How can you lower your risk of developing benign prostatic hyperplasia. What lifestyle changes can help manage BPH symptoms. Which factors increase the likelihood of BPH. How do medications impact BPH prevention and management. What are the key signs that indicate a need for medical attention regarding prostate health.

Understanding Benign Prostatic Hyperplasia (BPH)

Benign Prostatic Hyperplasia, commonly known as BPH, is a condition characterized by the enlargement of the prostate gland. This non-cancerous growth affects a significant portion of men as they age, with approximately 90% of men experiencing BPH by their 80s. While complete prevention of BPH may not be possible due to its strong association with aging, there are several strategies that can help manage symptoms and potentially slow its progression.

What exactly is BPH?

BPH occurs when the prostate gland, located just below the bladder, grows larger than normal. This enlargement can lead to various urinary symptoms that can significantly impact a man’s quality of life. It’s important to note that while BPH is common, it is not cancerous and does not increase the risk of prostate cancer.

Recognizing the Symptoms of BPH

Early detection of BPH symptoms is crucial for effective management. Men should be aware of the following common signs:

• Difficulty starting urination
• Weak urine stream or stream that stops and starts
• Frequent urination, especially at night
• Feeling that the bladder is not completely empty after urination
• Urgency to urinate
• Dribbling at the end of urination

If you experience these symptoms, it’s advisable to consult a healthcare professional for proper evaluation and guidance.

When do BPH symptoms require immediate medical attention?

While most BPH symptoms can be managed with lifestyle changes or medication, some situations demand urgent medical care. Seek immediate medical attention if you experience:

• Complete inability to urinate
• Severe pain or discomfort in the lower abdomen
• Blood in the urine
• Frequent, painful urination accompanied by fever and chills

Risk Factors for Developing BPH

Understanding the risk factors associated with BPH can help men take proactive steps towards managing their prostate health. The primary risk factors include:

Age-related risk of BPH

The likelihood of developing BPH increases significantly with age. While it’s rare in men under 40, the prevalence rises sharply in men over 50. By age 80, up to 90% of men may have some degree of prostate enlargement.

Genetic predisposition to BPH

Family history plays a role in BPH risk. Men whose fathers or brothers have BPH are more likely to develop the condition themselves. This genetic link underscores the importance of being aware of your family’s medical history.

Ethnicity and BPH risk

Studies have shown that BPH affects black and white men more frequently than Asian men. Additionally, black men may experience symptoms at a younger age compared to other ethnic groups.

Health conditions linked to increased BPH risk

Certain health conditions can elevate the risk of developing BPH. These include:

• Obesity
• Heart disease
• Type 2 diabetes
• High blood pressure

Managing these conditions through lifestyle changes and appropriate medical care may help reduce the risk or severity of BPH symptoms.

Lifestyle Modifications for BPH Prevention and Management

While lifestyle changes cannot completely prevent BPH, they can play a significant role in managing symptoms and potentially slowing the progression of the condition. Here are some key strategies:

How can diet impact BPH?

A heart-healthy diet rich in fruits, vegetables, and whole grains may help manage BPH symptoms. Some specific dietary recommendations include:

• Increasing intake of vegetables, especially those high in antioxidants
• Limiting consumption of red meat and high-fat foods
• Reducing alcohol intake, as it can irritate the bladder and exacerbate symptoms
• Limiting caffeine consumption, which can increase urinary frequency and urgency

Exercise and its role in BPH management

Regular physical activity can have multiple benefits for men with or at risk of BPH:

• Helps maintain a healthy weight, reducing the risk of BPH progression
• Improves overall cardiovascular health, which is linked to prostate health
• May help the bladder empty more effectively, reducing urinary symptoms

Aim for at least 30 minutes of moderate exercise most days of the week. Activities like brisk walking, swimming, or cycling can be particularly beneficial.

Weight management and BPH

Maintaining a healthy weight is crucial in managing BPH risk and symptoms. Obesity is associated with an increased risk of BPH and more severe urinary symptoms. Losing excess weight through a combination of diet and exercise can help alleviate symptoms and potentially slow the progression of prostate enlargement.

Medications and Their Impact on BPH

Certain medications can affect BPH symptoms or risk. It’s important to be aware of these interactions and discuss them with your healthcare provider.

Medications that may increase BPH risk

Beta-blockers, commonly used to treat high blood pressure and migraines, have been associated with an increased risk of BPH. If you’re taking beta-blockers and experiencing urinary symptoms, consult your doctor about potential alternatives.

Medications to avoid with BPH

Some over-the-counter medications can worsen BPH symptoms. These include:

• Decongestants
• Antihistamines
• Certain pain medications

These medications can tighten the muscles controlling urine flow, making it more difficult to urinate. If you have BPH, discuss safe alternatives with your healthcare provider.

Medical Interventions for BPH Prevention and Management

While lifestyle changes are important, medical interventions can play a crucial role in managing BPH, especially for men at higher risk or with more severe symptoms.

Alpha-1 blockers for symptom management

Alpha-1 blockers are medications that relax the muscles in the prostate and bladder neck, making it easier to urinate. These drugs can provide rapid relief of BPH symptoms but do not prevent the progression of prostate enlargement.

5-alpha reductase inhibitors for prostate shrinkage

5-alpha reductase inhibitors work by blocking the hormone responsible for prostate growth. These medications can actually shrink the prostate over time, potentially reducing symptoms and slowing disease progression. However, they may take several months to show significant effects.

Combination therapy for comprehensive BPH management

For some men, a combination of alpha-1 blockers and 5-alpha reductase inhibitors may be recommended. This approach can provide both immediate symptom relief and long-term management of prostate growth.

Emerging Research and Future Directions in BPH Prevention

The field of BPH prevention and management is continually evolving, with ongoing research exploring new strategies and treatments.

Potential role of nutritional supplements

Some studies have investigated the potential benefits of certain supplements in managing BPH symptoms. While results are mixed, supplements such as saw palmetto, beta-sitosterol, and pygeum have shown promise in some research. However, it’s crucial to consult with a healthcare provider before starting any supplement regimen.

Advancements in minimally invasive treatments

Research is ongoing into new minimally invasive procedures for treating BPH. These include various forms of thermal therapy, injection treatments, and novel surgical techniques that aim to provide effective symptom relief with fewer side effects than traditional surgeries.

Personalized medicine approaches to BPH

As our understanding of the genetic and molecular basis of BPH improves, there is growing interest in developing personalized treatment strategies. This approach aims to tailor prevention and treatment plans based on individual risk factors, genetic profile, and specific characteristics of the prostate enlargement.

Importance of Regular Prostate Health Screenings

Regular prostate health screenings are crucial for early detection and management of BPH and other prostate conditions. These screenings typically involve:

• Digital rectal examination (DRE) to assess prostate size and texture
• Prostate-specific antigen (PSA) blood test to check for potential prostate issues
• Urinary flow tests to evaluate the severity of urinary symptoms

The frequency of these screenings may vary based on age, risk factors, and overall health status. Consult with your healthcare provider to determine the appropriate screening schedule for your individual needs.

When should men start regular prostate screenings?

The American Urological Association recommends that men discuss prostate cancer screening with their healthcare provider starting at age 55, or earlier for those at higher risk. However, discussions about prostate health and BPH can begin even earlier, especially if you have a family history or are experiencing urinary symptoms.

By understanding the risk factors, recognizing symptoms early, and implementing appropriate lifestyle changes and medical interventions, men can take proactive steps to manage their prostate health and minimize the impact of BPH on their quality of life. Regular communication with healthcare providers and staying informed about the latest developments in BPH prevention and treatment are key to maintaining optimal prostate health throughout life.

How To Avoid & Prevent BPH

Men with BPH have a larger-than-normal prostate. Some 9 in 10 men will have it by the time they’re in their 80s. Even with those chances, you still might ask: Are there things I can do to prevent it?

The short answer is no. For most men, the prostate gland is just going to grow, and it might lead to benign prostatic hyperplasia, as it’s formally known.

But it still helps to know when you’d want to see your doctor, what makes you more likely to get it, and how you can keep the symptoms at bay.

When Should I See a Doctor?

Growth of this gland, which is just below the bladder, is typical. But problems when you pee aren’t. Even if you don’t think it’s a big deal, it’s worth getting checked out if you have common BPH symptoms, such as:

• Dribbling when you finish peeing
• A hard time starting a stream
• Having to pee a lot — 8 or more times a day
• Waking up several times a night to pee
• A weak urine stream or you pee in stops and starts

Some problems with urine flow can be more serious. See your doctor or go to the emergency room right away if you:

• Can’t pee at all
• Feel intense pain or discomfort in your lower belly
• Have blood in your pee
• Keep needing to pee right away, it hurts to pee, and you have fever and chills

Who’s More Likely to Get BPH?

You may have a greater chance of an enlarged prostate based on your:

• Age. BPH is more common the older you get and doesn’t usually affect men younger than 40.
• Family history. If your dad or your brothers have the condition, you have a higher chance of getting it, too.
• Ethnicity. This affects black and white men more often than Asian men. Black men may get symptoms at a younger age.

