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![Rowatinex in urolithiasis treatment
33
Primary endpoint
Group of
randomisation
N
Stone diameter
[mm]
Treatment
duration [d]
Success rate
[ %, (n)]
Mukamel 1987 Stone expulsion rate in ureteric calculi
Rowatinex 23 5.2 (1-12) 10.8 (1-21) 78 (18/23)
Placebo 17 2.5 (1-7) 11.7 (2-21) 52 (9/17)
Engelstein 1992 Stone expulsion rate in ureteric calculi
Rowatinex 43 4.0 (1-12) ~ 14 81 (35/43)
Placebo 44 2.6 (0.5 - 7) ~ 14 59 (26/44)
Aldemir 2010
Stone expulsion rate in distal ureteric
calculi < 10 mm
Rowatinex 30 6.8 (3-10) 6 43.3 (13/30)
Tamsulosin 31 6.7 (4-10) 3.5 80.6 (25/31)
Placebo 29 6.6 (4-10) 7 37.9 (11/29)
Djaladat 2009 Fragment expulsion rate post ESWL
Rowatinex 50 10 - 20 28
d:14 d:28
18 (9/50) 24 (12/50)
Placebo 50 10 - 20 28 4 (2/50) 18 (9/50)](https://image.slidesharecdn.com/rowatinexpresentationurologenohneromicsupdateohnemengenangaben-160407064058/85/Rowatinex-33-320.jpg)
Uploaded byNaturpharma (Medicina Biológica)
Rowatinex
Dr. Leonardo Ebeling presented on recent advances in medical therapy for urolithiasis. He discussed treatment options including watchful waiting, pain control, and invasive or noninvasive surgery. Noninvasive options include extracorporeal shock wave lithotripsy (ESWL) and medical expulsive therapy (MET). MET uses pharmaceuticals to help pass stones naturally. Potential drug targets discussed included calcium channels, alpha1-adrenergic receptors, anti-inflammatories, phosphodiesterases, and muscarinic receptors. Rowatinex, a traditional herbal medicine containing purified terpenes, was highlighted as a multi-target MET option that may help reduce stone formation and passage through various
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Rowatinex
- 1. Dr. Leonardo Ebeling Dr.Ebeling & Assoc. GmbH, Hamburg, Germany 30th June 2011 – Hong Kong – Sheraton Hotel Recent Advances in Medical Therapy of Urolithiasis
- 2. Table of Contents •Treatment of Urolithiasis • Medical Expulsive Therapy • Rowatinex • Rowatinex in urolithiasis treatment • Conclusions 2
- 3. Treatment of Urolithiasis Watchfulwaiting (in cases when a stone causes no problems) Symptomatic stones: pain control with non-steroidal anti- inflammatory drugs (NSAIDs) or opioids or terpene combination Invasive forms of surgery (e.g. percutaneous nephrolithotomy or placement of an ureteral stent) Noninvasive forms like Extracorporeal Shock Wave Lithotripsy (ESWL) and/or Medical Expulsive Therapy (MET) 3
- 4. Treatment of Urolithiasis ExtracorporealShock Wave Lithotripsy (ESWL) •Standard non-invasive method •Works best with stones with a diameter of 4 - 20 mm which are still located in the kidney •ESWL can be also used to break up stones which are located in a ureter •Principle: Successive shock wave pressure pulses result in shearing forces and cavitation bubbles surrounding the stone, leading to fragmentation of the stones into smaller pieces that can pass through the ureter 4
- 5. Medical Expulsive Therapy MedicalExpulsive Therapy (MET) •Pharmaceutical support for ESWL is standard of care in the daily urological routine •MET can also be used as primary treatment •MET offers a cost-effective, non-surgical approach for patients •An appropriate agent should reduce ureteral inflammation, edema, ureteral spasm and uncoordinated ureteral contrac- tions without altering propulsive peristalsis 5
- 6. Medical Expulsive Therapy Possibledrug targets for MET •Calcium channels •Alpha1-adrenergic receptors •Targets in inflammatory pathways (e.g. COX-2) •Phosphodiesterases (PDE) •Muscarinic acetylcholine receptors (mAChRs) •Multi-target approach (terpene combination) 6
