Effects on Urinary Incontinence and Overactive Bladder
Tracey Seipel, ND
Bladder Issues affect one in five Americans. The National Institute of Health estimates 17 million Americans can medically be diagnosed with urinary incontinence (UI). An estimated 33 million Americans suffer with overactive bladder (OAB).1 In addition to urinary urgency, frequency and nocturesis, one in three cases of OAB also experience urge incontinence.
The current medical treatment options for urinary incontinence and overactive bladder include behavioral interventions (e.g., bladder control training), drug medications, devices (e.g., catheters), and surgical procedures. Current drug therapy includes anticholinergics (with antispasmodic effects, e.g., oxybutinin), smooth muscle relaxants (antispasmodics), tricyclic antidepressants (e.g., imipramine), alpha-adrenergic antagonists, alpha-adrenergic agonists (e.g., phenylpropanolamine), antimuscarinics (e.g. solifenacin), prostaglandin synthesis inhibitors, calcium channel blockers and others.2,3,4 Unfortunately, most drug treatments are associated with unpleasant side effects, and this impacts on patient compliance.2,3,4,5,6
In summary, the problem is widespread and affects people of all ages including children and young adults. NAFC (National Association for Continence) estimates on the basis of multiple studies and expert opinion that 25 million adult Americans experience transient or chronic urinary incontinence.7,8
Supporting Bladder Health
UroLogic™ is a proprietary herbal and mineral formula found in Vesteva™ that has been clinically researched to show its effectiveness in supporting the bladder and surrounding tissues and in helping to maintain proper bladder tone. It contains Opteva™, a proprietary extract of Crateva, an Indian herb that is specifically sourced, extracted and tested to ensure quality. A Drug Master File (DMF) has been developed for Opteva™ (Crateva extract) to ensure consistent quality and efficacy of UroLogic.
UroLogic also contains the better-known herb Horsetail (Equisetum arvense), which is standardized for two active components, and the minerals, calcium phosphate, magnesium phosphate and silica. The Horsetail used in UroLogic is extracted using a method that destroys thiaminase-like effect (which would break down thiamine - vitamin B1) in the body; therefore UroLogic will not produce any long-term problems with vitamin B1 deficiency.
UroLogic works by improving the tone of the bladder wall and surrounding area. Both Horsetail and Crateva are documented in traditional texts for use in addressing UI and OAB.9,10,11 In Ayurvedic medicine, Crateva is highly regarded for its use in the management of uropathies.11 In addition, Western traditional texts recommend the use of Equisetum.9,10 Both herbs contain saponins and plant sterols. Crateva contains flavonoids, glucosinolates and the plant sterol, lupeol; while Equisetum contains silica, glycosides (isoquercetin, luteolin, and kaempferol) and the saponin, equisetin.9,10,11,12,13,14
Crateva has been shown in animal studies to increase the tone of both smooth and skeletal muscle in vitro. Animal studies show that 40 days of treatment with Crateva results in hypertonic curves of the urinary bladder when compared to initial curves.14 The term hypertonic refers to a state of greater than normal tension or of incomplete relaxation. Hypotonic refers to defective muscular tone or tension.
Human studies show, in cases of hypotonic bladder due to prostatic hypertrophy, the total bladder capacity increased markedly.14 Crateva administration produced a marked relief of symptoms of frequency, incontinence, pain and retention of urine. Crateva increases the expulsive force of urine, thereby helping effective evacuation. Cystometric studies show conclusively that Crateva significantly decreased residual urine volume and normalizes the tone of the urinary bladder.13
Crateva has anti-inflammatory and antibacterial properties. It has been shown to inhibit acute, sub-acute and chronic inflammations. Isoquercetin, found in Equisetum, is known to have anti-inflammatory effects via inhibition of inflammatory prostaglandins.9,10,11,12,13
The minerals calcium and magnesium are known to support proper nerve and muscular function and electrical transmission. They have been included in UroLogic to assist with general support of electrical nerve transmission and proper tone of the bladder wall and surrounding muscles.
Overactive Bladder (OAB) may occur because of neurogenic (flaccid or spastic) bladder problems, where the damage to nerves can interfere with communication between the bladder and the brain. When this occurs the brain does not receive the message that the bladder is full and urgency, with inadequate time to reach the toilet, can occur. Neurogenic bladder problems can usually be traced to strokes, spinal cord lesions and nerve-debilitating diseases such as Parkinson's and Multiple Sclerosis.15
Some research specifically supports the use of magnesium for bladder problems in women with bladder urgency. A double-blind trial found those women who took 350 mg of magnesium hydroxide (providing 147 mg elemental magnesium) twice per day for four weeks had better bladder control and fewer symptoms than women who took a placebo.16
Support for the benefit of these minerals in bladder problems is also indicated with drugs such as calcium channel blockers that often result in the side effect of urinary incontinence.17 This would imply that the reverse of calcium channel blocking, i.e. supporting the calcium channel and ensuring adequate calcium levels, may assist with symptoms of urinary incontinence.
