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Blackwell Publishing IncMalden, USAJSMJournal of Sexual Medicine1743-6095 2007 International Society for Sexual Medicine200742477484Original ArticlesTopical Treatment of Peyronies DiseaseFitch et al.
ORIGINAL RESEARCH—PEYRONIE’S DISEASE
Topical Verapamil HCl, Topical Triﬂuoperazine, and Topical
Magnesium Sulfate for the Treatment of Peyronie’s Disease—
A Placebo-Controlled Pilot Study
William P. Fitch, III, MD,* W. Jerry Easterling, RPH,† Robert L. Talbert, PharmD,‡Michael J. Bordovsky, RPH,§ and Michael Mosier, PhD¶
*Urology Consultants, P.A., San Antonio, TX, USA; †PDL, San Antonio, TX, USA; ‡University of Texas Health Science Center
at San Antonio, San Antonio, TX, USA; §Private Consultant, San Antonio, TX, USA; ¶Washburn University, Topeka, KS, USA
A B S T R A C T
Transdermal and intralesional verapamil has been reported to be useful in the treatment of Peyronie’s
Disease. This study evaluates a topically applied calcium channel blocker (verapamil hydrochloride 15% gel), a
topically applied calmodulin blocker (triﬂuoperazine), and a topically applied weak calcium channel blocker (mag-
nesium sulfate), each incorporated in a transdermal vehicle.Aim.
This pilot study was conducted to assess the efﬁcacy of a 15% verapamil gel applied topically to the penile
shaft twice daily for the treatment of Peyronie’s Disease.Main Outcome Measure.
To assess improvement in curvature, plaque size, resolution of painful erections, and
improvement in erection quality.Methods.
Two simultaneous, three armed, double blinded, placebo-controlled studies were conducted. After ran-
domization into one of four groups, patients were treated for 3 months. At the end of 3 months’ treatment using
blinded drug, each patient was treated with open label topical verapamil for 6 months. The studies were completed
after each patient had been treated and evaluated for 9 months after randomization.Results.
Fifty-seven patients were randomized. In total, 94.4% of patients treated for 9 months with topical
verapamil experienced improvement in curvature with an average percent curvature change of 61.1% compared
with 43.6% curvature improvement at 3 months. At 9 months the average percent plaque change was 84.7%
compared with 55% at 3 months. Pain resolution at 9 months was 100% compared with 87.5% at 3 months. Patient
perception of erection quality also increased at 9 months to 81.8% compared with 72.7% at 3 months.Conclusions.
Topical verapamil gel proved effective in eliminating pain on erection, decreasing the size of plaque,
decreasing curvature, and improving erection quality in patients with Peyronie’s Disease. Treatment results
improved signiﬁcantly after 9 months’ treatment as compared with 3 months’ treatment. Fitch WP III, Easterling
WJ, Talbert RL, Bordovsky MJ, and Mosier M. Topical verapamil HCl, topical triﬂuoperazine, and topical
magnesium sulfate for the treatment of Peyronie’s Disease—A placebo-controlled pilot study. J Sex Med
Peyronie’s Disease, Calcium Channel Blocker; Topical Verapamil; Placebo
. The ﬁbrotic process is characterized by palpa-ble ﬁbrotic plaque, penile curvature, pain with
ibrosis of the penile tunica albuginea was ﬁrst
erections, and decreased quality of erection. The
described by Francois de la Peyronie in 1743
incidence of Peyronie’s Disease in the general
2006 International Society for Sexual Medicine
male population has been reported to be as high
The sample sizes for this trial were small. Because
Aggeler et al.
demonstrated that antimicrotu-
of the small sample size, the comparison of pro-
bular agents, calcium antagonists, and calmodulin
portions between treatments (such as the propor-
blockers resulted in a change in ﬁbroblast cell
tion of patients showing improvement on clinical
shape . Kelly demonstrated with in vitro exper-
endpoints) was conducted using Fisher’s Exact
iments the importance of calcium in ﬁbroblast
Test, rather than the more common chi-squared
test. Expected counts for some cells in each con-
Levine et al.
