharmacologic interventions to treat OAB can be effective but require patients to be highly motivated. In terms of pharmacologic therapy, treatment with an antimuscarinic agent is the mainstay of current therapy. Solifenacin succinate is a once-daily oral antimuscarinic for the treatment of OAB. The recommended dose is 5?mg once daily and can be increased to 10?mg once daily if 5?mg is well tolerated.

Objectives: This paper reviews clinical experience with solifenacin 5?mg in patients with OAB as this is the recommended dose according to FDA product labeling.

Findings: In Phase 3 studies, based on data captured in 3-day micturition diaries, greater than half of patients who were incontinent at baseline no longer reported experiencing incontinence episodes after 12 weeks of double-blind treatment with solifenacin 5?mg. Furthermore, compared with placebo, solifenacin treatment resulted in statistically significant reductions in incontinence episodes, micturition frequency and urgency episodes, with significant increases in volume voided (based on an analysis of key symptom outcomes in two pooled Phase 3 studies presented here). The most common treatment-related adverse events were expected anticholinergic side effects (dry mouth, constipation, and blurred vision), and these were generally mild to moderate. Discontinuation rates due to adverse events in the treatment and placebo groups were comparable.

Conclusion: Solifenacin 5?mg was found to be efficacious and had an acceptable tolerability profile in patients with OAB in these trials and this treatment may provide QoL benefits to patients.     

Clinical efficacy of controlled-release oxycodone 20 mg administered on a 12-h dosing schedule on the management of postoperative pain after breast surgery for cancer

SUMMARY

Objective: To assess clinical efficacy of controlled-release oxycodone (CRO) 20?mg on a 12-h dosing schedule in this prospective, randomised, placebo-controlled, double-blinded study of 40 ASA physical status I-III women undergoing breast surgery for cancer.

Research design and methods: General anaesthesia using remifentanil and propofol was performed for surgery. Both groups received premedication with oral midazolam 7.5?mg 1?h before surgery. In the controlled-release oxycodone group, one tablet of 20?mg CRO was administered with the premedication, and 12?h after the premedication another 20?mg CRO. In the placebo (PL) group, a placebo tablet was administered with the premedication, and 12?h later another placebo tablet. All patients had access to opioid rescue medication via an IV patient-controlled analgesia (PCA) device.

Main outcome measures: Area under the curve (AUC), based on IV opioid rescue consumption over 24?h postoperatively.

Results: The AUC for IV PCA opioid consumption was significantly lower in the CRO group than in the PL group (p?=?0.01). The CRO group required less IV opioid loading dose (p?<?0.001), and consumed less opioid rescue medication 4h (p?=?0.036), 16h (p?=?0.01), and 24?h (p?=?0.005) postoperatively. AUC for VAS scores at rest was significantly lower in the CRO group than in the PL group (p?=?0.05). VAS scores at rest were lower in the CRO group 16?h (p?=?0.04) and 24h (p?=?0.03) postoperatively. There was no difference in AUC for pain scores on movement (p?=?0.103) and for quality of analgesia (p?=?0.139). There was no difference in nausea between groups (p?=?0.34). Pruritus, arterial hypotension or hypertension, bradycardia, and tachycardia were not observed in either treatment group. None of the patients showed signs of confusion, agitation, or respiratory depression.

Conclusion: The administration of CRO 20?mg on a 12-h dosing schedule halves postoperative IV PCA opioid consumption. CRO 20mg is effective in preventing pain after breast surgery for cancer with only mild side-effects.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.     

Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus

SUMMARY

Aim: This Swiss multicentre study examined the efficacy and safety of oral pioglitazone in patients with type 2 diabetes.

Methods: Patients were randomised to pioglitazone at once-daily doses of 30mg for 20 weeks (n?=?76), 30?mg for 12 weeks followed by 45?mg for 8 weeks (n?=?74), or 45?mg for 20 weeks (n?=?84); 94.9% of patients completed 12 weeks and 88.9% completed all 20 weeks. Almost all (96.6%) patients received pioglitazone in combination with other anti-diabetic treatments.