The phosphate forms of calcium and magnesium are used in UroLogic as these forms are considered to best complement the body’s mineral absorption pathways and enhance the effectiveness of the proprietary blend of Opteva™ and Horsetail. Silica is another important nutrient for bladder health. It is well known for its effects in supporting collagen and connective tissue structure.
Clinical research has shown that the combination of herbs and minerals in UroLogic is the optimal combination and dosage to support proper bladder tone and function in cases of UI associated with aging and with childbirth.19,20
Recent research has suggested that HRT contributes to incidence and worsening of UI as it may weaken the collagen support of the bladder and surrounding area.18 The mechanism of action of UroLogic is considered to be via improving collagen and connective tissue support in the bladder and surrounding area not via anticholinergic effects which are associated with side effects such as dry mouth, dry eyes, blurred vision and memory loss. As such, the therapeutic effects of UroLogic increase over a one to two month period, with 50 percent of trial participants experiencing effects at one month of use and 80-85 percent of trial participants experiencing best effects after two months of use.20
Clinical Trials
A pilot trial assessing the effectiveness of Crateva and Equisetum in reducing the symptoms of urinary incontinence found that it was effective in reducing the symptoms of urinary incontinence, including frequency, nocturia, urgency and bladder discomfort.19
Two further clinical trials have been undertaken to assess the efficacy and safety of UroLogic.
Clinical Trial (Australia)
The first study conducted in Australia assessed the effectiveness of UroLogic on 34 participants (6 males and 28 females) experiencing symptoms of urge incontinence and/or stress incontinence.20
Efficacy was assessed by measuring the frequency of urination during the day and night (nocturia). The impact of incontinence was assessed using 2 validated questionnaires. The Incontinence Impact Questionnaire (IIQ) measures impact on daily activities, such as household chores, physical activity and social activities, and the Urogenital Distress Inventory (UDI) measures physical symptoms such as leakage and urgency. The questionnaires were completed prior to treatment (month 0) and at month 1, 2 and 3 of treatment. All questions are rated on a scale of 0 - 3 (0 - not bothered, 1- slightly bothered, 2 - moderately bothered, 3 - extremely bothered).
The results indicate that, on average, the frequency of urination during the day reduced steadily during the 3 months of treatment. The number of times participants needed to empty the bladder reduced from 12.3 times per day (prior to treatment), to 9.3 times per day (after 1 month) and 7.4 times per day (after 2 months). By month 3 urination frequency reduced to 6.2 times per day, which is within the normal range (Figure 1). 
There was a gradual reduction in night awakenings (Nocturia) from 2.5 times per night initially to 1.8 times, 0.94 times and 0.74 times per night (month 1, 2 and 3 respectively) (Figure 1). Many of the participants were able to sleep though the night after 2 months of treatment.
The results of the UDI and IIQ questionnaires clearly showed that quality of life (assessed through difficulty in doing daily and social activities as well as emotional health and feelings of frustration) are adversely affected by having the symptoms of incontinence. In all areas participants were less bothered (and more confident) in these activities within 4 weeks of treatment, with continual improvement reported throughout the rest of the study.
In conclusion the study found that UroLogic was a suitable and effective treatment for both men and women. Symptom relief occurred after 4 weeks of treatment, with the severity of symptoms reducing further, especially in the 4-8 week period of use. UroLogic was not associated with any adverse reactions.
Clinical Trial (U.S.A.)
A second randomized, double-blind, placebo-controlled, clinical trial was recently completed by the Sphera Research Institute (Los Altos, CA). This 98-participant trial assessed the effectiveness of UroLogic, in reducing the symptoms of overactive bladder (OAB) and urinary incontinence (UI). 20
Subjective quantitative measurements of urinary symptoms were recorded during interview at baseline, month 1 and month 2.
• Frequency of daily urination (daily)
• Frequency of nocturia (daily)
• Frequency of day time incontinence episodes (weekly)
• Frequency of night time incontinence episodes (weekly)
Qualitative measurements of symptoms were assessed by the validated Quality of Life Questionnaires UDI and IIQ (as used in the previous study):
Results showed that participants on the UroLogic treatment demonstrated greater response in reduction of frequency and leakage compared to placebo in these quantitative measures by month 2.20
The total average bothered rating for the UDI decreased in the active and placebo group at month 1, the active group maintained this at month 2, and the placebo group returned to baseline levels. Significant results were seen in specific questions relating to the effect of frequency and leakage. No significant response was seen in the placebo group.
The results of the IIQ indicated that the women on active treatment reported an improvement in quality of life by month 2. The specific areas where quality of life increased was travel and feeling frustrated. There was no significant difference in the placebo group.
The results of this clinical trial will be presented in more detail at the Experimental Biology Conference, San Francisco in April 2006.