Some health conditions can also raise the odds you’ll get BPH, such as:

If you use beta blockers — a type of medication used to treat conditions such as high blood pressure and migraines — you may be more likely to get BPH.

Can Lifestyle Changes Help?

Lifestyle changes can’t prevent BPH, but they may still be good for your prostate. For starters, exercise and a heart-healthy diet can help manage your weight, which is great for your prostate. Exercise can also help your bladder empty at a normal rate.

• To control symptoms, it may help to:
• Avoid or limit how you use decongestants and antihistamines during colds and allergy outbreaks as they tighten the muscles that control urine flow and make it harder to pee

• Do exercises to strengthen your pelvic floor muscles
• Limit how much caffeine and alcohol you take in; they make you pee more and can irritate your bladder
• Lower the amount of fluids you drink, especially before you go out or go to bed
• Pee when you first feel the urge because it’s easier on your bladder
• Stay warm. Cold can make it feel more urgent to pee.

[Primary and secondary prevention of benign prostatic hyperplasia: current knowledge and implications for clinical management]

Histological benign prostatic hyperplasia (BPH) and the BPH disease are frequent, lead to a reduction of quality of life, are both progressive and potentially associated with complications in the lower and upper urinary tract. A PubMed/MEDLINE search was conducted for the years 1990 to 2011. This article summarizes known selective measures of primary and secondary disease prevention.Measures of primary disease prevention aim to inhibit histological BPH and the development of clinically relevant BPH. Weight loss, regular physical activity, vegetable consumption, alcohol intake, 5α-reductase inhibitors, avoidance of overweight and reduction of fatty food can reduce the probability of histological and clinical BPH. Selective measures of secondary prevention aim to inhibit disease progression and BPH-associated complications. The regular and long-term use of α1-blockers reduces lower urinary tract symptoms (LUTS) and inhibits symptomatic disease progression but cannot prevent BPH-associated complications (e.g. urinary retention or need for prostate surgery). 5α-Reductase inhibitors can reduce the probability of symptomatic disease progression, urinary retention or need for surgery but the combination of α1-blocker and 5α-reductase inhibitor is more efficacious than either monotherapy. Especially older men with enlarged prostates (>40 cm(3)) and elevated serum PSA concentration (>1.6 µg/l) profit from measures of secondary disease prevention.For primary disease prevention, data quality is low and early treatment with 5α-reductase inhibitors is not been approved. For secondary disease prevention, men with risk factors of disease progression should use a treatment containing 5α-reductase inhibitors. Despite several epidemiological and clinical investigations on BPH disease progression no official programme exists in Germany for disease prevention.

Crucial Advice to Help Reduce the Risk and Growth of BPH

By: Mark A. Moyad, MD, MPH
|
Posted on: 23 Aug 2017

What kind of cruel joke is nature playing on us men? As we age, everything with our bodies seems to get smaller (or shorter) except for our stomachs and prostate gland! Benign prostatic hyperplasia (BPH) is the most common male-specific health condition in the United States.

I believe the most successful BPH supplements work by lowering cholesterol, which improves your heart health. Cutting your cardiovascular disease risk can make a difference with all kinds of health conditions, from BPH to varicose veins.

Supplements

Supplements can be used with normal BPH treatment options, but all patients are different and you should talk to your doctor before taking a new supplement. The following supplements might be helpful:

• Beta-sitosterol and other plant sterols. 60 to 195 milligrams a day in divided doses (or up to 2,000 to 3,000 milligrams a day in divided doses potentially).
• Pygeum africanum. 75 to 200 milligrams a day in divided doses. 
• Flaxseed and SDG. 300 to 600 milligrams a day.
• Pumpkin seed (cucurbita pepo) oil. 320 milligrams a day.

As an honorable mention, I’d include Cernilton (a pollen extract mixture) on this list above. Cernilton has been shown to improve quality of life and reduce pain in men with chronic prostatitis/chronic pelvic pain syndrome.

BPH supplements that do not have a lot of evidence to support their effectiveness include DHEA, which could increase the size of the prostate. Zinc is also very popular as a BPH supplement, yet it has no better evidence than a placebo to support its effectiveness. Some of the older and better preliminary studies suggest that higher supplemental dosages (more than 100 mg/day) could actually increase the risk of aggressive prostate cancer.

Lifestyle Changes

Heart healthy = prostate healthy. Pretty much every lifestyle change found to be heart healthy has been shown to reduce the risk or growth of BPH. Keep a normal blood pressure, blood sugar and cholesterol level along with a healthy weight and waist size.

Drinking in moderation is also vital to lowering the risk of BPH and reducing the symptoms tied to BPH. Of course, this doesn’t mean you should start drinking alcohol if you already don’t drink! Alcohol in moderation has been associated with a lower risk of BPH and in excess could reduce the efficacy of BPH drug therapy.

Make sure to work up a sweat. Exercise on a regular basis to prevent BPH or reduce the growth of it, is to exercise regularly. Try to exercise at least 30-minutes per day. In a famous Harvard study, regular physical activity was even associated with a lower risk of getting surgery for BPH!

How can benign prostatic hyperplasia (BPH) be prevented?

Can men prevent an enlarged prostate?

Prostate cancer is the most common cancer in American men. But prostate enlargement affects even more men- about half of all men over age 50 and up to 90 percent of men over age 80. This condition, known as benign prostatic hyperplasia (BPH) does not indicate prostate cancer risk. Yet some researchers suggest that whatever hormones or other influences cause BPH to develop may also spur the onset of cancer.

BPH occurs when normal (noncancerous) prostate cells grow abnormally. As the prostate enlarges, it presses down on the urethra, the tube that carries urine out of the bladder for voiding. This pressure can lead to the following symptoms: sensation that the bladder is not empty, even after urinating; feeling an urgent need to urinate; a weak urinary stream and dribbling; the need to stop and start several times when urinating; and the need to urinate several times during the night.

Although a few studies have been done in this area, it is still uncertain why some men get BPH and not others, or what might prevent the condition. The only established risk factors for BPH are age and family history. Hormones are believed, however, to promote prostate cell growth.

Study links high calorie intake
One study of the problem links higher calorie intake, as well as diets higher in protein and some kinds of polyunsaturated fats, with prostate enlargement. Researchers suggest that excess calorie consumption could somehow directly stimulate prostate enlargement.

The excess body fat that accumulates and its effects on hormone levels could also be the link.

Evidence from a number of studies that group too many calories, obesity and insulin resistance with cancer promotion suggest indirectly that if you avoid these three influences you can also reduce your risk of BPH. Other studies suggest that regular exercise can help protect against prostate cancer. Because keeping active directly affects hormone levels and helps weight control, activity may also discourage BPH.

Greek men who eat more fruit decrease their odds of developing BPH, according to one study. Since fruits are loaded with a variety of vitamin and natural antioxidant phytochemicals, free radicals (highly reactive compounds that can damage our cells’ DNA) could be involved in BPH, just as many scientists believe they are in prostate cancer. A laboratory study found that lycopene, an antioxidant especially in cooked tomatoes, can slow the growth of prostate cells.

BPH symptoms, treatments
Men who are significantly bothered by the symptoms of BPH should discuss them with their doctor. Burning sensation, pain or blood that appears when urinating demand immediate visits to the doctor. While these symptoms could indicate BPH, the problem could also be an infection, cancer or another obstruction that needs medical treatment.

If BPH is the diagnosis, your doctor can offer treatment through medications or surgery. Supplements such as saw palmetto and pygeum are also popular alternatives to block the effects of hormones and reduce BPH symptoms. But since supplements are unregulated in the U.S., the quality and safety of these products is unreliable. Research is underway to evaluate if prostate cancer can be prevented through soy, selenium, vitamin E and vitamin D. But the potential impact of these substances on either prostate cancer or BPH is unknown.

To prevent BPH, maintaining a healthy weight by avoiding excess calories and keeping physically active is a good step based on today’s evidence. Eating a balanced plant-based diet loaded with vegetables, fruits, whole grains and beans, which the American Institute for Cancer Research advocates for lower cancer risk, is another. For now, that’s the soundest advice to avoid the seemingly unavoidable enlargement of the prostate.

Prostate Cancer: Prevention | Johns Hopkins Medicine

While many people may wonder how to prevent prostate cancer, there’s no one way to avoid the disease. Staying healthy as you age, or working to reverse existing health problems, can lower your risk. However, like all cancers, prostate cancer has certain risk factors that cannot be avoided.

Things You Can’t Change: Age, Race and Genes

Prostate cancer is primarily a “disease of aging.” As you get older, your chances of developing prostate cancer increase. Race and genetics also play a significant role. If you are African American, your chances of developing prostate cancer are double those of white American men. If your father, brother or multiple blood relatives had prostate cancer, you are more likely to get it, too.

Preventing prostate cancer might be difficult if you have these risk factors, but screening early and often can help ensure that if you do get cancer, it’s diagnosed and treated as soon as possible.

Things You Can Change: Diet and Lifestyle

Men in western countries have much higher rates of prostate cancer than men in Asia. While no one can definitively explain this phenomenon, experts suspect differences in eastern and western diets are to blame. Poor eating habits and diets that heavily rely on fats and animal proteins can cause DNA damage and lead to cancer.

