Microsoft word - 121044-patent-wo 2011 _2_
PHARMACEUTICAL COMPOSITION FOR
TREATING DISEASES OF THE LOWER GENITOURINARY SYSTEM
Field Of The Invention
The claimed invention relates to medicine, specifically, to a medicinal
preparation, namely suppositories comprising a medication for the treatment of
lower genitourinary system diseases. This invention can be widely used in
medical practice for treating urological and gynecological diseases.
Background of the invention
The medication in suppository form, used for the treatment of chronic
prostatitis, comprises 4 – 6 mg of a bioactive compound from bovine prostate
concentrate per each suppository weighing 2.0 – 2.2 g and also, a purified liquid
α-interferon concentrate or a recombinant interferon [RU # 2160114, M.cl.6 A61K
35/48, 2000]. The suppositories are gelatin-, glycerin-, and sodium carbonate-
bicarbonate buffer-based. Interferon provides antiviral protection, thus, the
suppositories may be used according to RU # 2160114 when treating chronic
prostatitis in immunocompromised patients.
However, the efficacy of said suppositories is low, which could be
attributed to the low concentration of the bioactive compound and interferon’s
The pharmaceutical composition in suppository form comprises 0.05 –
0.40 g of the bioactive compound and 0.7 g of the antimicrobial agent per each
suppository weighing 2.15 - 2.35 g [RU # 2304979, M.cl.7 61K 38/02, 2007]. The
composition contains a bovine prostate bioregulatory peptide complex as a
bioactive compound. The composition also contains antibiotics of the
fluoroquinolone, penicillin, cephalosporin, or tetracycline, etc. groups as
antimicrobial agents. Suppositories according to RU # 2304979 could also
comprise antiviral agents and antiprotozoal drugs. They were tested on a
Antibiotics in suppositories according to RU # 2304979 may cause the
usual complications expressed in humans i.e., allergic reactions to antibiotics as
well as lowered immunity usually caused by antibiotics.
Pharmaceutical compositions according to RU # 2160114 and RU #
2304979 have one common disadvantage – the use of the bioregulatory peptide
Typically for any naturally derived products, their structure is not fully identified
since the methods used for their identification and standardization are
complicated and also, because they are not always available to both the
manufacturer and the researcher. The content of the active ingredients does not
exceed 20%. A naturally derived preparation always contains a number of high-
molecular-weight compounds inseparable from the active ingredients.
All this narrows the spectrum of the drug’s activity.
Disclosure of the invention
The invention is directed to broadening the spectrum of activity of the
The invention is also directed to the departure from the use of natural
The stated objective is achieved by making a pharmaceutical composition
in suppository form, said composition comprising a bioactive compound and a
fatty base, wherein the bioactive compound is a mixture of amino acids
comprising glutamic acid, lysine, alanine, arginine and glycine and further
comprising zinc in the form of zinc chloride in the following component ratio
expressed in grams per one suppository weighing 2.7 – 2.9 g each:
The pharmaceutical composition may further comprise 10 – 30 mcg of
selenium as anhydrous sodium selenite or 0.020 – 0.035 g of sodium fumarate
Different amino acids are known to regulate different physiological
functions of living organisms [Chirkin A.A., Danchenko Ye.O., Biochemistry. M.,
“Meditsinskaya literatura” (Medical Literature), 2010, 608 p.] Thus, there are
medications in suppository form that are used for the treatment of female sexual
dysfunctions [RU application # 2000120537, M.cl.7 A61K 45/06, 2002]
comprising 2 – 10 mg of the α-adrenergic receptors antagonist (Yohimbine,
hentolamine, etc.) and 1 – 8 g of arginine exhibiting NO-donor activity.
Also known in the art are the anti-herpes medications, for example, in
suppository form [RU #2264819, M.cl.7 A61K 35/74, 2005 and RU application #
2004128635, M.cl.7 A61K 31/19, 2006] comprising anti-herpes virion vaccine and
polyoxidonium immunomodulator as well as valine, lysine, isolysine and a
combination of at least two amino acids selected from the group including but not
Also known in the art is a pharmaceutical composition, for example, in
suppository form, for treatment of erectile dysfunction [RU application
#2000100301, M.cl.7 A61K 31/475, 2001] comprising 2 – 8 mg of Yohimbine and
None of the known pharmaceutical compositions comprising single amino
acids or even mixtures thereof [RU #2264819, RU application #2004128635] is
potent in treating prostate diseases. All the main ingredients in the compositions
of the present invention belong to other classes of active ingredients, while amino
acids are just additives and, as a rule, are present in large amounts.