reported that intralesional vera-
tingency table are certainly less than 5, making the
pamil injection of Peyronie’s plaque resulted in an
84% resolution of pain, improvement in curvature
Comparisons between treatments of the aver-
in 62% of patients, and improved sexual perfor-
age percent change in clinical endpoints were per-
formed using the Wilcoxon Rank Sum Test. This
The purpose of this study was to evaluate a
nonparametric procedure provides valid inference
topically applied calcium channel blocker (vera-
regardless of the distribution of the variables
pamil hydrochloride), a topically applied calm-
which cannot be adequately assessed with limited
odulin blocker (triﬂuoperazine), and a topically
applied weak calcium channel blocker (magne-
For the treatment comparisons of verapamil at
sium sulfate), each incorporated in a transder-
3 months with verapamil at 9 months, methods
mal vehicle for the treatment of Peyronie’s
appropriate for paired data were used. For pro-
portions of patients achieving improvement,McNemar’s test was used. For average changefrom baseline endpoints, the Wilcoxon Signed
Two simultaneous three armed, double blindedplacebo-controlled studies were conducted in this
pilot study. The ﬁrst study was a comparison oftopical verapamil 15% vs. topical triﬂuoperazine
Fifty-seven patients with Peyronie’s Disease were
10%, and topical placebo. The second study com-
evaluated and randomized into one of six sub-
pared topical verapamil 15% vs. topical magne-
sium sulfate 10% and placebo. After signing aninformed consent, patients were assigned a proto-
col number by drawing. Each group had similar
• Topical verapamil 15% (10 patients).
demographics, symptoms, and duration of symp-
• Topical triﬂuoperazine 10% (seven patients).
toms. After randomization into one of four
groups, patients were treated for 3 months. Thedrug preparations were applied to the entire penile
Note: because of serious side effects (anxiety,
shaft (excluding the glans) twice daily. The 0.5 mL
agitation, blurred vision, insomnia, and depres-
dose was measured with a paper dosimeter.
sion) with triﬂuoperazine 10%, enrollment was
Patients were seen and evaluated at 1-month
terminated after enrolling seven patients.
intervals. Plaque was measured with calipers and
the surface area calculated. The person measuringplaque size was blinded as to active treatment vs.
• Topical verapamil 15% (10 patients).
placebo. Pain was measured by a “Yes” or “No”
• Topical magnesium sulfate 10% (10 patients).
answer as the treatment objective was the total
elimination of pain. Degree of curvature and erec-tion quality were described.
At the end of 3 months’ treatment using
The patients’ ages ranged from 30 years to 83 years
blinded drug, each patient was treated with open
with the mean age being 56.3 years (Tables 1–4).
label verapamil gel for an additional 6 months.
Fifty-three patients completed the study.
Patients continued to be seen and evaluated at 1-month intervals. The study was completed after
each patient had been treated and evaluated for
Of the 20 patients randomized to topical vera-
pamil, two patients (11.1%) experienced contact
Topical Treatment of Peyronies Disease
patients was 55% after 3 months’ treatment withtopical verapamil. Of the 11 patients with dimin-
ished quality erections and treated with topical
verapamil, eight patients (72.7%) experienced
In comparing patients with Peyronie’s Disease
with less than 6 months’ duration with patients
with greater than 12 months’ duration, we saw no
statistical signiﬁcant difference in results related toduration of disease.
Of the seven patients started on topical triﬂuoper-
azine, ﬁve (71.4%) had serious side effects includ-
ing anxiety, agitation, blurred vision, insomnia,
and depression. Three patients (42.9%) with cur-
vature experienced improvement of curvature.
The duration of symptoms prior to randomization ranged from
The average improvement in degrees of curvature
2 months to 15 years with a mean of 3.35 years.
was 9.5%. Five patients (71.4%) had plaque reduc-tion. The average plaque reduction was 15.8%. Ofthe three patients with pain, two (66.7%) had total
pain relief. Three (50%) of the six patients with
decreased quality of erection had improvement
with topical triﬂuoperazine. In comparing triﬂu-
operazine with placebo, there was no statistically
signiﬁcant difference in results. Because of the
severity of side effects, treatment with topical tri-
Of these 57 patients, 56 had palpable Peyronie’s plaque, 56 patients
ﬂuoperazine was discontinued prior to completion
complained of penile curvature, 20 patients complained of painful
erections, and 39 patients reported decreased quality of erections.