Even men who are already at greater risk due to age, race or genetics can reduce their chances of developing prostate cancer by adopting healthy diets and lifestyles.

Improve Your Diet

Researchers don’t completely understand the relationship between diet and prostate cancer prevention, but studies suggest that certain eating habits may help.

• Reduce fat intake. Eat less trans fats and saturated fats. Focus on healthy fats such as omega-3 fatty acids from nuts, seeds and fish.

• Eat more fruits and vegetables. Incorporate a wide variety of produce, including plenty of leafy greens. The antioxidant lycopene, which is plentiful in cooked or processed tomatoes, has been shown in some studies to slow the growth of prostate cancer cells. Cruciferous vegetables (e.g., broccoli and cauliflower) contain a compound called sulforaphane that may protect against cancer.

• Add green tea and soy. Clinical trials have suggested that soy may lower PSA levels, and that green tea may help men who are at high risk for prostate cancer lower their risk.

• Avoid charred meat. Charred meat, from frying or grilling at high temperatures, may produce a chemical compound that leads to cancer.

Maintain a Healthy Weight

Obesity can be a risk factor for developing more aggressive prostate cancer. In general, losing weight and maintaining a healthy weight as you age can help reduce your risk of cancer and many other health problems.

Get Regular Exercise

In addition to helping you achieve a healthy weight, exercise can reduce inflammation, improve immune function and fight some of the negative health effects of a sedentary lifestyle—all of which can help prevent cancer.

Stop Smoking and Drink Less

Quitting smoking can improve your health in many ways, including lowering your cancer risk. And if you drink, do so in moderation. Some studies suggest that red wine has antioxidant properties that may benefit your health.

Increase Your Vitamin D

Most people don’t get enough vitamin D. It can help protect against prostate cancer and many other conditions. Vitamin D-rich foods include cod liver oil, wild salmon and dried shitake mushrooms. Since the sun is a better, more readily available source of vitamin D, many experts recommend getting 10 minutes of sun exposure (without sunscreen) every day. Doctors often recommend vitamin D supplements. However, you should talk to your doctor before taking any vitamin or supplement.

Stay Sexually Active

Two studies appear to show that men who have a higher frequency of ejaculation (with or without a sexual partner) were up to two-thirds less likely to be diagnosed with prostate cancer. Studies are ongoing, but some experts theorize that ejaculation clears the body of toxins and other substances that could cause inflammation.

Drugs to Prevent Prostate Cancer

Men with benign prostatic hyperplasia (BPH) are often treated with dihydrotestosterone (DHT)-lowering drugs called finasteride or dutasteride. These drugs have been studied extensively to determine whether they can prevent prostate cancer, and results suggest that they could reduce cancer risk by about 25 percent. Patients who develop cancer while on the drugs are more likely to get an aggressive form of the disease, so discuss the advantages and disadvantages with your doctor.

[[prostate_cancer_links]]

Enlarged prostate: Does diet play a role?

The risk of an enlarged prostate, also called benign prostatic hyperplasia (BPH), increases with age. By age 50, half of men will show signs of BPH. But making some healthy changes to your diet and exercise habits may help you manage BPH symptoms such as increased urinary frequency and urgency.

While there’s no one magic bullet, research suggests that these measures may lessen BPH symptoms:

• Avoid liquids a few hours before bedtime or before going out
• Limit caffeine and alcohol as these may stimulate the urge to urinate
• Eat a low-fat diet
• Eat a large variety of vegetables each day
• Eat a few servings of fruit daily, and be sure to include citrus fruits
• Participate in moderate to vigorous physical activity most days of the week
• Maintain a healthy weight

The role of total protein in the diet and its link to BPH is unclear. Some studies found an increased risk of BPH in men who ate more red meat. But other studies found a decreased risk of BPH in men with a high total protein intake, especially protein intake of leaner forms of protein such as fish.

Studies on dietary supplements and herbal therapies — such as saw palmetto, lycopene and beta-sitosterol — and BPH have had mixed results. Ask your doctor for advice before taking supplements.

The bottom line? Healthy habits such as regular exercise, watching your waistline, eating vegetables and fruits, and keeping an eye on dietary fat may help with BPH as well as lower your risk of erectile dysfunction, diabetes and heart disease.

• Bladder outlet obstruction
• Increased PSA levels

July 11, 2020

Show references

1. ElJalby M, et al. The effect of diet on BPH, LUTS and ED. World Journal of Urology. 2019; doi:10.1007/s00345-018-2568-0.
2. Das K, et al. Benign prostate hyperplasia and nutrition. Clinical Nutrition ESPEN. 2019; doi:10.1016/j.clnesp.2019.07.015.
3. Chughtai B, et al. Benign prostate hyperplasia. Nature Reviews|Disease Primers. 2016; doi:10.1038/nrdp.2016.31.
4. Chen Y, et al. Relationship among diet habit and lower urinary tract symptoms and sexual function in outpatient-based males with LUTS/BPH: A multiregional and cross-sectional study in China. BMJ Open. 2016; doi:10.1136/bmjopen-2015-010863.
5. Cunningham GR, et al. Medical treatment for benign prostatic hyperplasia. https://www.uptodate.com/contents/search. Accessed April 14, 2020.

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Products and Services

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Premier Publishing s.r.o.

Epidemiology and clinical manifestations of benign
prostatic hyperplasia in the Khorezm region

DOI : https://doi.org/10.29013/ESR-17-1.2-145-147

Pages : 145 – 147

Authors : Khudaybergenov U. A., Akilov F. A., Makhmudov A. T.

Abstract : Epidemiologic studies are becoming relevant solution for efficient prophylactic tactics in urological disease treatment
and prognosis. This paper is an attempt to highlight regional basis epidemiology of benign prostatic hyperplasia (BPH),
particularly in Khorezm Region of Central Asia. This study focused preventive measurements of preventive therapy for the early
detection of BPH and reduce the incidence of complications. Output of this study concludes that prevalence of symptoms of
BPH increases progressively with age

Keywords : Epidemiology, benign prostatic hyperplasia (BPH), urine flow data

Bibliography :
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M., – 2002. – S. 33–42.
2. Nurullaev RB Epidemiological aspects, treatment and prevention of the most significant urological diseases. Abstract of thesis.
diss. Dr. med. – T., – 2005 .– 37 p.
3. Tarasenko BV, Klepov Yu. Yu., Nurullaev RB Benign prostatic hyperplasia: prevalence and natural development of the disease
// Problems of biology and medicine. – Samarkand, – 2001. – No. 4. – P. 7–17.
4. Alcaraz A. et al. Is there evidence of a relation between benign prostatic hyperplasia and prostate cancer? // Eur. Urol. – 2009. – 55:
864-875.
5. Egan K. B. “The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms: Prevalence and Incident
Rates”. Urol Clin North Am – 2016. – 43 (3): – P. 289-297.
6. Homma Y., Kawabe K., Tsukamoto T., Yamanaka H., Okada K., Okajima E., Yoshida O., Kumazawa J., Gu FL, Lee C., Hsu TC, de
la Cruz RC, Tantiwang A., Lim PH, Sheikh MA, Bapast SD, Marshall VR, Tajima K., Aso Y. Epidemiologic survey of lower
urinarytract symptoms in Asia and Australia using the International Prostate Symptom Score // Int Urol – 1997. – P. 40–46.
7. Mohammad R. S. Prevalence of benign prostatic hyperplasia in a population-based study in Iranian men 40 years old or older. Urology
and Nephrology Research center, Shaheed Beheshti University of Medical Sciences, P. O. Box 19395-1849, Tehran, Iran.
8. Kjaerulff T. M., A. K. Ersboll, A. Green M. Emneus E. Pukkala K. Bolin K. Stavem P. Iversen K. Brasso J. Hallas and L. C. Thygesen.
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of prostatism in Japanese men in a population based study with comparison to a similar American study // J … Urol – 1995. – 154. – P.
391–395.

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COMPOSITION FOR TREATMENT AND PREVENTION OF BENIGN PROSTATE HYPERPLASIA

FIELD OF THE INVENTION

The present invention provides a composition for the treatment and prevention of benign prostatic hyperplasia. More specifically, the present invention provides a composition comprising a peptide derived from telomerase, wherein the composition is for the treatment and prevention of benign prostatic hyperplasia.

BACKGROUND OF THE INVENTION

Benign prostatic hyperplasia (BPH) is the most common age-related disease in men, which is accompanied by a deterioration in the functioning of the urinary tract. Symptoms associated with this disease begin to appear after age 40, but most clinical symptoms occur in patients over 50. The decline in quality of life seen with BPH can cause sexual dysfunction, and sexual function can also be affected by BPH treatment and surgery for BPH.

Hyperplasia causing BPH is dependent on male sex hormones. In particular, male sex hormones are required for the normal proliferation of prostate cells as well as for the inhibition of normal apoptosis. The most well-known endogenous cause of this disease is aging. The prostate enlarges with aging and with the normal functioning of the testes. As the male sex hormone on which prostate function depends, testosterone plays an important role in regulating prostate growth and differentiation and is metabolized by 5-alpha reductase to form dihydrotestosterone (DHT), which plays an important role in regulating prostate growth and gene expression.