It is known in the art that when different biologically active compounds are
combined in a pharmaceutical composition, their cumulative beneficial effect and
even their compatibility are unpredictable [see, for example, Kochetygov N.I.
“Blood substitutes after blood loss or shock”. L., “Meditsina”, 1984, p. 148; edited
by Oleynik S.A. “Sports pharmacology and dietology”. M. OOO I.D. Williams,
2008, 256 p.; “Fundamental of clinical nutrition. Course lectures for the European
Association of Parenteral and Enteral Nutrition”. M., ItelTec, 2003, 416 p.]
Thus, the physiological activity of the claimed composition in the treatment
of prostate diseases (prostatitis, prostate adenoma, etc.) as well as in the
treatment of gynecological diseases, such as vaginitis, was unexpected and
All components of the claimed composition are commercially available.
The following components were used: glutamic acid (Ajinomoto, Japan), lysine
(Sigma-Aldrich, Germany), alanine (Merck, Germany), arginine (Ajinomoto,
Japan), glycine (Jizhou City Huayang Chemical, China), and zinc chloride
(Merck, Germany); its content in the claims is given calculated for zinc.
When the composition contains 10 – 30 mcg of selenium, it is present in
The composition may also contain 0.020 – 0.0035 g of sodium fumarate.
The base could be made of but not limited to cocoa butter, edible fats, a
mixture of mono-, di, and fatty acid triglycerides (Witepsol) and other fatty bases
The suppositories are prepared as follows:
Example 1. Preparation of the suppositories
Preparation of the suppository mass.
Preparation of the premix.
The premix is prepared in a homogenizer with a heatable jacket.
To prepare the premix, a sufficient amount of suppository base
(Witepsol/W35) is placed into a homogenizer and melted.
The premeasured amounts of glutamic acid, alanine, lysine, arginine,
glycine, zinc, and also, possibly, sodium fumarate and selenium are added. The
premix is homogenized for 20 – 30 min. The premix is checked for quality upon
completion of the process: the mass must be homogeneous.
Mixing the premix with the base
The suppository base ((Witepsol/W35) is placed in a reactor and melted.
The premix is added to the base and the resulting mixture is stirred for 1 hr. The
suppository mass must be homogeneous with no visible inclusions.
Making the suppositories
Filling blister molds with the suppository mass (filling)
Blister molds are filled with a dispenser. The suppository mass is
transferred into the dispenser’s hopper. The molds are filled with the suppository
mass at a constant temperature with stirring.
The blister mold filled with the suppository mass is rolled with guide rollers
and passed onto the “Suppository chilling” step.
Chilling the suppositories
The suppositories are cooled in a refrigerator at 10 - 15°C for 1 – 2 hrs.
Acute and chronic toxicity of the claimed suppositories was examined as
per the requirements of the “Guide to the Experimental (Preclinical) Study of
Novel Pharmaceutical Substances (2005).” Acute toxicity was studied on 36
outbred white female mice. Chronic toxicity was studied on 45 outbred white
In the acute toxicity study, the preparation was administered in increasing
doses of 1.0, 2.0, 4.0, 8.0 and 10.0 g/kg (per finished dosage form) as per
Litchfield-Wilcoxon, based on an average suppository weight of 2.0 g.
A single administration of the preparation of the present invention to
animals in doses exceeding the clinically recommended therapeutic dose by
more than 500 times was not shown to cause any toxic reactions, which validates
the wide therapeutic application range of the preparation.
A chronic toxicity study of the preparation showed no side effects following
the use of the suppositories over a period of 30 days in doses exceeding
therapeutically recommended doses by more than 200 times. The study did not
yield any credible evidence of the effect of the preparation of the present
invention on the morphological and biochemical peripheral blood indicators, on
the ESR, and the erythrocyte resistance. Additionally, total protein in blood
serum was determined by Lowry Protein Assay, while potassium and sodium
were determined by plasma spectrophotometry. A pathomorphological study of
the brain, spinal fluid, spinal ganglions, thyroid gland, parathyroid glands, adrenal
glands, testicles, pituitary glands, heart, lungs, aorta, liver, kidneys, bladder,
pancreas, stomach, small intestine, large intestine, thymus, spleen, lymph nodes
and bone marrow was conducted upon completion of the experiment.