- 7. Medical Expulsive Therapy Calciumchannel blockers •Increase of cytoplasmic free cal- cium concentration is one princi- pal mechanism initiating ureteral contraction •Endogenous prostaglandin synthesis and calcium influx induce spontaneous rhythmic contractions of the human ureter •Calcium channel blockers like nifedipine and verapamil have shown to counteract the phasic-rhythmic activity and the spontaneous rhythmic contractions 7
- 8. Medical Expulsive Therapy Alpha1-adrenoreceptorantagonists •Alpha1-adrenoreceptor agonists generally lead to constrictions of smooth muscles •Heterogeneous distribution of alpha1-adrenoreceptors, with highest density in the distal ureter •Alpha1-adrenoreceptor antago- nists like nifedipine, tamsulosin and 5-methylurapidil inhibit contractions of ureteral musculature, reduce the basal tone and decrease peristaltic frequency and colic pain 8
- 9. Medical Expulsive Therapy Anti-inflammatoryagonists •Non-steroidal anti-inflammatory drugs (NSAIDs, e.g. aspirin, ibuprofen, diclofenac, etc.) are commonly used for their anti- inflammatory and anti-edematous effects •However, stone expulsion rates are not affected, therefore, NSAIDs should be used only as an addition to other MET strategies 9
- 10. Medical Expulsive Therapy Phosphodiesteraseinhibitors •PDE inhibitors demonstrated relaxing effects on ureteral smooth muscle in vitro •Papaverine also led to smooth muscle relaxation, showing an analgesic potential similar to opioids or NSAIDs in recent randomised trials. However, further studies are necessary to assess a potential role in MET. 10 cAMP
- 11. Medical Expulsive Therapy Antimuscarinics •Antimuscarinics(N-butylscopolamin, hyoscine) could relax genitourinary smooth muscle, thereby reducing colic pain •However, studies could not detect any favourable effect in analgesia or stone expulsion rates 11
- 12. Medical Expulsive Therapy Terpenes •Terpeneshave diuretic, anti-inflammatory, analgesic, hyper- emic and spasmolytic properties (“multi-targeting agent”) •Anti-inflammatory effect is achieved by the suppression of arachidonic acid metabolism and cytokine production •Terpenes are a large class of organic compounds, produced primarily by conifers •Terpenes are derived biosynthetically from units of isoprene 12
- 13. Rowatinex Rowatinex ingredients •Rowatinex isa traditional medicinal product in Europe •First registration as a medicinal product in Germany in 1954 •Launched in over 60 countries worldwide •Rowatinex contains seven highly purified substances: - α-Pinene - β-Pinene - Camphene - 1,8-Cineol - Fenchone - Borneol - Anethole 13
- 14. Rowatinex Rowatinex ingredients •Rowatinex wasoriginally produced by mixing six purified essential oils (pine needle oil, juniper berry oil, fennel oil, turpentine oil, rosemary oil, and eucalypt oil) •This mixture was chosen, because the included terpenes were described as being especially suitable in the treatment and prophylaxis of urolithiasis •The original formulation was later replaced by the corres- ponding highly purified synthetic terpenes in order to ensure a constant formulation with a reproducible efficacy and safety (as oils may vary depending on season and source) 14
- 15. Rowatinex Rowatinex ingredients •The terpenesincluded in Rowatinex belong to the subclass of bicyclic monoterpenes, which consist of two isoprene units that underwent two sequential cyclisation reactions: 15