Topical Magnesium Sulfate
Of the 10 patients initially treated with topical
dermatitis, and subsequently one of these patients
magnesium sulfate, three (30%) had improvement
withdrew from the study. One patient was lost
in curvature while six (60%) experienced a
to follow up. At 3 months, 87.5% of the eight
decrease in plaque size. The average improvement
patients with pain experienced complete pain res-
in degrees of curvature was 14.1%. The average
olution. Of the 18 patients with curvature, 14
decrease in plaque size was 20.3%. Only one
(77.8%) had reduction in curvature. The average
patient randomized to topical magnesium sulfate
improvement in degrees of curvature after
initially complained of pain, and this patient expe-
3 months of treatment with topical verapamil was
rienced complete resolution of pain after treat-
43.6%. Of the 18 patients with palpable plaque,
ment with topical magnesium sulfate. Three
18 (100%) had reduction in plaque size after
patients (50%) of the six patients who complained
3 months’ treatment with topical verapamil. The
of diminished erection quality experienced im-
average reduction in plaque size in this group of
provement. In comparing magnesium sulfate with
Characteristics placebo vs. verapamil treated patients
Topical verapamil vs. placebo at 3 months (percentage improved)
Patients with erection quality improvement
*Fisher’s Exact Test.
†Wilcoxon Rank Sum Test.
placebo, there was no statistically signiﬁcant dif-
four (25%) experienced improvement. Of the
eight patients complaining of pain and treatedwith topical placebo, three patients (37.5%) expe-
The placebo effect may appear unrealistic. How-
Finally, it is possible that one or more of the
ever, the small number of patients, along with the
chemical excipients that make up the placebo may
dramatic results achieved by ﬁve of the patients,
have a positive treatment affect on the scar tissue.
indicates that additional studies need to be per-
The fatty layer of the protective stratum corneum
formed with much larger placebo populations. For
is reversibly modiﬁed to allow the carrier and
example, one patient experienced an 83% curva-
active drug to traverse the stratum corneum and
ture improvement and an 87% plaque improve-
deposit in the diseased underlying tissue. Further
research will be conducted to investigate this
curvature improvement and a 64% curvature
possible positive treatment effect of the placebo.
improvement. Another patient experienced a 33%
Tissue remodeling is complex, and it is not incon-
curvature and a 100% plaque improvement.
ceivable that one of the chemical excipients could
Another patient experienced a 100% curvature
affect one or more of the glycosaminoglycans,
improvement along with an 84% plaque improve-
proteoglycans, growth factors, or cytokines in-
ment, but only had a 5-degree curvature at the
volved in the healing and remodeling process
Eighteen patients were treated with placebo.
The data pertaining to the use of topical
Two patients immediately discontinued the study.
verapamil for 9 months was compared with the
After 3 months of using topical placebo, ﬁve
3-month data (Table 6). After using topical vera-
patients (29.4%) of 17 patients with curvature
pamil for 9 months, 17 (94.4%) of patients expe-
experienced decreased penile curvature. The aver-
rienced a decrease in curvature compared with 14
age improvement in degrees curvature was 18.5%.
patients (77.8%) after 3 months of treatment. The
Six patients (33.3%) had decreased plaque size
average curvature reduction in degrees was 61.1%
while three patients had increased plaque size.
at 9 months compared with 43.6% at 3 months.
The average reduction in plaque size was 5%. Of
One patient (5.6%) had total resolution of curva-
the 16 patients complaining of decreased quality
ture at 3 months. Four patients (22.2%) had total
erections who were treated with topical placebo,
resolution of curvature at 9 months. One hundred
Topical verapamil at 3 months vs. 9 months
Patients with erection quality improvement
*McNemar’s Test (for paired proportions).
†Wilcoxon Signed Rank Test (for paired data).
For completeness, statistical tests were performed for all endpoints comparing verapamil at 3 months to verapamil at 9 months, even though in some cases theuse of a statistical test is clearly not needed. For example, when nearly all patients showed improvement at 3 months, there is no room left for further improvementat 9 months. Such a “ceiling effect” will cause the statistical comparison of the two time points to be nonsigniﬁcant, even though there is very clear evidence ofan effect at 3 months, which is sustained through 9 months.