Exogenous causes include male sex hormones, estrogen, glucocorticoids, and substances related to endocrine enzymes, induced by diet and environmental conditions. The physiological effects of these exogenous causes are mediated by peptides of different types of growth factors.

BPH may occur in men between the ages of 20 and 50, characterized by histological changes induced by the synergistic action of male sex hormones and estrogen.With age, the estrogen / DHT ratio increases and the likelihood of developing BPH increases.

In addition, it is widely known that the prostate grows up to early 20s and then maintains its size up to 50 using very complex mechanisms, including endogenous growth factors, signaling pathways, regulation of cell cycles, cell division and apoptosis. A change in the factors that regulate the cell cycle can induce the development of BPH.

Genetic factor may be a major contributor to the development of BPH. It has been reported that among patients with a family history of BPH, the incidence of BPH is more than 60%, and that treatment with a 5α-reductase inhibitor is less effective in the group of patients with a family history of BPH. This can be explained by the fact that the development of BPH is mediated by mechanisms in which androgens are not involved.

Surgical and therapeutic methods can be used to treat BPH. Therapeutic methods include the administration of drugs, adjusted for the age and clinical condition of the patient.Recently, the number of BPH patients in Korea and around the world has increased significantly, and the incidence of the disease among younger patients has also increased. Various drugs are used for treatment, but their use is limited by side effects.

Sulpiride is a type 2 dopamine receptor antagonist which is widely used as a depressant drug. Dopamine, produced as an intermediate in the synthesis of epinephrine and norepinephrine, is an inhibitory neurotransmitter. Sulpiride inhibits the binding of dopamine to its receptor, which, in turn, inhibits the secretion of prolactin in the framework of the dopaminergic effect, and increases the concentration of prolactin in the blood. An increase in the concentration of prolactin as a result of prolonged administration of sulpiride causes hyperprolactinemia.

Prolactin has been shown to be associated with prostate proliferation, prostate cancer, and the development and regulation of BPH. In addition, prolactin is known to increase prostate proliferation in combination with androgen.It is also known that prolactin, by participating in another mechanism, acts as a stress hormone, increasing the expression of 5α-reductase, and induces prostate proliferation. Prolactin, which is one of the non-steroidal factors, is involved in prostate proliferation and BPH induction. With age, prolactin levels increase and testosterone levels decrease. Prolactin has been described to induce BPH in the elderly. It has been shown that prolactin is involved in the proliferation and differentiation of the prostate in rats and humans.In accordance with this work, it is believed that prolactin is induced by receptors involved in signal transduction pathways.

[Prior Art Document]

[Patent Document]

KR 2011-0062943 A

KR 2011-0057049 A

EP 1020190 A3

[Non-Patent Document]

MCCONNELL, John D., et al … ‘The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with Benign Prostate Hyperplasia’, New England Journal of Medicine, 1998, Vol.338, No. 9, pp. 557-563.

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL PROBLEM

Thus, the present inventors are attempting to provide a composition for the treatment and prevention of BPH that has minimal side effects and superior therapeutic effect, thereby completing the present invention.

The present inventors have found that a peptide derived from telomerase allows for the treatment and prevention of BPH with high efficacy, thus completing the present invention.

An object of the present invention is to provide a composition capable of contributing to the treatment and prevention of BPH.

SOLUTION TO PROBLEM

To solve the above technical problem, the present invention provides a composition for the treatment and prevention of BPH, which contains a peptide with the sequence SEQ ID NO: 1 or a fragment thereof (hereinafter referred to as “PEP1”, “GV1001” or “GV”) , or a sequence that is 80% or more homologous to SEQ ID NO: 1.

The specified fragment, which is part of the composition for the treatment and prevention of BPH of the present invention, may contain 3 or more amino acids.

The content of the peptide in the composition for the treatment and prevention of BPH of the present invention may be from 0.01 mg to 1 mg, preferably 0.56 mg (4 nmol peptide / kg body weight).

The composition for treating and preventing BPH of the present invention may be a pharmaceutical composition.

The composition for treating and preventing BPH of the present invention may be a food composition.

In accordance with another embodiment, the present invention provides a method for treating and preventing BPH by administering a composition for treating and preventing BPH to an individual in need of such administration.

In the method of treating and preventing BPH of the present invention, the administration of the composition can be performed 3 times a week.

EFFECT OF THE INVENTION

The composition of the present invention, which contains a peptide of SEQ ID NO: 1, or a sequence 80% or more homologous to said sequence, provides treatment and prevention of BPH with superior efficacy and minimal side effects.

BRIEF DESCRIPTION OF DRAWINGS

FIG.1 shows photographs depicting the process of removing target organs in order to measure their mass.

FIG. 2 shows photographs of the results of electrophoresis in an experiment confirming the effect of PEP1 in the treatment of BPH, which demonstrate the effect of the expression of 5α-reductase in the ventral lobe of the prostate of each experimental group, established using RT-PCR.

FIG. 3 is a graph showing the results of an experiment to confirm the effect of PEP1 on BPH treatment, which includes measuring the mass of seminal vesicles in each experimental group.

FIG. 4 is a graph showing the results of an experiment to confirm the effect of PEP1 on BPH treatment, which includes the measurement of prostate mass in each experimental group.

FIG. 5 is a graph showing the proliferation rate of the stromal cell line of the BPH animal model (WPMY-1) receiving PEP1 treatment.

FIG. 6 is a graph showing the proliferation rate of an epithelial cell line in an animal model BPH (RWPE-1) treated with PEP1.

FIG. 7 is a graph showing the ability of PEP1 to bind to the androgen receptor as measured using PEP1-FITC (fluorescein isothiocyanate) conjugate in a BPH-induced animal model stromal cell line (WPMY-1).

FIG. 8 is a graph showing the ability of PEP1 to bind to the androgen receptor as measured using PEP1-FITC (fluorescein isothiocyanate) conjugate in an animal model BPH epithelial cell line (RWPE-1).

FIG. 9 shows a photograph of the results of electrophoresis, demonstrating the effect of PEP1 on the expression of PCNA (nuclear antigen of proliferating cells), which is at an increased level in the model of induced BPH.

FIG. 10 shows a photograph of the results of immunostaining, demonstrating the effect of PEP1 on the expression of Ki67 (MK67), which is at an increased level in the model of induced BPH.

FIG. 11 is a photograph of the results of an experiment conducted in animal models of BPH using H&E staining, which demonstrate the effect of PEP1 on BPH tissue-related cells.

FIG. 12 is a photograph of the results of an animal model of BPH using Masson’s trichrome staining, which demonstrates the effect of PEP1 on BPH tissue-related cells.

FIG. 13 is a graph showing the change in body weight of animals in an experiment involving the measurement of the effect of PEP1 on an animal model of BPH.

FIG. 14 is a graph showing the change in prostate mass in animal models in an experiment involving the measurement of the effect of PEP1 on an animal model of BPH.

FIG. 15 is a graph showing the change in the mass of seminal vesicles of animals in an experiment involving the measurement of the effect of PEP1 on the animal model of BPH.

BEST METHOD FOR TESTING THE INVENTION

Since the present invention can be adapted to different applications through various modifications, the present invention is described in more detail below. However, there are no restrictions on the form of practical application; it should be understood that the invention includes the concept and scope of technology in all modifications, equivalents and alternatives.In describing the present invention, all detailed descriptions of the prior art that conflict with the fundamental principles of the present invention are omitted.

Telomere is known as a repeating sequence of genetic material present at the ends of chromosomes that prevents chromosomes from being damaged or fused with other chromosomes. The telomere length decreases with each cell division and after a certain number of cell divisions it reaches a critical value at which the cell stops dividing and dies.On the other hand, it is known that lengthening of telomeres leads to an increase in the lifespan of the cell. For example, cancer cells secrete an enzyme called telomerase, which prevents telomere from shortening, allowing cancer cells to proliferate. The present inventors have found that a peptide derived from telomerase can effectively treat and prevent BPH, and thus completed the present invention.

In one embodiment of the present invention, a peptide with the amino acid sequence SEQ ID NO: 1, a peptide fragment of the aforementioned peptide, or a peptide whose sequence is 80% or more identical to the amino acid sequence of the aforementioned peptide, is a telomerase, in particular Homo sapiens telomerase …The peptides disclosed herein may include peptides comprising an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% homologous to the peptide sequence of SEQ ID NO 1, or a fragment thereof. In addition, the peptides disclosed in the present invention may include peptides differing from SEQ ID NO: 1 or a fragment thereof by at least one amino acid, by at least 2 amino acids, by at least 3 amino acids, by at least 4 amino acids, at least 5 transformed amino acids, at least 6 transformed amino acids, or at least 7 amino acids.

In one embodiment of the present invention, amino acid changes result in a change in the physical and chemical characteristics of the peptide. For example, amino acid changes can be made to increase the thermal stability of the peptide, change the substrate specificity, and change the optimal pH value.