Results: Mean HbA1c at baseline was 8.8?±?1.2%, and changes to endpoint were ?1.1?±?1.1%, ?1.1?±?1.4% and ?0.9?±?1.6%, respectively for the three dose groups (p?<?0.001 for each group). Triglyceride concentrations decreased in each group and the overall mean change during the study was ?0.58?mmol/l (p?<?0.001 versus baseline). HDL-cholesterol increased, with an overall mean change of 0.10?mmol?l^?1 (p?<?0.001 versus baseline). Blood pressure decreased from baseline, particularly for hypertensive patients with mean changes: systolic -10mmHg, p?<?0.001, diastolic-8mmHg, p?<?0.001 versus baseline. Serum alanine aminotransferase and γ-glutamyl transferase concentrations were significantly (p?<?0.001 for each) reduced during the study.

Conclusions: The study demonstrates the efficacy of pioglitazone 30?mg?day^?1 and 45?mg?day^?1 in the treatment of type 2 diabetes, with an improved lipid profile and decreased blood pressure in addition to improved glycaemic control.     

Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats

Context: Hypericum perforatum Linn. (Hypericaceae) (St. John’s wort) attenuates opium withdrawal signs.

Aim: To explore the therapeutic potential of Hypericum perforatum in the management of opium-induced withdrawal syndrome.

Materials and methods: The effect of the Hypericum perforatum hydro-ethanol extract was investigated for potential to reverse naloxone (0.25?mg/kg)-induced opium withdrawal physical signs. Rats received opium extract (80–650?mg/kg) twice daily for 8 days along with Hypericum perforatum (20?mg/kg, orally) twice daily in chronic treatment and the same single dose 1?h before induction of withdrawal syndrome in the acute treated group.

Results: Hypericum perforatum reduced stereotype jumps and wet dog shake number in the chronic treatment compared to the saline control group (F(2, 24)?=?3.968, p?F(2, 24)?=?3.689, p?F(2, 24)?=?4.850, p?F(2, 24)?=?4.88, p?F(2, 240?=?5.364, p?F(2, 24)?=?4.907, p?Discussion and conclusion: This study reveals that the extract of Hypericum perforatum attenuates some physical signs of opium withdrawal syndrome possibly through direct or indirect interaction with opioid receptors. Further study is needed to clarify its mechanism.     

Nephro-protective potential of Morus alba,a prospective experimental study on animal models

Context: Morus alba L. (Moraceae) is traditionally used for the treatment of urinary incontinency due its strong diuretic properties.

Objective: The present study explores the renal protective effects of M. alba, due to its free radical scavenging properties, in order to provide experimental evidence for its established use.

Materials and methods: Ethanolic extract (200?mg/kg/d) derived from M. alba fruit was employed in rabbits as a co-therapy (GM-al) with gentamicin (80?mg/kg/d) for a period of 3?weeks. Biochemical kidney functioning parameters, urinary isozymes, and histopathological examination were performed.

Results: The results showed that ethanol extract of Morus alba L. prevented alterations in serum creatinine (4.02?±?0.14, p?<?0.0001), blood urea nitrogen (54.18?±?2.60, p?<?0.0001), and serum uric acid levels (2.34?±?0.12, p?<?0.001). However, a decrease in creatinine clearance and urinary volume was observed in experimental groups. Histopathological examination and urinary enzymes excretion also suggested the protective role of the extract.

Discussion and conclusions: The co-administration of M. alba with gentamicin prevented renal functioning alterations expected with the use of gentamicin alone. Therefore, it can be concluded that M. alba to protect from kidney damage, which may be because of its free radical scavenging and diuretic properties.     

A randomized,double-blind,placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain

ABSTRACT

Objective: To evaluate the relative efficacy and tolerability of tapentadol immediate release (IR) and oxycodone IR for management of moderate to severe pain following orthopedic surgery (bunionectomy).

Methods: Randomized patients (N?=?901) received oral tapentadol IR 50 or 75?mg, oxycodone HCl IR 10?mg, or placebo every 4–6?h over a 72-h period following surgery. Acetaminophen (≤2?g) was allowed in the first 12?h after the first dose of study drug. In the primary analysis, tapentadol IR (50 and 75?mg) was evaluated for efficacy superior to placebo and non-inferior to oxycodone HCl IR 10?mg (using sum of pain intensity difference [SPID] over 48?h), and tolerability superior to oxycodone IR (using incidence of treatment-emergent adverse events [TEAEs] of nausea and/or vomiting).