Topical Treatment of Peyronies Disease
percent of patients using topical verapamil for
clinical question related to erectile dysfunction is
9 months had decreased plaque size. The average
“does the treatment worsen the erectile dysfunc-
plaque size decrease at 9 months was 84.7% com-
tion?” Our data clearly show that it does not.
pared with 55% at 3 months. Seven patients
Perhaps the International Index of Erectile Func-
(38.9%) experienced complete resolution of
tion questionnaire should be utilized in future
plaque at 9 months compared with ﬁve patients
(27.8%) at 3 months. One hundred percent of the
Important observations made during this study
patients experiencing pain secondary to Peyronie’s
Disease had complete resolution of pain at
• Based on the data shown in Table 5 comparing
9 months compared with 87.5% at 3 months.
Nine patients (81.8%) who experienced dimin-
should be treated with topical verapamil as long
ished quality of erections had improvement in
as there is continued measurable improvement
erection quality after treatment with topical vera-
in pain, plaque size, curvature, and erection
pamil for 9 months compared with 72.7% at
• There may be a signiﬁcant reduction in
plaque prior to observed improvement incurvature.
• Successful treatment is directly related to
patient compliance and physician follow-up.
Some feel that ultrasonic measurements of plaque
We suggest that physicians examine patients
should be performed while others prefer palpation
after 1 month of treatment with follow-up every
and physical measurement. We unsuccessfully
attempted ultrasound on 10 patients with palpableplaque. We found that calculating area using mea-
The results reported using topical verapamil 15%
surements with calipers was the most accurate and
are better than the reported results obtained by
using intralesional verapamil injections for several
We felt that a simple “Yes” or “No” for the
presence of pain was more objective than a visual
• Multiple injections into the plaque are trau-
analog pain scale which would have been appro-
matic and may cause an increase in inﬂamma-
priate had we been evaluating degrees of pain
reduction as opposed to complete elimination of
• The plaque’s density prevents adequate entry
Curvature can be measured by patient estima-
• Patients oftentimes do not return for follow-up
tion, with photography, and by using intracavern-
treatment and observation because of the pain
osal injection of vasoactive drugs. Photography
and trauma experienced with the ﬁrst injections.
can be misleading because of varying camera posi-tion. Vasoactive drug injection involves risks such
Speciﬁc data are presented in Table 7.
as priapism, ﬁbrosis of the tunica albuginea, and
Topical verapamil is administered to the entire
ﬁbrosis of the cavernosal smooth muscle. Cavern-
shaft of the penis. In addition to treating observed
osal injection may cause problems in enrolling and
plaque, this also may reverse any undiagnosed
retaining patients in studies. We utilized patient
ﬁbrotic tissue that could be subject to injury. Addi-
estimation of curvature because error in patient
tionally, a uniform concentration of verapamil is
estimation of curvature is diluted by the number
maintained throughout the entire plaque forma-
of patients in the study. The most important
tion rather than randomly as administered by
aspect in quantifying curvature change is the
patient perception of improvement or absence of
because it has been formulated and designed to
Measurement of erection quality may be the
allow only negligible concentrations of active drug
most controversial. While the baseline patient
into the circulation and to allow for the majority
estimate may not be totally accurate, the patient
of absorption and concentration of the active drug
and his partner certainly are able to discern the
into the invading plaque. In 1990 Lee and Ping
presence or absence of improvement. The treat-
noted that the therapeutic serum levels of vera-
ment was designed to lessen curvature and elimi-
pamil used for the treatment of hypertension and
nate pain as the primary outcomes. The important
cardiac arrhythmias range from 0.01 to 0.2 μM.
Topical veraparmil vs. intraplaque verapamil injection
On the other hand, the concentration necessary to
packaged in a material that is nonreactive chemi-
inhibit extracellular matrix collagen synthesis in
cally or physically to the active ingredient or any
their in vitro study was in the 100 μM range .