The term “amino acid” as used herein includes not only the 22 standard amino acids that naturally occur in peptides, but also D-isomers and modified amino acids.Thus, in a specific embodiment of the present invention, the peptide described herein includes a peptide comprising D-amino acids. In addition, the peptide may contain non-standard amino acids, such as amino acids modified after translation. Examples of post-translational modification include phosphorylation, glycosylation, acylation (including acetylation, myristorylation, palmitoylation), alkylation, carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, chemical modification (e.g., deimidation, deamidation β-removal) and structural modifications (e.g. formation of a disulfide bridge).In addition, amino acid changes include changes resulting from a chemical reaction during the attachment of the crosslinking agent, resulting in the formation of a peptide conjugate, such as changes in the amino group, carboxyl group, or side chain.

A peptide disclosed herein may be a wild-type peptide identified and isolated from a natural source. At the same time, the peptides disclosed herein may be artificial variants containing one or more amino acid substitutions, deletions or insertions compared to SEQ ID NO: 1 or fragments thereof.Amino acid changes in wild-type polypeptides – not only in artificial variants – include changes that affect protein folding and / or conservative amino acid substitutions that do not significantly affect activity. Examples of conservative substitutions include substitutions within the groups of basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagines), hydrophobic amino acids (leucine, isoleucine, valine and methionine), aromatic amino acids (phenylalanine, tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine).Amino acid substitutions are known in the art that generally do not alter specific activity. The most common substitutions are Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Tyr / Phe, Ala / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, Asp / Gly and reverse substitutions. Other examples of conservative substitutions are shown in the following table 1:

Significant changes in the biological properties of peptides are achieved by choosing to replace residues that are significantly different from the original ones, provided that they allow: (a) to preserve the structure of the polypeptide skeleton in the area of ​​replacement, such as a folded or helical three-dimensional structure, (b) to preserve the electrical charge or hydrophobicity of the molecule at the target site, or (c) maintain the volume of the side chain.Natural residues are divided into groups according to the general properties of the side chains as follows:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) sour: asp, glu;

(4) basic: asn, gin, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions can be made by replacing a member of one of the above classes with a member of another class.Any cysteine ​​residue that is not involved in maintaining the corresponding three-dimensional structure of the peptide can usually be replaced by serine, which improves the oxidative stability of the molecule and prevents the formation of incorrect cross-links. Conversely, increased stability can be achieved by adding cysteine ​​bond (s) to the peptide.

Another type of amino acid variants of peptides are peptides with altered glycosylation patterns. The term “change” as used herein includes the deletion of at least one carbohydrate residue present in the peptide and / or the addition of at least one glycosylated residue not present in the peptide.

Glycosylation of peptides is usually carried out as N-linked or O-linked. The term “N-linked” as used herein means that carbohydrate residues are attached to the side chain of asparagine residues. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are recognized by enzymes that attach a carbohydrate residue to the asparagine side chain. Therefore, the presence of one of these tripeptide sequences in a polypeptide indicates the presence of a potential glycosylation site.The term “O-linked glycosylation” means that one of the sugars, including N-acetylgalactosamine, galactose or xylose, is attached to the hydroxyl group of the amino acid. The most common hydroxyl-containing amino acids are serine or threonine, but 5-hydroxyproline or 5-hydroxylysine can also be used.

The addition of a glycosylation site to a peptide is usually carried out by changing the amino acid sequence to introduce the above tripeptide sequence (in the case of N-linked glycosylation sites).This change can be accomplished by adding at least one of the serine or threonine residues to the first antibody sequence, or by replacing them with these residues (in the case of O-linked glycosylation sites).

In addition, the peptide of the present invention containing the amino acid sequence of SEQ ID NO: 1, a peptide containing an amino acid sequence homologous to the above sequence by more than 80%, or fragments of the above peptide have the advantage of low toxicity and high stability in living tissues …As used herein, SEQ ID No: 1 is a 16 amino acid peptide derived from telomerase.

SEQ ID NO: 1 EARPALLTSRLRFIPK

In one embodiment, the present invention provides a composition for the treatment and prevention of BPH, which comprises a peptide with the amino acid sequence of SEQ ID NO: 1, a peptide with an amino acid sequence homologous to the above sequence by more than 80%, or fragments of the above peptide.

In one embodiment of the present invention, the composition can be administered to all animals such as human, dog, chicken, pig, cow, sheep, guinea pig, and monkey.

In one embodiment, the present invention provides a pharmaceutical composition for the treatment and prevention of BPH, which contains a peptide with the amino acid sequence of SEQ ID NO: 1, a peptide with an amino acid sequence homologous to the above sequence by more than 80%, or fragments of the above peptide.In accordance with one embodiment of the present invention, the pharmaceutical composition can be administered orally, rectally, intradermally, intravenously, intramuscularly, intraperitoneally, into the bone marrow, epidurally, or subcutaneously.

Oral administration forms may include, without limitation, tablets, pills, soft or hard capsules, granules, powders, solutions, or emulsions. Forms for other than oral administration may include, but are not limited to, injectables, infusions, lotions, ointments, gels, creams, suspensions, emulsions, suppositories, patches, or sprays.

In one embodiment of the present invention, the pharmaceutical composition, if necessary, may contain additives such as diluents, fillers, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, aromas or sweeteners … In one embodiment of the present invention, the pharmaceutical composition can be produced industrially using conventional methods known in the art.

In one embodiment of the present invention, the dose of the active ingredient in the medical composition may vary depending on the age, sex, weight, pathology and condition of the patient, the route of administration, or the judgment of the physician. Taking these factors into account, a person skilled in the art can determine a dose, which may include, without limitation, a dose in the range of 0.01 μg / kg / day to 10 g / kg / day, for example, from 0.1 μg / kg / day to 1 mg / kg / day, generally from 1 μg / kg / day to 0.1 g / kg / day, more specifically from 1 μg / kg / day to 10 mg / kg / day, preferably from 1 μg / kg / day to 1 mg / kg / day, more preferably from 0.005 mg / kg / day to 0.05 mg / kg / day, most preferably 0.01 μg / kg / day, however, the indicated dose can be adjusted, if there are differences in the effect achieved with the administration of the dose.For adults, the dose administered is preferably 0.1 mg to 1 mg, preferably 0.4 mg to 0.6 mg, for example, the most preferred dose is 0.56 mg.

In one embodiment of the present invention, the pharmaceutical composition may be administered, without limitation, 1 to 3 times a day.

In one embodiment of the present invention, the composition may contain from 0.01 g / L to 1 kg / L, for example, from 0.1 g / L to 100 g / L, more particularly from 1 g / L to 10 g / l of a peptide whose amino acid sequence consists of at least SEQ ID NO: 1, a peptide whose amino acid sequence is at least 80% homologous to the above sequence, or a fragment of the above peptide.If the content of the peptide is in the above ranges, the composition can meet the requirements of safety and stability, and, in addition, the indicated ranges correspond to the optimal cost effectiveness.

In one embodiment, the present invention provides a nutritional composition for the treatment and prevention of BPH, which contains a peptide with the amino acid sequence of SEQ ID NO: 1, a peptide with an amino acid sequence homologous to the above sequence by more than 80%, or fragments of the above peptide.

In one embodiment of the present invention, the food composition is not limited to specific forms, but may be, for example, in the form of tablets, granules, powder, liquid and solid forms. Each form, in addition to the active ingredient, may contain ingredients conventionally used in the industry, suitably selected by those skilled in the art, and may produce a synergistic effect in combination with other ingredients.

As used herein, the terms are intended to describe embodiments but not to limit the present invention.Terms without numbers in front of them are not intended to limit the number, but demonstrate that there may be more than one item designated by the term used. The terms “consisting of”, “having”, “including” and “comprising” should be interpreted in an open sense (ie, as “including without limitation”).

The only reason numeric values ​​are specified as ranges is because ranges are easier to describe than individual values.Unless otherwise indicated, it should be understood that each particular numerical value is to be described separately and included in this description. Thresholds of all ranges are included in the description and can be combined independently.

Unless otherwise indicated, or the context clearly dictates otherwise, all methods described herein may be performed in due order. Each embodiment and all embodiments, or typical expressions (eg, “such as”, “like ~”), if not included in the claims, are used to more fully describe the present invention, but not to limit the scope of the present invention.Any expression present in this description, other than the claims, should not be interpreted as binding on the present invention. Unless otherwise indicated, the technical and scientific terms used herein have their traditional meanings known to those skilled in the art to which the present invention belongs.

Preferred embodiments include the best mode known to the inventors for carrying out the present invention. Variations in the preferred embodiments may become apparent to those skilled in the art upon reading the above explanations.The inventors of the present invention hope that those skilled in the art will be able to use the variations appropriately and that the present invention can be accomplished using methods other than those described herein. Thus, the present invention, in accordance with patent law, includes equivalents, modifications and variations of the basic provisions of the invention set forth in the appended claims. In addition, unless explicitly indicated otherwise, or unless the context dictates otherwise, all possible variations within any combination of the above components are included in the present invention.Although the present invention has been described and demonstrated by means of illustrative embodiments, it is well known to those skilled in the art that the form and details of the invention may be subjected to various changes without departing from the spirit of the invention and its scope as defined in the following claims.

MODES FOR CARRYING OUT THE PRESENT INVENTION

Hereinafter, the present invention is described in more detail by means of examples and test examples. However, the following examples and test examples are given for illustrative purposes only, and it should be obvious to those skilled in the art that the scope of the present invention is not limited to the examples and test examples.

