Advances in Medical Therapy of Urolithiasis

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
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3. Treatment of Urolithiasis
Watchful waiting (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)
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4. Treatment of Urolithiasis
Extracorporeal Shock 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
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5. Medical Expulsive Therapy
Medical Expulsive 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
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6. Medical Expulsive Therapy
Possible drug 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)
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7. Medical Expulsive Therapy
Calcium channel 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
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8. Medical Expulsive Therapy
Alpha1-adrenoreceptor antagonists
•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
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9. Medical Expulsive Therapy
Anti-inflammatory agonists
•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
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10. Medical Expulsive Therapy
Phosphodiesterase inhibitors
•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.
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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
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12. Medical Expulsive Therapy
Terpenes
•Terpenes have 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
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13. Rowatinex
Rowatinex ingredients
•Rowatinex is a 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
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14. Rowatinex
Rowatinex ingredients
•Rowatinex was originally 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)
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15. Rowatinex
Rowatinex ingredients
•The terpenes included in Rowatinex belong to the subclass of
bicyclic monoterpenes, which consist of two isoprene units that
underwent two sequential cyclisation reactions:
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16. Rowatinex
Rowatinex ingredients
•α-Pinene
•β-Pinene
•Important constituents of pine resin, but also found in the
resins of many other conifers, as well as in non-coniferous
plants
•Pharmacological effects: diuretic, anti-bacterial
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17. Rowatinex
Rowatinex ingredients
•Camphene
•Minor constituent of 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
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18. Rowatinex
Rowatinex ingredients
•1,8-Cineol (eucalyptol)
•1,8-Cineol comprises 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
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19. Rowatinex
Rowatinex ingredients
•Fenchone
•Fenchone is the essential oil of fennel
•Pharmacological effect: anti-bacterial
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20. Rowatinex
Rowatinex ingredients
•Borneol
•Borneol can be 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
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21. Rowatinex
Rowatinex ingredients
•Anethole
•Anethole is a 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
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22. Rowatinex
Pharmacodynamics
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Pharmacologic effect Test Result
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 the recommended 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
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24. Rowatinex in urolithiasis treatment
Effects of Rowatinex in the urolithiasis treatment
•n=4 Open controlled studies
•n=4 Prospective randomised trials
•Casuistics – clinical experience (data from 1095 patients)
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25. Rowatinex in urolithiasis treatment
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
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Treatment of urolithiasis with terpene preparation, ROWATINEX.
Department of Urology, Faculty of Medicine, Nagoya University, Japan,
1959

26. Rowatinex in urolithiasis treatment
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
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Med Welt. 1961;31:1576-81

27. Rowatinex in urolithiasis treatment
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)
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Urol Res 2010 38:205-209

28. Rowatinex in urolithiasis treatment
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
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Magyar Urologia 1998;10:139-146

29. Rowatinex in urolithiasis treatment
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%)
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J Urol (Paris) 1987;93:31-33

30. Rowatinex in urolithiasis treatment
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)
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J Urol (Paris) 1992;98:98-100

31. Rowatinex in urolithiasis treatment
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%)
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Int Urol Nephrol 2010 Jun 10

32. Rowatinex in urolithiasis treatment
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%)
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Urology Journal 2009;6:9-13

33. Rowatinex in urolithiasis treatment
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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 urolithiasis treatment
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:
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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 urolithiasis treatment
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
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36. Conclusions
• MET (alone or 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
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37. Dr. med. Leonardo EbelingDr. 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
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