Because of this comparatively high dose, it appears
The authors state that it is unlikely that vera-
necessary to administer verapamil locally to avoid
pamil would be found in ﬁbrotic scar tissue. How-
systemic toxicity while exposing ﬁbroblasts within
ever, treating ﬁbrotic connective tissue is the
the plaque to an adequate verapamil concentra-
essence of transdermal treatment and should lead
tion. In order to maintain a 100 μM concentra-
tion, a sustained release of active drug must be
Verapamil is extensively metabolized by cyto-
maintained ﬁrst to establish therapeutic drug equi-
chrome P4503A4, and only 3–4% is excreted
librium and thereafter to maintain therapeutic
unchanged in the urine. Based on the reported
equilibrium. The Dow Pharmaceutical Science
urinary concentration of 46 ng/mL, and using data
skin absorption study data of the product utilized
provided by Saseen et al.
 the back extrapo-
in this study indicate that the product meets this
lated plasma concentration would have to be
1400 ng/mL to achieve the reported urinary con-
Martin et al. reported that the transdermal
centration, and the estimated dose to produce this
application of verapamil gel to the penile shaft fails
plasma concentration is approximately equivalent
to inﬁltrate the tunica albuginea . The accuracy
to an oral dose of 960 mg daily. The observed
of this study is questionable for the following rea-
urinary verapamil is most likely due to contamina-
sons: only eight patients were studied; none of the
tion. The conclusions noted in Martin’s publica-
patients studied had Peyronie’s Disease. Verapamil
tion were addressed to and published by The
was applied twice before surgery and was removed
Journal of Urology
, Volume 173, p. 1830, May
prior to surgery. It is highly unlikely that two
applications would result in equilibration between
The verapamil 15% formulation utilized in our
epidermal tissue and the tunica albuginea. Appli-
study was evaluated by Dow Pharmaceutical Sci-
cation occurred over only the sides of the penile
ences. The bioavailability of this topically applied
shaft and not the entire penile shaft as described
drug formulation of verapamil HCl was assessed
utilizing an in vitro percutaneous absorption test.
Furthermore, few details are provided concern-
Radiolabeled (3H) verapamil HCl absorption
ing active ingredient, and no information is pro-
was measured utilizing Bronaugh ﬂow-through
vided regarding whether verapamil or verapamil
diffusion cells and evaluated for potential effec-
hydrochloride was used. Verapamil hydrochloride
tiveness in the topical treatment of Peyronie’s
is preferred because of its stability. Drug vehicle
and compounding technique are critical. The
Human abdominal skin was dosed with the sub-
vehicle must be designed to traverse the stratum
ject formulation, and the absorption characteris-
corneum to the extent that it reaches subdermal
tics were evaluated every 6 hours for 24 hours.
connective tissue but at the same time minimizes
The kinetic proﬁle of the drug’s penetration was
studied by plotting dose penetration vs. time. Epi-
dermal, dermal, and receptor solution samples
ducible and must provide a product of consistent
were assessed. In total, 87.58% of the applied dose
characteristics such as viscosity, particle size, pH.
was recovered. The receptor solution concentra-
Stability is essential. The drug must be protected
tion correlates with the amount of drug systemi-
from light to prevent degradation, and it must be
cally available following the application of a
Topical Treatment of Peyronies Disease
clinically relevant dose to normal, non-occluded
ease. This conclusion is reinforced by the 9-month
data presented and supports the fact that an
The PDLabs 15% topical verapamil HCl com-
extended treatment period (more than a year) is
pound resulted in very low levels in the receptor
necessary for some patients to experience optimal
solution (0.028%). This predicts very low levels of
verapamil HCl systemic exposure following topi-
This was a pilot study, and the patient numbers
cal application, which is one desired characteristic
were small, but the results were encouraging.
of the product as the targeted area of treatment
Multicenter, randomized, double-blinded studies
lies very close to the dermis of the skin. Untoward
comparing verapamil with placebo should be
systemic effects are minimized. Dermal and epi-
performed in the future utilizing a larger patient
dermal levels of deposition suggest that the vehicle
and the drug to a large degree partition in theepidermis, thereby creating a signiﬁcant reservoirfor sustained release of verapamil HCl from
human skin without the use of mechanical depotsof drug such as those manufactured in sustained
Conception and design: William P. Fitch, III, MD and
W. Jerry Easterling, RPH; analysis and interpretation
This combination of high dose loading and
of data: William P. Fitch, III, MD, W. Jerry Easterling,
high epidermal deposition, following the applica-
RPH, Michael J. Bordovsky, RPH, and Robert L. Tal-bert, PharmD; statistical expertise: Michael Mosier,
tion to skin, indicates that the PDLabs formula-
PhD and William J. Cady, PharmD; percutaneous skin
tion of 15% verapamil HCl should result in
penetration studies: Dow Pharmaceutical Sciences;
effective, sustained delivery of the verapamil HCl
administrative, technical or logistic support: Janice K.