No pathologies were detected in the animals when evaluating the overall
condition thereof, the morphological and biochemical indicators of peripheral
blood, the morphology of internal organs, the condition of the cardiovascular and
respiratory systems, and liver and kidney function.
Due to the absence of general toxicity, the suppositories may be
recommended for testing in vivo in experimental genitourinary pathology. The
pharmacological effect of the claimed composition was studied on the
experimental models of prostatitis and vaginitis.
Example 2. Efficacy of the suppositories on a model of irritant
prostatitis in rats
The experiments were conducted on outbred male rats weighing 180 –
200 g, raised in the RAMS nursery “Rappolovo.” Before the experiments, the
animals were quarantined for 14 days and randomized. Marks and identity
numbers of the animals were registered in the laboratory test protocols. The
animals were kept in a vivarium on a standard diet.
Chronic prostatitis was simulated by administering a 10% aqueous
solution of dimexidum mixed with turpentine to all the experimental animals in a
4:1 volumetric ratio. Prior to the administration, the mixture was shaken for 1 min
until a fine emulsion had occurred. The freshly obtained emulsion was
administered to the rats rectally, 20 – 25 mm deep in a 1 ml volume with a rectal
infusion device (dispenser) ensuring a trauma-free procedure. The animals were
immobilized in a horizontal position with canvas gloved hands. Prior to the
administration, the mixture was shaken until formation of a fine emulsion.
Turpentine in said rectal administration mixture is used to produce
pathological hyperemia in the prostate, while the aqueous dimexidum solution is
a conductor facilitating turpentine’s penetration through the tissues and acting as
The preparations of the present invention were administered to rats in
different groups individually; 28 days post pathology stimulation in the doses
below. The animals were divided into the following groups, 10 rats each:
- control 2 (irritant prostatitis + comparator drug Prostatilen
(bioregulatory peptides from bovine prostate) 190 mg/kg p.r.)
- Irritant prostatitis + claimed suppositories, 240 mg/kg p.r.
The preparations of the present invention were administered to each male
rat individually in a molten state with an atraumatic probe.
The reduction in urodynamics was measured (by indicators of a
spontaneous 24-hr diuresis) with individual exchange cells from Techniplast
(Italy). Baseline diuresis indicators (28 days post pathology stimulation) and post
therapy indicators (58 – 59 days) were determined.
The 24-hr urine level was tested for excreted protein by quantitative
Upon collecting urine in exchange cells, the rats were instantly
decapitated under light halothane anesthesia. Blood samples were collected into
vacuum clot activator tubes Vacutest SER (Vacutestkima, Italy). The samples
were heated for 30 min at 37°C in a thermostat, cooled for 1 hr. in a refrigerator,
and centrifuged at 2,050 rpm. Blood serum was separated into Microtubes
Eppendorf test tubes (Plastibrand, Germany.)
Blood serum was tested for the testosterone level by IFA kits (XEMA);
nitrogen oxide by Griess photometric assay at 520 nm; thiobarbiturate-reactive
products (malonic dialdehyde) by a photometric assay at 537 nm; C-reactive
protein by IFA (BD kits); ceruloplasmin levels by Ravin’s photometric assay;
prostatic acid phosphatase activity by kinetic photometric assay with Olvex
For histological assay, the ventral prostate was immobilized in a 10%
neutral formalin solution and, upon a standard passage through a series of
solvents, poured into paraffin. Tissue slices 5 – 7 mcm thick were stained with
The following 5-point scale was used to compare the severity of prostatitis
1 point – traces of prostatitis (small foci of fibrosis, interstitial lymphocytic
2 points – foci of chronic prostatitis with inflammatory infiltration (mainly
interstitial) covering less than ¼ of the gland slice;
3 points – foci of prostatitis with large inflammatory infiltrates around the
ducts, acini and blood vessels, with leucocytes accumulated in glandular lumens
4 points – severe prostatitis covering ¼ - ¾ of the gland slice;
5 points – acute prostatitis covering more than ¾ of the gland slice.