- 16. Rowatinex Rowatinex ingredients •α-Pinene •β-Pinene •Important constituentsof pine resin, but also found in the resins of many other conifers, as well as in non-coniferous plants •Pharmacological effects: diuretic, anti-bacterial 16
- 17. Rowatinex Rowatinex ingredients •Camphene •Minor constituentof many essential oils such as turpentine, cypress oil, camphor oil, citronella oil, neroli, ginger oil, and valerian •Pharmacological effects: hyperaemic, choleretic, spasmo-lytic, anti-bacterial 17
- 18. Rowatinex Rowatinex ingredients •1,8-Cineol (eucalyptol) •1,8-Cineolcomprises up to 85 percent of eucalyptus oil and is also found in camphor laurel, bay leaves, tea tree, mugwort, sweet basil, wormwood, rosemary, sage and other aromatic plant foliage •Pharmacological effects: anti-bacterial, spasmolytic 18
- 19. Rowatinex Rowatinex ingredients •Fenchone •Fenchone isthe essential oil of fennel •Pharmacological effect: anti-bacterial 19
- 20. Rowatinex Rowatinex ingredients •Borneol •Borneol canbe found in several species of Artemisia, Dipterocarpaceae, Blumea balsamifera and Kaempferia galanga •Borneol is a natural insect repellent •Pharmacological effects: vasodilatatory, anti-bacterial, analgesic, spasmolytic 20
- 21. Rowatinex Rowatinex ingredients •Anethole •Anethole isa phenylpropene, which is synthesised from the amino acid phenylalanine •Anethole contributes to the distinctive flavors of anise and fennel (Apiaceae), anise myrtle (Myrtaceae), liquorice (Fabaceae), and star anise (Illiciaceae) •Pharmacological effects: diuretic, anti-inflammatory, anti- bacterial, and hyperaemic 21
- 22. Rowatinex Pharmacodynamics 22 Pharmacologic effect TestResult Anti-lithogenic /litholytic Rat Decreased oxalic acid concentration, calcium oxalate formation and calcium content in renal tissue, dissolution and disintegration of renal and urinary calcium oxalate stones Anti-bacterial In vitro: agar diffusion test, inhibition in liquid media, etc. e.g. Staphylococcus aureus, Enterococcus, Escherichia coli, Proteus vulgaris, Salmonella typhi, Streptococcus vulgaris, Saccharomyces cerevisiae Spasmolytic, vasodilatatory Guinea pig, rabbit, cat Antispasmodic efficiency in smooth muscle preparations (intestine, bladder, aorta) Analgesic In vitro: bovine adrenal chromaffin cells Inhibition of nicotinic acetylcholine receptor agonist mediated effects Anti-inflammatory Rat, mouse Suppression of arachidonic acid metabolism and cytokine production
- 23. Rowatinex Animal toxicity •At therecommended therapeutic dosages, Rowatinex is without any significant toxicity •Toxic signs or symptoms (treated animals became quieter and somnolent) were only observed in animal experiments at dosages that exceeded the human clinical dose 12 - 400 times •LD50 of Rowatinex in rats and mice varied between 4.20 - 8.97 ml/kg bw and 4.98 - 6.61 ml/kg bw 23
- 24. Rowatinex in urolithiasistreatment Effects of Rowatinex in the urolithiasis treatment •n=4 Open controlled studies •n=4 Prospective randomised trials •Casuistics – clinical experience (data from 1095 patients) 24
- 25. Rowatinex in urolithiasistreatment Open controlled studies (only MET) •Asai et al. (1959): Rowatinex treatment of patients with urolithiasis - n = 24 patients - 4 x 3 or 4 drops/day until stone passage - spontaneous stone passage in 14/24 - within 2 weeks from treatment initiation 9 patients with stone passage expelled their stone, 12 additional patients had significant stone migration - improvement in patient symptoms in 21/24 25 Treatment of urolithiasis with terpene preparation, ROWATINEX. Department of Urology, Faculty of Medicine, Nagoya University, Japan, 1959