EXAMPLE 1: Synthesis of Peptide

The peptide SEQ ID NO: 1 was synthesized using a conventional solid phase peptide synthesis method. More specifically, the peptide is synthesized by C-terminus addition of the next amino acid by Fmoc solid phase peptide synthesis, SPPS, using ASP48S (Peptron, Inc., Daejeon ROK). To obtain peptides, the following resins are used, to which the first amino acids of the peptides are attached:

NH ₂ -Lys (Boc) -2-chlorotrityl resin

NH ₂ -Ala-2-chlorotrityl resin

NH ₂ Arg (Pbf) -2-chlorotrityl resin

All amino acids required for peptide synthesis are protected by the Fmoc group at the N-terminus, and amino acid residues are protected with Trt, Boc, t-Bu (t-butyl ester), Pbf (2 , 2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), which can be removed in an acidic environment.Examples include the following protected amino acids:

Fmoc-Ala-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Pro-OH, Fmoc-Leu-OH, Fmoc-Ile- OH, Fmoc-Phe-OH, Fmoc-Ser (tBu) -OH, Fmoc-Thr (tBu) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Trp (Boc) -OH, Fmoc-Met-OH, Fmoc-Asn (Trt) -OH, Fmoc-Tyr (tBu) -OH, Fmoc-Ahx-OH, Trt-mercaptoacetic acid.

HBTU [2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethylaminium hexafluorophosphate] / HOBt [N-hydroxybenzotriazole] / NMM [4-methylmorpholine] are used as condensing reagents.Piperidine in 20% DMF is used to remove Fmoc. To remove protection from amino acid residues, or to separate the synthesized peptides from the resin, use a mixture for cleavage [TFA (trifluoroacetic acid) / TIS (triisopropylsilane) / EDT (ethanedithiol) / H ₂ O = 92.5 / 2.5 / 2 , 5 / 2.5].

Peptide synthesis is carried out using a solid-phase support, repeating the following processes: first, each amino acid is protected, then it is subjected to a separate reaction, washed with solvents and deprotected.Each peptide is synthesized using a solid phase support, to which the first protected amino acid is attached, by separately reacting with the corresponding amino acid, washing with a solvent and removing the protecting groups, repeating these processes. After separation from the resin, the synthesized peptides are purified by HPLC, analyzed by mass spectrometry and lyophilized, the synthesis is confirmed by MS and then lyophilized.

The purity of the obtained peptides, determined by high performance liquid chromatography, is 95% or higher.

The specific synthesis process for PEP 1 can be represented as follows:

1) Addition

Protected amino acid (8 equivalents), NH ₂ -Lys (Boc) -2-chlorotrityl resin and HBTU condensing reagent (8 equivalents) / HOBt (8 equivalents) / NMM (16 equivalents) diluted in DMF are mixed and incubated at room temperature (RT) for 2 hours. After incubation, the reaction mixture is washed sequentially with DMF, MeOH and DMF.

2) Removal of the Fmoc protecting group

Add piperidine in 20% DMF and incubate at RT for 5 minutes 2 times, after which it is successively washed with DMF, MeOH and DMF.

3) Preparation of the main peptide framework NH ₂ -E (OtBu) -AR (Pbf) -PALLT (tBu) -S (tBu) -R (Pbf) LR (Pbf) -FIPK (Boc) -2-chlorotrityl resin) by repeating the above reactions 1) and 2).

4) Cleavage: A cleavage mixture is added to the fully synthesized peptide to separate it from the resin.

5) To the resulting mixture is added pre-cooled diethyl ether and centrifuged to precipitate the collected peptide.

6) After purification by preparative HPLC, confirm the molecular weight by LC / MS and lyophilize to give a powder.

EXAMPLE 2: Confirmation of the effect of PEP1 on BPH in an experiment using an animal model of induced BPH.

1) Obtaining an animal model of induced BPH

Among androgens, testosterone is the most abundant hormone in the body. However, the most active hormone among the androgens associated with prostate development is 5α-dihydrotestosterone (DHT), which is produced from testosterone by the action of 5α-reductase. In rats, sulpiride, administered for 30 days at a concentration of 40 mg / kg, inhibits the dopamine type 2 receptor, increasing the concentration of prolactin in the body and inducing hyperprolactinemia, which leads to the activation of 5α-reductase; it has also been shown that when administered with testosterone it has a synergistic the effect.As described, the DHT produced by hyperprolactinemia increases the mass of the lateral prostate more than the dorsal or ventral. In view of this fact, an experiment was carried out using PEP1 obtained according to the method of Example 1, which was administered to an animal model of induced BPH alone or in conjunction with another test agent. Mature male Sprague-Dawley rats (6 weeks old) are obtained from the Jae-il Experimental Animal Breeding Center and kept for a week (up to 7 weeks, 49 days) for decontamination, after which they are used in the experiment.To induce BPH, sulpiride (40 mg / kg) is administered orally once a day for 30 days. Each experiment is carried out after receiving the result of the previous experiment (Van Coppenolle et al., 2001). The administration of the test substances to all animals is started every day at 10 am. After administration of the test substances, the general condition and specific symptoms of each animal are observed every day. In addition, before the administration of the test substances, the body weight of each animal is measured and recorded.

2) Test Substances and Doses

Sulpiride used as a test substance in the experiment was obtained from Sigma Chemical Co. (St. Louis, MO, USA). The present inventors administer sulpiride (40 mg / kg) once a day sequentially for 60 days by intraperitoneal injection to induce BPH due to hyperprolactinemia. Each time before the administration of the test substances, sulpiride is first dissolved in 0.1 N HCl solution and then neutralized to pH 7.0 with 0.1 N NaOH solution.In the coadministration group, PEP1 prepared according to the method of Example 1 and finasteride are administered after sulpiride by intraperitoneal injection. PEP1 (0.01, 0.1, 1 and 10 mg / kg) is prepared immediately prior to use and administered by subcutaneous injection. Finasteride is administered using 15% ethanol in corn oil (v / v) as medium every day. The dose to be administered is calculated on the basis of a concentration of 0.5 ml / kg, taking into account the body weight, which is measured every day. To confirm the effect of PEP1 on BPH, the test substances were administered to the 7 groups described in Table 2 below.

1) After the end of the experiment with the introduction of PEP1 and test substances from models of induced BPH, organs are harvested, preserved and their weight is measured

24 hours after the end of the administration of the test substances, which was carried out for 60 days, all animals are anesthetized with ether, blood is collected from abdominal aorta and separate the serum.The separated serum is stored at -80 ° C until assayed for hormones.

After testing, the foreskin (PPS), auxiliary reproductive organs, such as the glans penis (Gp), seminal vesicles and coagulatory glands (SV), the ventral lobe of the prostate (VP), Cooper’s gland (CpG), are sequentially isolated after testing. levator aniplus bulbocavernosus muscle (LABC). The isolation technique is in accordance with the OECD protocol in detail.

To isolate Gp as indicated in FIG. 1, a portion of the Gp is ​​clamped with forceps and cut along the separation line of the foreskin.As indicated in FIG. 1, to isolate the lung, after removing the bladder from the abdominal muscle layer, open the left and right lobes of the lung covered with a lipid layer, raise the bladder to detect SV, separate the lipid from the left and right lobes of the lung with forceps, cut off the left lobe of the lung from the urethra after pulling with microtweezers, and cutting off the right lobe of the lung after separating from the urethra with forceps. In the case of SVs containing coagulatory glands, as indicated in FIG.1, SV is laid on a paper towel and muscles, lipid layer and glands are separated. The base of the SV, containing the seminiferous tubules connected to the urethra, is clamped to prevent leakage during the removal of the seminal vesicles. After lipid removal, the associated accessory organs are washed, the clamp removed, and the seminal vesicles are placed on a dish to measure their mass.

2) Effect of PEP1 administration on 5α-reductase expression in an experimental animal model induced by BPH

After administration of sulpiride with test substances for 60 days and collection of the ventral lobes of the prostate, their effect on 5α-reductase expression is measured by RT-PCR.Namely, total RNA (25 mg) is isolated from the ventral lobe of the prostate and resuspended by the addition of DEPC-treated water. Then the quantitative determination of RNA is carried out using a spectrophotometer. First strand cDNA is synthesized using the methods of Torres and Ortega (2004). The PCR profile includes denaturation at 94 ° C (30 sec), annealing at 55 ° C (30 sec) and extension at 72 ° C (30 sec), repeating the cycle 30-35 times. As a control for quantitative determination by electrophoresis, GAPDH is used, the expression level of which does not change under the influence of other drugs.The results show that the increase in 5α-reductase levels by sulpiride is inhibited in the PEP1 group in a dose-dependent manner, with the inhibitory effect in the high-dose PEP1 group (GV 10, 10 mg PEP1 group) being higher than in the group receiving finasteride (see Fig. 2). Thus, PEP1 may have a dose-dependent therapeutic and beneficial effect on BPH by inhibiting 5α-reductase.