Orem; study coordinators: Judy Lochte, Virginia Von
The mechanism of action involved with the
Lehmden; provision of study materials: Prescription
use of topically applied calcium channel blockers
and calmodulin blockers to treat ﬁbrotic connec-tive tissue disorders is not fully understood. How-
William P. Fitch, MD,
ever, the proposed mechanism of action involves
Urology Consultants, P. A, 8038 Wurzbach Suite 430,
blocking the cellular entry of divalent calcium or
San Antonio, TX 78229, USA. Tel: (210) 616-0410;Fax: (210) 615-1295; E-mail: janice@urologyconsults.
inhibiting the binding of calmodulin antagonists
to calmodulin binding protein within the cell.
The result appears to be a tissue remodeling
Conﬂict of Interest:
effect that involves the production of a metallo-proteinase (MMP) or serine protease thatdegrades matrix proteins such as collagen, lami-
nin, and ﬁbronectin. MMP, or collagenase, ishighly dependent on divalent calcium and/or
1 Peyronie F. de la: Sur quelques obstacles qui s’oppo-
serta l’ejaculation naturelle de la semence. Mem’l
divalent zinc to become active. MMPs are com-
monly expressed by cells involved in tissue injury.
2 Lindsay MB, Schain DM, Grambsch P, Benson RC,
MMPs are also signaled by inﬂammatory cytok-
Beard CM, Kurland LT. The incidence of Peyro-
ines . Further research is required to fully
nie’s Disease in Rochester, Minnesota, 1950 through
understand the interaction of ion channels and
3 Schwarzer U, Klotz T, Braun M, Wassmer G,
Englemann U. Prevalence or Peyronie’s Disease:Results of an 8,000 man survey. J Urol Suppl
The data obtained from these studies conﬁrm that
4 Rhoden EL, Teloken C, Ting HY, Lucas ML,
a properly formulated topical verapamil 15% is an
Teodosio da Ros C, Ary Vargas Souto C. Preva-lence of Peyronie’s Disease in men over 50-y-old
effective treatment for Peyronie’s Disease.
from Southern Brazil. Int J Impot Res 2001;13:
Topical verapamil proves more effective than
topical triﬂuoperazine, topical magnesium sulfate,
5 Aggeler J, Frisch SM, Werb Z. Changes in cell
and topical placebo for improving curvature,
shape correlate with collagenase gene expression
decreasing plaque, resolving pain, and improving
in rabbit synovial ﬁbroblasts. J Cell Biol
erection quality in patients with Peyronie’s Dis-
6 Kelly RB. Pathways of protein secretion in Eukary-
penile shaft fails to inﬁltrate the tunica albuginea. J
7 Laurence A, Levine Karen E, Goldman Jason M.
10 Saseen JJ, Porter JA, Barnette DJ, Zajec EJ Jr,
Greenﬁeld: Experience with intraplaque injection
Carter BL. Postabsorption concentration peaks
of verapamil for Peyronie’s Disease. J Urol
with brand-name and generic verapamil: A double
blind, cross-over study in elderly hypertensive
8 Lee RC, Ping JA. Calcium antagoniss retard extra-
patients. J Clin Pharmacol 1997;37:526–34.
cellular matrix production in connective tissue
11 Alberts B, Bray D, Lewis J, Raff M, Roberts K,
equivalent. J Surg Res 1990;49:463–6.
Watson J. Molecular biology of the cell, 3rd edition,
9 Martin DJ, Badwan K, Parker M, Mulhall JP.
CH 19. Garland Publishing Inc: New York, NY;
Transdermal application of verapamil gel to the
This chapter discusses a forward chaining rule based system and its expert system applications. It shows how the forward chaining system works, how to use it, and how to implement it quickly and easily using Prolog. A large number of expert systems require the use of forward chaining, or data driven inference. The most famous of these is Digital Equipment Corporation's XCON system. It configures
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