- 26. Rowatinex in urolithiasistreatment Open controlled studies (only MET) •Hammer & Rothe (1961): Patients with radiologically proven calculi in the distal ureter or renal pelvis treated with Rowatinex - n = 50 patients - dosis: 6 - 10 drops, 2 - 3 times/day - treatment period: intervals of 2 - 3 weeks for 6 - 10 months - spontaneous stone passage in 37/50 - improvement in patient symptoms: 43/50 26 Med Welt. 1961;31:1576-81
- 27. Rowatinex in urolithiasistreatment Open controlled studies (only MET) •Marickar et al. (2010): Effects of patient triggered blind medical treatment of urolithiasis - n = 338 patients (non-responders to self-triggered medical treatment) attending the author‘s stone clinic - 7% of these patients had taken Rowatinex before seeking further treatment - urine citrate concentration (citrate being an important inhibitor of calcium oxalate crystallisation) was significantly higher in Rowatinex users compared to control group (278 mg/d vs. 167 mg/d) 27 Urol Res 2010 38:205-209
- 28. Rowatinex in urolithiasistreatment Open controlled studies (MET after ESWL) •Siller et al. (1998): Evaluation of the effect of Rowatinex in patients who received ESWL - n = 50 patients - patients were treated with Rowatinex post ESWL - inclusion criteria (IC): stone size <20 mm - exclusion criteria (EC): obstruction of the urinary tract, history of deobstructing interventions (e.g. stent placement) - treatment: 3 capsules/day for 28 days - 84% started to pass fragments on day 1 post ESWL treatment - 60% were stone-free on day 14 - 82% were stone-free at day 28 - 94% were pain free at day 28 28 Magyar Urologia 1998;10:139-146
- 29. Rowatinex in urolithiasistreatment Prospective randomised trials (only MET) •Mukamel et al. (1987): Effects of Rowatinex on spontaneous stone passage - n = 40 patients - IC: acute renal colic, definite evidence of ureteric stones - treatment: 4 x 4 capsules/day until stone passage - patients treated with Rowatinex had sigificantly higher rates of treatment success (i.e. spontaneous stone passage or disappearance of dilatation of the collecting system on intravenos urography) after 3 weeks compared to placebo (78% vs. 52%) - expulsion rates in patients with stones >3 mm: 61% (placebo: 28%) 29 J Urol (Paris) 1987;93:31-33
- 30. Rowatinex in urolithiasistreatment Prospective randomised trials (only MET) •Engelstein et al. (1992): Effects of Rowatinex on spontan-eous stone passage (confirmative study on Mukamel et al.) - n = 87 patients - treatment: 4 x 4 capsules/day until stone passage - patients treated with Rowatinex had sigificantly higher rates of treatment success after 3 weeks compared to placebo (81% vs. 59%) - only mild adverse reactions (seven patients experiencing mild nausea or abdominal pain) 30 J Urol (Paris) 1992;98:98-100
- 31. Rowatinex in urolithiasistreatment Prospective randomised trials (only MET) •Aldemir et al. (2010): Efficiency of tamsulosin (α1a-adreno- receptor antagonists), Rowatinex and diclofenac in patients with distal ureteral stones - n = 90 patients - IC: age >17 y, stones located in distal ureter, size <10 mm - EC: urinary tract infection, solitary kidney, renal insufficien- cy, diabetes, multiple stones, pregnancy, previous MET - patients treated with tamsulosin had a significantly higher stone expulsion rate (tam: 80.6%; Row: 43.3%; dic: 37.9%) - Rowatinex patients had slightly higher stone expulsion rate and lower need of additional analgesic treatment compared to the diclofenac group (50% vs. 62.1%) 31 Int Urol Nephrol 2010 Jun 10