3) Effect of PEP1 on the organs of an experimental animal model of BPH-induced

Table 3 below shows that PEP1 peptide affects seminal vesicle mass, prostate mass and prostate index in each experimental group.The prostate index shown in Table 3 is calculated from the body weight / final prostate weight equation.

The results shown in Table 3, vol.e. The results of measuring seminal vesicles after administration of PEP1 and finasteride (5 mg / kg) in animals with BPH induced by administration of sulpiride are presented in the form of a graph that demonstrates that the mass of seminal vesicles after administration of a high dose of PEP1 (10 mg / kg) decreases significantly (see Fig. 3). In addition, in an animal model of BPH-induced co-administration of sulpiride and PEP1, prostate mass is significantly reduced (see Fig. 4). If the P value is less than 0.05, the result is significant.

Therefore, the results obtained in Example 2 indicate that administration of PEP1 to an animal model with BPH induced by sulpiride can effectively and in a dose-dependent manner reduce 5α-reductase expression, seminal vesicle mass and prostate mass. Thus, the results of the analysis of the expression of 5α-reductase and measurements of the mass of the reproductive organs indicate that the administration of PEP1 can effectively treat and improve the painful symptoms associated with BPH.

EXAMPLE 3: Confirmation of the effect of PEP1 on BPH by observing changes in the proliferation of stromal and epithelial cells of the prostate according to the DHT level

1) Obtaining cells for testing and experimental procedure

After injection into the body, testosterone is converted to DHT by the action of 5α-reductase and induces proliferation of prostate cells by inducing BPH.Using this fact, an experiment was carried out to demonstrate the effect of the PEP1 obtained in Example 1 on the proliferation of a prostate cell line. As cell lines, WPMY-1 (prostate stromal cell line) and RWPE-1 (prostate epithelial cell line) obtained from animal models were used. The experiment was carried out by plating WPMY-1 (2.5 × 1090,767 3, cells) and RWPE-1 (1 × 10,^{4 90,768 cells) into a 96-well plate, taking into account the individual experimental groups described in Table 4 to observe the change proliferation.The change in proliferation is observed by placing a CCK-8 solution in each well of the medium in an amount of 10 μl after sucking off the culture medium and measuring the optical density for 1-4 hours at a wavelength of 450 nm.}

2) Confirmation of observed results and effects

In groups not treated with DHT (groups 1-3), there was no significant difference between the group not receiving PEP1 (group 1) and groups receiving PEP1 (groups 2 and 3), in both cell lines WPMY-1 and RWPE-1.In the DHT-treated groups (groups 4-6), there were significant differences between the PEP1-free group (group 4) and the PEP1-treated groups (groups 5 and 6), with significant inhibition of proliferation observed in the PEP1-treated groups (see table 4 and fig. 5, 6). Therefore, PEP1 can effectively inhibit prostate cell proliferation by acting on DHT-induced BPH.

EXAMPLE 4: Confirmation of the ability to bind the androgen receptor and the mechanism of BPH inhibition by PEP1

1) Preparation of cells for testing and the procedure for the experiment

DHT produced by 5α-reductase stimulates proliferation of prostate cells by binding of the androgen receptor and induces BPH …Using this fact, an experiment for studying the proliferation of prostate cells was carried out, in which the PEP1 obtained in Example 1 was introduced into the body. WPMY-1 and RWPE-1 obtained from animal models were used as cell lines. WPMY-1 and RWPE-1 are divided into a group that is treated with an anti-androgen receptor antibody and an isotypic control group, a competition assay is performed by incubating with each antibody by the addition of PEP1-FITC (fluorescein isothiocyanate), and the fluorescence value is measured.The fluorescence value is measured by flow cytometry.

2) Confirmation of observed results and effects

For each of WPMY-1 and RWPE-1, fluorescence values ​​are measured first in the case of interaction with a control antibody (competing antibody, peak far right), then in case of interaction with an antibody against the androgen receptor (competing antibody, peak in the middle) and in the absence of interaction with the two antibodies and binding to FITC (peak far left) (see.fig. 7 and FIG. eight). When competing with a control antibody isotypic to the anti-androgen receptor antibody, PEP1 binds to the anti-androgen receptor antibody and the fluorescence value of the PEP1-FITC conjugate increases (peak shifted to the right in the histogram of the graph). When competing with an anti-androgen receptor antibody, PEP1 weakly binds to an anti-androgen receptor antibody and the fluorescence value decreases (peak shifted to the left in the histogram of the graph). Therefore, based on the fact that PEP1 inhibits BPH induced by DHT, which binds to an anti-androgen receptor antibody, PEP1 can affect BPH by directly binding to an anti-androgen receptor antibody.

EXAMPLE 5: Confirmation of the effectiveness of the effect of PEP1 on BPH in vivo using an animal model of induced BPH

1) Obtaining experimental animals

Male C57BL / 6 mice 6-8 weeks old (n = 10 / group), grown in the SPF (absence of specific pathogens) in the experimental animal breeding laboratory of the Seoul University College of Medicine. 50 mg of testosterone enanthate (TE obtained from EVER Pharma Hena GmbH, Germany) for injection and 0.5 mg of estradiol valerate (obtained from EVER Pharma Hena GmbH, Germany) are respectively mixed in a volume of 70 μl of a microosmotic pump (Alzet pump, obtained from DURECT Corporation, USA), after which the pump is transplanted into the back of a mouse under anesthesia.The design of the pump allows the hormone to be released in the mouse body at a concentration of 0.11 μl per hour for 28 days (2 weeks) due to the phenomenon of osmosis.

2) Test substances and administration doses

Testosterone and finasteride were used as test substances. To obtain animal models, one individual (mouse model weighing 25 g) is injected (injected) each day with 250 μg of PEP1 prepared according to the method of Example 1 and 2500 μg of finasteride (in DMSO or cyclodextrin obtained from Sigma Aldrich, USA), respectively.2 weeks after the administration of the test substances (4 weeks after the transplantation of the animal model pump), blood is collected from the supraorbital vein and centrifuged at 14000 rpm, 4 ° C, for 30 min to separate the serum, the prostate is isolated and frozen in liquid nitrogen at -70 ° C, go fix with fixing liquid. The experimental groups used in this experiment are described in Table 5 below.

3) Measurement of the reduction of BPH inducing factors

Induction of BPH increases the level of PCNA (proliferating cell nuclear antigen, a protein required for replication) and Ki67 (MK167, a protein required for cell proliferation) in prostate tissues.In view of this fact, a test was carried out to measure the effectiveness of PEP1 in inhibiting the expression of PCNA and Ki67 in a BPH-induced mouse model. PCNA is measured by 2D gel electrophoresis using protein extracted from prostate tissue cells, and Ki67 is measured by immunostaining to detect tissue expression levels. The results show that the levels of expression of PCNA and Ki67, increased in the prostate tissues of animals with induced BPH, are reduced by PEP1 (see.fig. 9 and FIG. ten). Hence, PEP1 inhibits BPH inducing factors and can be effectively used to treat and improve BPH.

4) Measurement of changes in tissues affected by BPH-induced

BPH is known to be induced as a result of abnormal proliferation of stromal and epithelial cells that make up the prostate gland. Based on this fact, histological analysis is performed to determine if PEP1 induces BPH-induced changes in prostate tissue in an animal model.The H&E staining method is used to detect changes in the total tissue, and the Masson trichrome staining method is used to measure the level of the inflammatory response and to more clearly detect the shape of the nuclei. The results show that the epithelial layer is thicker in the BPH-induced group than in the control group, however, in the PEP1-treated group, the epithelial layer is arranged in a regular manner, similar to the control group, and the epithelial thickness is less than in the BPH-induced group (see Fig.fig. 11 and 12). Therefore, PEP1 can be effectively used to restore changes in tissues of animals with induced BPH and return tissues to a normal state without signs of BPH.

5) Measurement of changes in organs affected by BPH

BPH can be detected by changes in the mass of the prostate and seminal vesicles. Based on this fact, in order to determine the effect of PEP1 on prostate and seminal vesicle mass, which directly indicates the presence of symptoms associated with BPH, in an animal model of induced BPH, body weight, prostate mass and seminal vesicle mass were measured.The measurement results are shown in Table 5 by group in the form of a graph (see Fig. 13, 14 and 15). Changes in total body weight have not been shown, but prostate mass in the PEP1 group has been shown to be significantly lower than in the hormone group, with the decrease in weight in the PEP1 group being comparable to the decrease observed in the group receiving finasteride, which is known as a drug against BPH, hence the results obtained confirm that the decrease observed in the PEP1 group is significant.The mass of seminal vesicles in the PEP1 group is less than in the hormone group. Therefore, PEP1 can effectively reduce the mass of organs carrying BPH symptoms.

In all of the above examples, through in vitro and in vivo experiments using animal models of induced BPH, PEP1, when administered, has been shown to have a significant effect on BPH inducing factors, hormone receptors and major reproductive organs. Therefore, it can be assumed that using PEP1 can effectively treat, improve and prevent BPH, in addition, there is a possibility that a composition for treating BPH and a method for treating BPH will be developed based on PEP1.

On the advisability of reinforcing pathogenetically substantiated medication prophylaxis for complications after surgical treatment of prostatic hyperplasia

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90,000 Benign enlargement of the prostate gland (prostate)

What causes benign enlargement of the prostate?