Statistical data were processed using a standard Microsoft Excel program
package. Substantial changes were calculated using Student’s t-test.
Experimental prostatitis simulation resulted in significant pathological
urodynamic changes in rats 28 days post phlogogen (a mixture of turpentine and
dimexidum) administration. Administration of the turpentine and dimexidum
mixture resulted in prostatitis, causing a reduction in urodynamics on account of
an inflammatory increase in the weight/volume gland indicators. In all
experimental groups, a 24-hr diuresis 28 days post simulation (pathology
baseline) was reduced by more than 40%. Proteinuria increased significantly
(5.4 times), which is attributed to the outpouring of inflammatory exudate into the
urethral lumen of the male rats, and its components contaminating the urine. An
increased output of acid phosphatase isoenzyme, the main marker of prostatitis
and adenoma, from the tissue occurred at the pathology baseline. The acute-
phase protein level was observed to increase 24 times for ceruloplasmin and 2.2
times for C-reactive protein, while the testosterone level decreased.
The experimental prostatitis model results in an inflammatory increase of
the weight/volume dimensions of the ventral prostate, which was assessed at the
end of the experiment based on the gland’s weight while evaluating the effect of
the medications on the course of the disease.
The gland’s enlargement was largely caused by edema and hyperemia of
the gland tissue. These changes play a significant role in the impairment of
urodynamics during the passage of urine, they are the main factor in the urinary
bladder wall hyperextension in patients suffering from prostatitis and prostate
adenoma as well as a cause of dysuric disorders, including pain during urination.
Therapy with the preparations of the present invention conducted over a
one-month period resulted in a significant weight normalization of male rats with
experimental prostatitis. Prostatilen decreased the ventral prostate weight by
23.7% as compared to the control receiving no treatment. The suppositories of
the present invention were somewhat more instrumental in the normalization of
Administration of the comparator drug Prostatilen significantly reduced
proteinuria in rats (3.2 times) and led to a 54.3% restoration of diuresis as
Administration of suppositories of the present invention facilitated the
restoration of urodynamics, yielding a 22.4% increase in diuresis; and the
reduction of daily spilling of protein into urine (proteinuria) by 2.2 times compared
to the pathology baseline in this group.
Therapy with the comparator drug Prostatilen reduced the intensity of the
oxidative processes in the gland, which was evident from the considerable
reduction in both nitrogen oxide levels (1.5 times) and the levels of the products
reacting with thiobarbituric acid (TBA-RP) (2.2 times) compared to control
Suppositories of the present invention, when administered to rats, had a
effect comparable to Prostatilen on the intensity of oxidative stress: nitrogen
oxide was reduced 1.8 times, and TBA-RP was reduced 1.9 times as compared
Therapy with Prostatilen was found to credibly reduce acid phosphatase
isoenzyme output (1.7 times) and to increase the testosterone level (1.6 times) in
Suppositories of the present invention had a significantly stronger effect
on the activity of prostatic acid phosphatase (2.4 times reduction as compared to
control and 1.4 times reduction as compared to the comparator drug) and the
testosterone level (1.4 times increase.)
Prostatilen reduced the acute-phase protein blood levels of ceruloplasmin
2.4 times and of C-reactive protein 1.8 times. Therapy with suppositories of the
present invention also helped normalize the ceruloplasmin level (2.5 times) and,
especially, the level of C-reactive protein (2.2 times).
A morphological study of the slices demonstrated that therapy with the
comparator drug Prostatilen reduced the intensity of the inflammatory infiltration
of the gland’s stroma and white blood cells detectable in the acini.
inflammation in histological preparations were observed in only 40% of the male
rats used in the study. The rest of the animals were found to have normal gland
The effect of the suppositories of the present invention was similar to that
of Prostatilen. Foci of chronic prostatitis with inflammatory infiltration (mostly
interstitial) covering more than ¼ of the gland slice occurred in only 40% of the
animals. The prostate gland structure in the rest of the rats corresponded to that
All in all, the claimed pharmaceutical composition has a similar or better
therapeutic effect on the experimental prostatitis as Prostatilen.
Example 3. Efficacy of the suppositories on a model of irritant
vaginitis in rats
The experiments were conducted on white outbred female rats weighing
Vaginitis was stimulated by a one-time intravaginal application of an
irritant, a mixture of oil of turpentine and dimexidum in a 1:1 ratio in the dose of
0.5 ml per 100 g of the animal’s weight.