Product Safety
The only adverse effect experienced during research was three reported cases of constipation. One of these cases had a history of constipation. In the placebo-controlled research one case of placebo also reported constipation.19,20
During the second placebo-controlled trial mentioned above participants took a vast number of drug medications concurrently with the test product during the study. These had both direct and indirect effects on bladder function.20 The most common side effect on the bladder for many of these medications is urinary frequency. The study showed significant reduction in urinary frequency highlighting that the product can be used concurrently with drug medications and still produce a therapeutic effect. As most of the target populations for this product are likely to be taking other medications, this research shows that positive therapeutic results may still be experienced by these people. The results from the study indicated that UroLogic had a therapeutic effect even with a concurrent ingestion of other medication.
Further Research
Antioxidant studies (ORAC, HORAC, NORAC, SOD and ROS)
Recent laboratory testing has shown UroLogic demonstrates a broad antioxidant activity. Results of ORAC, HORAC and NORAC testing indicated very high antioxidant activity (value per gram greater than blueberries) and further in-vitro studies demonstrated a substantial inhibitory effect on the Reactive Oxygen Species (ROS) formation in human neutrophil (white blood) cells. Further measurement of anti-oxidant activity was shown via testing for SOD (superoxide dismutase) activity where UroLogic™ produced low, yet confirmed antioxidant SOD activity.
Human cytochrome P450 in vitro testing
Testing of UroLogic on immortalized hepatocytes showed that in vitro UroLogic does not interfere with liver enzymes involved in drug metabolism.
Toxicology – in vitro
The genotoxic effect of UroLogic was studied using Bacterial Reverse Mutation Test. The study indicated that UroLogic is not mutagenic up to the highest tested concentration of 5000 mg/plate in the 6 strains tested, with confirmation.
References
1.Tubaro A. Defining Overactive Bladder: Epidemiology and Burden of Disease., J.Urology, Dec 20, 2004.
2. Sullivan and Abrams, Eur. Urol., 36 Suppl 1:89-95 (1999).
3. Andersson, Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14(2):291-313 (2000).
4. Owens and Karram, Drug Saf., 19(2):123-39 (1998); Wada et al., Arch. Int. Pharmacodyn Ther. 330(1):76-89 (1995).
5. Wada et al., Comparison of the effects of various anticholinergic drugs on human isolated urinary bladder. Arch. Int. Pharmacodyn Ther. 330(1):76-89 (1995)2-5.
6. Apell R. The newer antimuscarinic drugs: Bladder control with less dry mouth. Cleveland Clinic Journal of Medicine. Vol 69. No 10. October 2002.
7. Resnick, NM, Improving treatment of urinary incontinence (commentary letter). JAMA. 1998;280 (23):2034-2035.
8. http://www.nafc.org/about_incontinence/what_incontinence.htm, National Association For Continence. “What is incontinence?” accessed: 31st Jan, 2006.
9. The Complete German Commission E Monographs. 1998, Blumenthal, M., ed., Austin, TX: American Botanical Council.
10. The British Herbal Pharmacopeia. Publ: Brisbane Herbal Medicine Association, 1983.
11. Nadkarni KM. Indian Materia Medica. Bombay Popular Prakashan.
12. Bone K. Clinical Applications of Ayurvedic and Chinese Herbs. Monographs for the western herbal practitioner. Phytotherapy Press, Warwick, Qld, Australia, 1997.
13. Pengelly A. The constituents of medicinal plants: an introduction to the chemistry and therapeutics of herbal medicine. Sunflower Herbal 2nd Edition, Merriwa, NSW, Australia, 1996, pp 27-30.
14. Deshpande PJ, Sahu M, Pradeep Kumar. Crateva nurvala Hook and Forst (Varuna) – the Ayurvedic drug of choice in urinary disorders. Indian J Med Res, 1982; 76(Suppl):46-53.
15.http://www.hmc.psu.edu/healthinfo/no/neurogenicbladder.htm. Penn State College of Medicine. A to Z Health and disease information. Neurogenic Bladder. Accessed 31st Jan, 2006. No author listed.
16. Gordon D, Groutz A, Ascher-Landsberg J, et al. Double-blind, placebo-controlled study of magnesium hydroxide for treatment of sensory urgency and detrusor instability: preliminary results. Br J Obstet Gynaecol 1998;105:667–9.
17. Weiss, B. Diagnostic Evaluation of Urinary Incontinence in Geriatric Patients. American Family Physician. 1998; 58.
18. Hendrix, S. et. al. Effects of Estrogen With and Without Progestin on Urinary Incontinence. JAMA, Feb 23, 2005-Vol 293, No 8.
19. Steels E. Ryan J., Seipel T., Rao A. Crateva and Equisetum reduce Urinary Incontinence Symptoms. Australian Continence Journal. Vol.8 Number 3, 2002.
20. Schauss AG,Spiller G, Chaves S, Gawlicka A. Reducing the symptoms of overactive bladder and urinary incontinence: results of a two-month randomized, double-blind, placebo-controlled clinical trial, 2006 (unpublished research).
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