Benign Prostatic Hyperplasia is a consequence of the enlargement of the inner part of the prostate for unknown reasons.Symptoms – problems with urination: weak stream, feeling of incomplete emptying of the bladder, problems with emptying of the bladder, urge to urinate and nocturnia.

Diagnosis

Diagnosis is clinical and is based on characteristic urinary problems and denial of other factors. In addition, as part of a medical examination, the prostate is palpated to measure the extent of enlargement and to deny suspicion of prostate cancer.

In the urology clinic of the Kaplan Medical Center the following examinations can be carried out:

Uroflow – an objective check of the power of urination. The patient is invited to urinate in a special apparatus that measures the amount of urine and the force of the stream.

Urodynamic examination – checks the function and capacity of the bladder, as well as the sensitivity and ability to contract the bladder. During the examination, a thin catheter is inserted through the urethra into the bladder and fluid flows through it until the bladder fills.During the examination, the patient’s sensitivity and reaction to the filling of the bladder, as well as the pressure inside it, are checked.

Ultrasound of the kidneys and ureters – a general examination of the function of the kidneys, bladder and prostate gland.

Treatment of benign enlargement of the prostate

There are several methods of treatment: medicinal and surgical.

First of all, the medicinal method is used, which includes two types of drugs:

1.Medicines that relax the muscles of the urinary bladder and prostate gland – these medications begin to work after a few days and usually have a positive effect on the jet power and the ability to empty the bladder

2. Medicines that lower the hormonal effect of the prostate gland and affect its shrinkage. Such drugs work for a longer period.

Today it is known that the combination of drugs of each group simultaneously leads to the most significant improvement in the condition.

The decision on surgery is usually done in the event of complications such as urinary accumulation, chronic infections in the ureters, bleeding from the ureters, etc.

There are several types of surgical approach, all designed to remove the inside of the prostate:

1. TURP – an endoscopic operation during which an optical device is inserted through the urethra and resection of the inside of the prostate is performed. After surgery, the patient remains with the catheter, which is usually removed after 2 days.

2. SPP – removal of the inner part of the prostate by the abdominal method. It is used in cases of a large gland.

3. PVP – vaporization of the prostate with a green laser through endoscopy, through the urethra. The Department of Urology at the Kaplan Medical Center has become one of the first places in Israel to use this technology. The green laser allows the treatment of cases in which patients are taking blood-thinning drugs. In such cases, the catheter is usually removed the next day.

Prostate adenoma

Prostate adenoma

Adenoma of the prostate is one of the most common diseases among men over 50 years of age. This is a benign enlargement of the prostate gland and, as a result, an obstacle to the normal outflow of urine from the bladder.

Adenoma of the prostate, as a rule, progresses very slowly and does not cause any discomfort to the man for a long time.However, without timely treatment, it can cause serious problems in the genitourinary system, as well as lead to damage to the bladder and kidneys.

At present, the therapy of prostate adenoma has been developed and widely used. However, taking medications does not always lead to positive results. In such cases, as well as with serious concomitant diseases, surgical intervention is possible.

Synonyms Russian

Prostate adenoma, benign prostatic hyperplasia (BPH), benign prostatic hyperplasia, prostatic hyperplasia.

Synonyms English

Prostate gland enlargement, Benign prostatic hyperplasia, BPH.

Symptoms

Symptoms of an uncomplicated course of prostate adenoma are usually limited to difficulty urinating. The manifestations of this disease can be divided into several groups:

• the number of urination increases, it becomes necessary to get up at night to empty the bladder, the total volume of night urine exceeds the daytime,
• a feeling of the need to urgently empty the bladder, the inability to postpone the process of urination even for a short time, with already started urination, a man cannot interrupt this process,
• decrease in the rate and volume of urination as the bladder empties – the stream becomes more and more sluggish, urine may be excreted intermittently or in drops,
• sensation of incomplete emptying of the bladder immediately after urination, urge to urinate less than 2 hours after the previous one – after urination, some urine remains in the bladder, which leads to the need to urinate again after a short period of time,
• Necessity of straining when urinating – it is difficult to start, you have to push, strain your abdominal muscles.

These symptoms are usually not painful. However, in some cases, the prostate gland can completely block the lumen of the urethra, which leads to urinary retention and severe abdominal pain. This condition requires urgent medical attention.

Who is at risk?

• Obese men leading a sedentary lifestyle.
• Men with family history of prostate adenoma.
• Men with sexual dysfunctions.

General information about the disease

The prostate gland, or prostate, is one of the organs of the male genitourinary system. It consists of two lobes, is located directly below the bladder and surrounds the initial section of the urethra. Behind the prostate is in contact with the wall of the rectum. Normally, iron is about the size of a walnut and weighs about 20 grams. The prostate enlarges greatly during puberty (approximately doubled) and begins to grow again after 40 years.These growth periods are directly influenced by the effects of male sex hormones such as testosterone and dihydrotestosterone. The tissue surrounding the prostate restrains its enlargement, which leads to squeezing of the urethral lumen by the gland. As a result of this process, many men, by the age of 45, are faced with certain symptoms of prostate adenoma.

It is considered a normal part of age-related changes in the male genitourinary system. After 50 years, almost half of men have it, after 60 – slightly less than 80%, and after 85 – 90% of men.

An increase in the size of the prostate is due to the growth of one or more nodules in it, which are benign and do not spread to other organs and tissues of the body. The severity of manifestations is determined by the direction of growth of nodules and the intensity of narrowing of the lumen of the urethra.

Diagnostics

Prostate adenoma is diagnosed based on symptoms and test results. To exclude other, more serious, diseases with similar manifestations, such as prostate cancer, prostatitis, diabetes mellitus, urolithiasis, a number of additional studies are needed.

• Complete blood count (without leukocyte count and ESR) – prostate adenoma has little effect on its indicators, but it can show the presence of other diseases or complications, in particular inflammation.
• General urine analysis with microscopy – with prostate adenoma, blood is often detected in the urine, as well as signs of complications (for example, cystitis – inflammation of the bladder).
• Biochemical blood test: serum urea, serum creatinine.Urea and creatinine are the end products of protein metabolism in the body and are excreted by the kidneys. Their blood levels are fairly stable. These indicators are used to judge how well the kidneys work.
• Prostate-specific antigen total (PSA total). Its level rises in diseases of the prostate gland – adenoma, prostate cancer, prostatitis.
• Prostate-specific antigen free (PSA free) – this test is necessary for the differential diagnosis of prostate cancer, it is carried out only in conjunction with the determination of total PSA.Calculate the ratio of free and total PSA: the larger the proportion of free PSA, the lower the likelihood of prostate cancer. This is necessary for the timely detection of prostate cancer, as well as for monitoring the effectiveness of its treatment and diagnosis of possible relapses.
• Digital rectal examination – the doctor, after wearing gloves, carefully inserts a finger into the patient’s rectum to feel the posterior surface of the prostate. This procedure is quite unpleasant, but very informative, as with its help the doctor determines the degree of enlargement, sensitivity and structure of the prostate gland.
• Ultrasound examinations of the prostate, bladder and kidneys provide information on the extent of enlargement, the structure of the prostate gland, the amount of residual urine in the bladder, and possible signs of kidney damage.
• Contrast pyelography – after intravenous administration of a special contrast agent, an X-ray is taken, which allows you to see the patency of the urinary tract.
• Cystoscopy is a visual examination of the bladder and urethra, which is carried out using a cystoscope, a special optical device in the form of a tube equipped with a video camera and a light source, which is inserted into the urethra.This allows you to determine the degree of patency of the urethra, to check the patient’s bladder.
• Urodynamic examination – special pressure sensors are inserted into the bladder and rectum, then the bladder is gradually filled with saline. When a patient has the urge to urinate, he is asked to urinate on a special device – a uroflowmeter. It determines the volumetric velocity of urine. These procedures allow you to find out if the bladder is contracting well, if there are any obstacles to the flow of urine.
• Prostate biopsy is one of the most effective ways to diagnose prostate cancer. Using a special thin needle inserted through the anus, the doctor obtains microscopic tissue samples, which are then examined under a microscope.

Treatment

At the moment, there are conservative (prescribing drugs) and surgical methods of treating prostate adenoma. For the treatment of prostate adenoma, alpha blockers, 5-alpha reductase inhibitors, or a combination of both are used.These drugs do not stop the growth of gland cells, but act on the smooth muscles of the prostate and bladder, relax them, which leads to an improvement in the outflow of urine and an improvement in the patient’s condition. However, drug therapy is not always effective. In some cases, surgery is necessary. The doctor does not remove the entire prostate, but the part of it that compresses the urethra. There are 2 options for removing excess prostate tissue: through an incision in the anterior abdominal wall or using a special device – a resectoscope, which is inserted into the lumen of the urethra.Treatment tactics are selected individually, depending on the age, general condition of the patient and concomitant diseases.

Prevention

Unfortunately, there are no effective methods for the prevention of prostate adenoma. Therefore, all men over 40 are recommended to regularly undergo a set of examinations aimed at the timely detection of this disease.

Also recommended

Children’s city polyclinic No. 118