The animals from the experimental group were treated 24 hours post
administration of the irritant. The preparation was administered vaginally over a
7-day period in doses corresponding to the daily human dose. The daily dosage
form recalculated for rats was 220 mg/kg. The preparation was administered
once a day. To prevent the suppositories from free evacuation, the vaginal
opening was plugged with a small cotton tampon for 30 min.
The animals of the control group did not receive treatment. They were
followed for the dynamics of the inflammatory process by evaluating the cell
composition of vaginal smears and by a microbiological study of the impression
smears at the onset and on the 1st, 3rd, and 7th day post application of the
irritant. The hematologic markers of the inflammatory process: white blood cell
content in the peripheral blood, white blood cell differential, and the ESR were
evaluated at the same times. The animals’ behavior and overall condition were
also followed. The following factors were also taken into consideration:
- Intensity of the local hyperemia expressed in points: 0 – visible vaginal
mucosa and skin around the vagina are unchanged; 1 – slight
hyperemia of the visible vaginal mucosa; 2 points – pronounced
hyperemia of the vaginal mucosa and the skin; 3 – pronounced
hyperemia of the vaginal mucosa and visible signs of self-inflicted
- Intensity of the vaginal discharge expressed in points: 0 –no discharge;
1- light discharge when pressed with a swab; 2 – moderate discharge,
the skin around the vagina is wet; 3 – heavy discharge, the skin around
Histological control was carried out on the 3rd, 7th, and 10th day. For the
histological study, the rats from the experimental and control groups were
euthanized by decapitation under light ether anesthesia.
The vagina was fixed in 10% formalin and after alcohol prep, it was
poured into paraffin. The slices were stained with hematoxylin-eosin and
examined under an MBI-6 biological microscope.
All the animals in all experimental groups were found to have severe
anxiety, vaginal discharge, and hyperemia of the visible vaginal mucous
membrane 24 hrs. post administration of the irritant.
The first day post stimulation of vaginitis, the control group showed anxiety
and a hypersensitivity to external irritants. They were observed to have reduced
food and water intake and ruffled fur. All the animals were found to have
seromucous vaginal discharge. By the third day of the experiment, behavioral
deviations of the animals were gradually diminished. On the 7th day, these rats’
behavior was no different from the behavior of the intact (not taking part in the
The condition and behavior of the animals receiving suppositories of the
present invention on the first day of the experiment was no different from the
control group. They were observed to have ruffled fur, increased anxiety, and
aggressive response to handling. Administration of the preparation was
accompanied by anxiety and vocalization. Reduced vaginal discharge and
hyperemia were observed on the 3rd day post administration of vaginal
suppositories. These changes were statistically significant compared to control.
On the 7th day of the experiment, all visible symptoms of inflammation completely
On the first day after the start of therapy, all experimental groups showed
signs of acute inflammation with severe leukocytosis and a white blood cell
differential shift to the left, to the formation of stab white blood cells,
lymphocytopenia. High ESR was also noted.
A positive result was observed already on the first day of therapy with the
suppositories of the present invention. The animals receiving treatment had
their ESR reduced 1.3 times; the number of leucocytes also decreased. This
trend was observed throughout the entire experiment.
On the 3rd day, while the animals of the control group showed no signs of
positive dynamics, the animals receiving suppositories of the present invention
showed a significant decrease in the number of leukocytes and segmented
neutrophils as well as reduced intensity of lymphocytopenia compared to the first
On the 7th day, the control group (receiving no treatment) began showing
some positive dynamics in the studied parameters. The group of animals
receiving suppositories of the present invention showed a significant decrease in
the total white blood cell count, a slight stab shift, and the restored number of
neutrophils and lymphocytes. The ESR on the 7th day was no different from the
Introduction of the irritant adversely affected vaginal microflora of the
animals in all experimental groups. Throughout the experiment, the control
group showed significant changes confirming an inflammatory process: a high
content of vegetative and nonvegetative yeast forms and an increased amount of
diplococcal and coccal flora in the smears. A trend towards normalization of
vaginal microflora was observed only on the seventh day.