Results: Statistically significantly higher mean SPID₄₈ values were observed with tapentadol IR (50 and 75?mg) and oxycodone HCl IR 10?mg than placebo (all p?<?0.001). The efficacy of tapentadol IR 50?mg and 75?mg was non-inferior to oxycodone HCl IR 10?mg. The incidence of TEAEs of nausea and/or vomiting was statistically significantly lower with tapentadol IR 50?mg versus oxycodone IR 10?mg (35 vs. 59%; p?<?0.001). No statistically significant difference in the incidence of nausea and/or vomiting was observed between tapentadol IR 75?mg and oxycodone IR 10?mg (51 vs. 59%; p?=?0.057). A possible limitation of this study was that the intense dose and patient monitoring may not represent real-world situations and may result in higher incidences of TEAEs than expected in a practice setting; this bias would be similar for all treatment groups.

Conclusions: Clinically meaningful and statistically significant improvements were observed with tapentadol IR 50?mg and 75?mg compared with placebo for the relief of moderate-to-severe acute pain after orthopedic surgery. Tapentadol IR 50?mg and 75?mg were non-inferior to oxycodone HCl IR 10?mg for the treatment of acute pain based on the primary efficacy endpoint of SPID₄₈ and the pre-specified margin of 48 points. The incidence of nausea and/or vomiting was statistically significantly lower for tapentadol IR 50?mg and numerically lower for tapentadol IR 75?mg than for oxycodone HCl IR 10?mg.     

Hypocholesterolemic efficacy of royal jelly in healthy mild hypercholesterolemic adults

Context: Royal jelly (RJ) has been reported for its health promoting factors such as antioxidant, anti-inflammatory and lipid lowering activities.

Objective: The present randomized, placebo-controlled study examines the hypolipidemic beneficial effect of RJ through evaluating anthropometric measurements, lipid profile and various hormone levels in mildly hypercholesterolemic participants.

Materials and methods: Forty subjects with mild hypercholesterolemia (180–200?mg/dL) were randomly selected and divided into two groups as experimental or placebo, who requested to intake nine capsules (350?mg/capsule) of RJ or placebo/day, respectively, for three months with one month of follow-up without any supplementation.

Results: No significant changes were noted in any of the anthropometric parameters like body weight, waist and body fat. The serum total cholesterol (TC; 207.05–183.15?mg/dL) and low-density lipoprotein cholesterol (LDL-c; 126.44–120.31?mg/dL) levels were reduced significantly (p?p?Discussion and conclusion: Intervention with RJ for three months considerably lowered the TC and LDL-c levels through improving the levels of DHEA-S and thus alleviates the risk of cardiovascular disease (CVD).     

Acute effects of caffeine on choroidal thickness and ocular pulse amplitude

Objective: To explore ocular changes in healthy people after caffeine consumption.

Methods: This prospective observational study was carried out with students of the Turgut Özal University Medical Faculty from May 15 to 15 December 2014. Enrolled in the study were 17 healthy subjects (n?=?17 eyes), with a median age of 24 (IQR 1), ranging between 21 and 26 years. The control group (6 females, 11 males) aged between 23 and 28 (median 25 years [IQR 4.75]). For study, one eye from each participant was randomly selected. To obviate the effect of diurnal variations, tests were performed at the same time of the day (10:00?a.m.–12:00?p.m.). Each subject was given an ophthalmologic examination before the study to exclude those with undiagnosed ocular disease. Version 6.0 Cirrus high-definition optical coherence tomography (HD-OCT) (Carl Zeiss Meditec, Dublin, CA) was used to measure CT at the fovea, and 1500?μm nasal and 1500?μm temporal to the fovea. After baseline OCT measurements, participants were asked to have 200?mg oral caffeine intake or a placebo capsule (200?mg lactose powder). Two further OCT measurements were applied at the first and fourth hours of caffeine intake. All participants also had intraocular pressure (IOP) and ocular pulse amplitude (OPA) measurements recorded before, first and fourth hours of caffeine intake. IOP and OPA were measured using the dynamic contour tonometry (DCT) (Swiss Micro Technology AG, Port, Switzerland).