- 32. Rowatinex in urolithiasistreatment Prospective randomised trials (MET after ESWL) •Djaladat et al. (2009): Effects of Rowatinex on stone passage and stone-free rates after uncomplicated ESWL - n = 100 patients - IC: renal calculi 10-20 mm - treatment: 100 mg, 3 times/day for 4 weeks - overall stone-free rate was comparable between both verum and placebo after 28 days - Rowatinex-treated patients demonstrated accelerated stone passage: 18% were considered stone-free after 14 days (control: 4%) 32 Urology Journal 2009;6:9-13
- 33. Rowatinex in urolithiasistreatment 33 Primary endpoint Group of randomisation N Stone diameter [mm] Treatment duration [d] Success rate [ %, (n)] Mukamel 1987 Stone expulsion rate in ureteric calculi Rowatinex 23 5.2 (1-12) 10.8 (1-21) 78 (18/23) Placebo 17 2.5 (1-7) 11.7 (2-21) 52 (9/17) Engelstein 1992 Stone expulsion rate in ureteric calculi Rowatinex 43 4.0 (1-12) ~ 14 81 (35/43) Placebo 44 2.6 (0.5 - 7) ~ 14 59 (26/44) Aldemir 2010 Stone expulsion rate in distal ureteric calculi < 10 mm Rowatinex 30 6.8 (3-10) 6 43.3 (13/30) Tamsulosin 31 6.7 (4-10) 3.5 80.6 (25/31) Placebo 29 6.6 (4-10) 7 37.9 (11/29) Djaladat 2009 Fragment expulsion rate post ESWL Rowatinex 50 10 - 20 28 d:14 d:28 18 (9/50) 24 (12/50) Placebo 50 10 - 20 28 4 (2/50) 18 (9/50)
- 34. Rowatinex in urolithiasistreatment Casuistics – clinical experience •Case reports, including data from 1095 patients, are published or reported •Reports give an overview of the successful therapeutic application of ROWATINEX since market authorisation in the following fields of indication: 34 nephrolithiasis/urolithiasis: unspecified lithiasis renal lithiasis ureteral lithiasis bladder stones pain/colic attacks infections: kidney infections (e.g. pyelitis, pyelo-nephritis) cystitis prostatitis, vesical carcinoma prophylactic treatment
- 35. Rowatinex in urolithiasistreatment Clinical efficacy of Rowatinex - Summary •Forced stone expulsion: expulsion rates are higher and accelerated •Impact on symptomatic improvement: high number of improved symptoms in treated patients •Excellent safety profile: no or only mild adverse reactions in response to treatment •Prevention: anti-lithogenic effect leads to decreased oxalic acid concentration, calcium oxalate formation and calcium content in renal tissue •Pharmacodynamics: represent a multi-targeted terpene action which covers the pathophysiological situation 35
- 36. Conclusions • MET (aloneor post ESWL) is a noninvasive appropriate procedure to facilitate stone passage by accelerating the stone expulsion rates and reducing colic events in the treatment of urolithiasis • Rowatinex is a long-established, traditional medicinal product, consisting of naturally defined terpenes • Terpenes have diuretic, anti-inflammatory, analgesic, hyperemic, anti-bacterial and spasmolytic properties • With its pharmacodynamic and clinical profile, the terpene combination Rowatinex is a modern, efficacious and safe add-on to the medicinal armamentarium and combines different drug treatment options at once 36
- 37. Dr. med. LeonardoEbelingDr. med. Leonardo Ebeling Dr. Ebeling & Assoc. GmbHDr. Ebeling & Assoc. GmbH Isestraße 5Isestraße 5 20144 Hamburg/Germany20144 Hamburg/Germany Tel: +49 (0)40 548007 0Tel: +49 (0)40 548007 0 Fax: +49 (0)40 548007 20Fax: +49 (0)40 548007 20 Email: ebeling@ebeling-assoc.comEmail: ebeling@ebeling-assoc.com Internet: www.ebeling-assoc.comInternet: www.ebeling-assoc.com 37