Treatment with the suppositories of the present invention resulted in a
decreased number of diplococci, yeast, gram-negative bacilli and gram-positive
cocci already on the 1st day. On the third day, the treatment of animals with the
suppositories of the present invention resulted in restoration of the natural
microflora composition (its qualitative and quantitative characteristics) to a level
practically identical to the norm. The presence of an increased amount of
lactobacteria with high antagonistic activity toward a wide range of pathogenic
and opportunistic pathogenic microbes must also be noted; this defines the
corrective effect of the preparation on the impaired bacterial biocenosis.
A 7-day treatment with the preparation reduced the pathogenic flora in the
smears and restored vaginal microbial biocenosis. Gram-positive and Gram-
negative cocci, Gram-negative bacteria and both vegetative and nonvegetative
yeast were all sensitive to the effect of the suppositories of the present invention.
Thus, the irritant vaginitis model demonstrated a strong antimicrobial
effect of the suppositories of the present invention. Treatment with the
preparation resulted in restoration of the natural balance of vaginal
A morphological study of vaginal slices of rats with irritant vaginitis was
conducted on the 1st, 3rd, and 7th day of the experiment.
In the first three days of the experiment, the control rats were found to
have destructive inflammatory changes in all layers of the vaginal walls. The
outer layer of the mucous membrane epithelium was in a state of necrobiosis and
was entirely missing in some spots. Hyperchromatism of the nuclear membrane
and chromatin lysis were observed. Polymorphonuclear leukocytes infiltrated the
submucosal layer and penetrated the epithelium. Hyperemia and edema of the
loose connective tissue were observed in the deeper strata of the submucosal
layer. On the third day, the destructive processes continued. A strong
inflammatory reaction was expressed as a massive infiltration with granular
leukocytes and the emergence of macrophages, lymphocytes and plasmatic
cells. By the 7th day of the experiment, the changes in vaginal mucous
membrane were not very pronounced: the epithelium of the mucous membrane
was fully regenerated, the nuclei of the epithelium cells were clearly defined;
hyperemia, edema, and leukocytic infiltration of the submucosal layer were not
Treatment with the suppositories of the present invention in the first three
days slightly reduced the intensity of the inflammation of the mucous membrane
epithelium. Cell necrobiosis was observed in the outer layers of the epithelium,
polymorphonuclear leukocytes infiltrated the inflammation zone, and isolated
polymorphonuclear leukocytes, leukocytes, and plasmatic cells were detected.
Treatment with the suppositories of the present invention for 7 days
promoted a full restoration of the epithelium integrity; the histological structure of
the vaginal mucous membrane did not differ from that of the intact rats.
Data from histological study fully correlated with the results of the
hematologic and microbiologic inflammation markers.
Thus, the claimed composition is effective in the treatment of experimental
Clinical efficacy of the suppositories was determined while administering
them to male and female patients suffering from diseases of the lower
Example 4. Efficacy of the suppositories in treating patients
suffering from chronic prostatitis
A study of clinical efficacy of the suppositories was conducted on 22
patients aged 25 – 47 suffering from chronic prostatitis.
Chronic prostatitis mainly presented as gnawing pain in a typical location,
various urination disorders, sexual dysfunctions, and signs of neuroticism.
All the patients earlier received traditional symptomatic and pathogenic
drugs providing short-term therapeutic effects and requiring patients to receive
increased doses of the preparations in the course of treatment over a long period
of time. The suppositories were administered rectally, at bedtime, over a 10 – 15
day period depending on the degree of severity of the disorder. The control
group consisted of 10 analogous patients receiving traditional treatment.
The efficacy of the treatment with the claimed suppositories was evaluated
based on the dynamics of patients’ complaints, complete blood count and
urinalysis, biochemical blood profile, and a coagulation profile test pre and post
treatment. Abdominal pressure during urination and the character of the urinary
stream was expressed in points from 1 to 5 (with 1 being normal and 5 – having
the most changes.) Peak and mean urine flow rates, time length of urination,
time to reach peak urine flow rate, and the flowmetric index were measured.