Results: The groups showed no significant difference by means of age, gender, spherical refraction and axial length (p?>?0.05). Baseline choroidal thickness measurements of the study and control group showed no significant difference. Oral caffeine intake caused a significant reduction in choroidal thickness compared with baseline, at all three measurement points, (p?<?0.05). There were no significant changes in IOP and OPA measurements compared with the baseline values (p?>?0.05). The choroidal thickness still continued to decrease for at least 4?h following caffeine intake; whereas, the difference between 1 and 4?h was not statistically significant (p?>?0.05). However, choroidal thicknesses, IOP and OPA values of the control group revealed no significant difference at all points when comparing measurements at baseline with 1 and 4?h after placebo intake (p?>?0.05).

Conclusions: We found no significant change in IOP and OPA following oral 200?mg caffeine intake, while CT significantly decreased, for at least 4?h.     

Effect of curcumin in mice model of vincristine-induced neuropathy

Abstract

Context: Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity.

Objective: The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model.

Materials and methods: Vincristine sulfate (0.1?mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14?d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10?mg/kg, p.o.) and curcumin (15, 30, and 60?mg/kg, p.o.) were administered for 14 consecutive days.

Results: Curcumin at 60?mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p?<?0.001) and allodynia (p?<?0.001); mechanical hyperalgesia (p?<?0.001); functional loss (p?<?0.001); and in the delayed phase of formalin test (p?<?0.001). Curcumin at 30 and 60?mg/kg exhibited significant changes (p?<?0.001) in antioxidant levels and in total calcium levels in vincristine-injected mice.

Conclusion: Curcumin at 30 and 60?mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.     

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes

Background: Miyazaki etal, demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n?=?23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment-Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations.

Study aim: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (～1000).

Research design and methods: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We

evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI.

Results: PIO 15, 30 and 45?mg enhanced HOMA-S compared with baseline (56.9-63.6%, p?=?0.0298); (53.7-64.7%, p?=?0.0008); (59.0-75.9%, p?<?0.0001), respectively. Only the 45?mg dose showed a difference from placebo (p?=?0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p?=?0.0026); (0.287-0.299, p?=?0.0001); (0.290-0.306, p?=?0.0001), respectively. Both the 30 and 45mg doses were different from placebo for QUICKI (p?=?0.0005, p?<?0.0001). PIO 15 and 30mg plus SU enhanced HOMA-S compared with baseline (58.4–.7%, p?=?0.0007; 53.2–68.4%, p?<?0.0001) and placebo plus SU (p?=?0.0129, p?<?0.0001, respectively). Likewise, PIO 15 and 30?mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p?=?0.0001; 0.287-0.305, p?=?0.0001, respectively). Both doses had different effects from placebo plus SU (p?=?0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2–82.2%, p?<?0.0001) and placebo plus MET (p?=?0.0002).     

Neuronal protective effect of Songling Xuemaikang capsules alone and in combination with carbamazepine on epilepsy in kainic acid-kindled rats

Context: Epilepsy is a common life-threatening neurological disorder that is often drug-resistant and associated with cognitive impairment. The traditional Chinese patent medicine Songling Xuemaikang capsules (SXC) is clinically used for epilepsy therapy and alleviation of cognitive impairment.

Objective: This study investigates the neuronal protective effect of SXC combined with carbamazepine (CBZ) on epilepsy and cognitive impairment in kainic acid-kindled SD rats.

Materials and methods: Kainic acid-kindled rats were established by injection of 0.45?μg kainic acid and randomly divided into 5 groups (n?=?14): saline (sham-operated), control, CBZ, SXC and CBZ?+?SXC combined group. Rats in the treatment groups received CBZ (50?mg/kg/d), SXC (600?mg/kg/d) or combined CBZ (50?mg/kg/d)?+?SXC (600?mg/kg/d) via intragastric injection for 60?days. Epileptic behaviours, cognitive impairment, neuronal apoptosis and expression of p-Akt, Akt and caspase-9 were measured, and the alleviation of cognitive damage and neuronal apoptosis was analyzed.

Results: The combined administration of SXC and CBZ significantly decreased the frequency of seizures (1.2?±?0.3) and the number of episodes (1.3?±?0.5) above stage III (p?p?p?p?p?Conclusions: The present findings confirm that the combined use of SXC with CBZ can effectively control epileptic seizures, alleviate damage to hippocampal neurons and protect against cognitive impairment. The mechanism of action might be related to the upregulation of p-Akt and inhibition of caspase-9 expression.