Along with the aforementioned studies, the prostate gland was palpated, its
secretion was analyzed in the laboratory, and an in-depth study of the copulative
function was performed. An ultrasonic examination of the prostate gland was
When evaluating the results obtained in the treatment of chronic
prostatitis, the clinical criteria received the most attention. Upon completion of
the treatment, the pain completely disappeared in 72.4% of the patients and
considerably diminished in 23.7% of the patients who had reported such
complaints. 52.6% of the patients suffering from sexual dysfunction showed a
complete recovery and 43.7% reported improvement. The suppositories had
positive effects on improved erectile function, enhanced orgasm, and abolition of
pain during orgasms. A longer duration of sexual intercourse was also reported.
By the end of the treatment, 50.6% of the patients reported a restored libido.
85.4% of the patients no longer complained of pollakiuria (frequent
urination). The need for nocturnal urination had disappeared. 82.7% of patients
reported no more strangury (painful urination) and 22.9% had a significant
improvement in the strength of the urinary stream and easier urination.
Urologic flowgrams recorded after the treatment in patients suffering from
prostatitis stage I and II showed the main urination parameters restored to their
normal values. On stage III of the disease, recovery was hindered by the
reduced elasticity of the urinary bladder neck due to sclerotic changes in the
prostate gland tissue, but these patients also reported a significantly stronger
urinary stream. When the prostate gland was palpated through the rectum after
the treatment with the claimed suppositories, it showed a trend to recover its size
and consistency. Additionally, the areas of induration had disappeared and the
examination itself was not painful. The observed reduction in the size of the
prostate gland could be attributed to the reduced edema of the intestinal tissue
and indicates the absence of inflammatory activity within, which was also
confirmed by ultrasound diagnostics. The complete clinical and biochemical
blood profile tests conducted in the process did not reveal any significant
deviations from the norm. No side effects were reported.
Due to the restoration of the prostate function by the suppositories, its
secretion quality had improved, which prompted a 23.7% increase in the active
sperm count of the ejaculate. The reduced activity of the inflammation process
was confirmed by a lowered number of leukocytes in the ejaculate, prostate
secretion, and urine. At the same time, the amount of exfoliated epithelial cells in
the material under study was found to be lower.
Example 5. Efficacy of the suppositories in treating older and
elderly patients suffering from dysuric disorders
49 patients, including 29 men aged 68 to 82, and 20 women aged 58 to
84, suffering from urination disorders participated in the study. All older and
elderly patients complained of frequent urination (10 – 20 times per 24 hrs),
especially at night (up to 5 – 10 times), which considerably affected their quality
of life and impeded their social adaptation.
The efficacy of treatment was evaluated based on the dynamics of their
complaints and urodynamic indicators. Peak and mean urine flow rates, time
length of urination, time to reach peak urine flow rate, and the flowmetric index
The patients were randomized into 2 groups. The control group consisted
of 18 people (11 men and 7 women) who receive traditional treatment including
spasmolytic preparations (Spasmex, Spasmol, Spasmoveralgin Neo) and
31 patients in the main group (18 men and 13 women) were subdivided
into 3 subgroups depending on the severity of their urination disorders. The
patients with most severe dysuric disorders expressed as frequent urination up to
15 – 20 times per 24 hrs, and especially at night (up to 10 times), were rectally
receiving the suppositories in the morning and at bedtime over 15 days.
The patients with moderate urination disorders expressed as frequent
urination (up to 10 times per 24 hrs. including up to 5 times at night) were rectally
receiving the suppositories at bedtime over 10 -15 days.
A comparison of the indicators for patients in the control and main groups
showed pronounced positive dynamics in the group of patients receiving the
All the patients receiving the suppositories assessed their condition as
“improved’ during evaluation of the dynamics of subjective indicators. 76.5% of
the main group patients no longer complained of pollakiuria (frequent urination),
they also no longer had nocturnal urinary urgency. 13.2% of the main group
patients reported significantly decreased pollakiuria (7 – 8 times per 24 hrs.), and
nocturnal urination was reduced 2 – 3 times.
The urodynamic indicators following the administration of the
pharmaceutical composition in suppository form to older and elderly patients
suffering from dyuric disorders is shown in the Table.
Effect of the suppositories on the urodynamic of older and elderly patients
with dysuric disorders
* - P < 0.05 in comparison to the indicator before treatment;
# - P < 0.05 in comparison to the indicator in the control group patients
It is noteworthy that the control group patients did not show any positive
dynamics of urinary bladder function based on both subjective and objective
indicators, despite the use of traditional medications.
The uroflowmetric index in the control group patients receiving traditional
therapy was practically unchanged after treatment.
The uroflowmetric index increased almost twofold in the main group
patients receiving the claimed suppositories, which confirms their positive effect
After treating older and elderly patients suffering from moderate dysuric
disorders with the suppositories, the recorded uroflowgrams showed restoration
of the main urinary parameters to their normal values.
Elderly patients with severe dysuric disorders did not achieve fully
normalized urination parameters due to the age-related lowered elasticity of the
urinary bladder neck; however, such patients receiving the suppositories showed
significant improvements in the strength of the urination stream and decreased
need to urinate during the day (down to 7 – 8 times) and at night (down to 2 – 3
These data confirm the therapeutic efficacy of rectally administered
suppositories over a 10 – 15 day period, depending on the severity of the
disorder, and makes them useful for treating patients with dysuric disorders of
different origins in order to restore functional activity of the detrusor-sphincter
Example 6. Efficacy of the suppositories in treating genitourinary
disorders in perimenopausal and postmenopausal women
24 perimenopausal and postmenopausal women aged 46 – 55 suffering
from genitourinary disorders were treated with the suppositories. The women
complained of hot flashes to the head and upper body, hyperhidrosis, high
irritability, and emotional lability. Vaginal atrophy symptoms (vaginal dryness and
itching, dyspareunia, recurrent vaginal discharge) and cystourethral atrophy
symptoms (frequent daytime (pollakiuria) and nighttime (nocturia) urination,
cystalgia, and urinary urgency were also reported.
The claimed suppositories were used vaginally at bedtime for 25 – 30
The suppositories were found to stop subjective manifestations of vaginal
(vaginal dryness and itching, dyspareunia, bleeding, etc.) and cystourethral
(pollakiuria, nocturia, urinary urgency, etc.) atrophy in 83% of the women. Said
symptoms disappeared both in perimenopausal and postmenopausal women.
Vaginal health index for these women increased to 4 – 5 points, vaginal epithelial
maturation went up to 57 – 79% (intermediate and surface cells appeared), the
The symptoms of urinary stress incontinence completely disappeared in
27% perimenopausal women receiving monotherapy with the suppositories.
For other forms of dysuric disorders, therapy with the suppositories
combined with hormone replacement therapy, behavior therapy, and M-
cholinolytics, selective serotonin reuptake inhibitors) were used from the start.
After such treatment, 82% of the patients showed positive results: daytime and
nocturnal urination frequency decreased 2.5 times and 93% of the patients no
longer experienced urge urinary incontinence.
Thus, the obtained results confirm the normalizing effect of the
suppositories on the genitourinary tract structures, such as improved trophism
and epithelium proliferation as well as normalizing detrusor overactivity due to
The claimed suppositories are useful as therapeutic and preventive agents
in combination with any nosotropic therapy used for the treatment of
genitourinary disorders in perimenopausal and postmenopausal women.
These studies showed that the claimed pharmaceutical composition in
suppository form was effective not only for the treatment of prostate diseases (as
well as the mixture of bovine prostate bioregulatory peptides) but also in treating
other diseases of small pelvic organs in both men and women.
The claimed pharmaceutical composition can be manufactured in any
pharmaceutical facility equipped for the production of suppositories.
1. A pharmaceutical composition for the treatment of diseases of the
lower genitourinary system in suppository form comprising a bioactive compound
and a fatty base, wherein the said bioactive compound of the said composition is
a mixture of amino acids: glutamic acid, lysine, alanine, arginine and glycine,
and further comprising zinc in the form of zinc chloride in the following
component ratio expressed in grams per one suppository weighing 2.7 – 2.9 g
2. The pharmaceutical composition according to claim 1, wherein said
composition further comprises 10 – 30 mcg of selenium in the form of anhydrous
3. The pharmaceutical composition according to claim 1, wherein said
composition further comprises 0.020 – 0.035 g of sodium fumarate.
CONTROL AND MANAGEMENT OF POISONOUS MUSHROOMS IN THE LANDSCAPE R. Michael Davis, Department of Plant Pathology University of California, Davis, 95616, A mushroom is the large and fleshy reproductive structure, or fruiting body, of certain fungi. Its purpose is the production and dispersal of spores. Generally, mushrooms have a cap, stalk, and some kind of spore-bearing surface, such as
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