Some Prescription Drugs and Their Off-Label Uses in Ageing Males

Here are some prescription medicines, which may have some off-label use which could benefit aging males.

1. Trimetazidine: Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries, for tinnitus and dizziness. It is an anti-ischemic (antianginal) metabolic agent of the fatty acid oxidation inhibitor class, meaning that it improves the heart muscle's ability to use glucose as a fuel by inhibiting its use of fatty acid metabolism. Interestingly, the beneficial actions of trimetazidine in heart failure have not only been observed in patients with an ischemic etiology, but also non-ischemic causes, including idiopathic dilated cardiomyopathy, diabetic cardiomyopathy, and anthracycline-induced cardiotoxicity. Studies have shown that trimetazidine improves Left Ventricular Ejection Fraction (LVEF) and Global Longitudinal Strain in patients with ischemic heart disease and reduced Ejection Fraction.

2. Clomiphene: Clomiphene (or clomiphene citrate) is an FDA-approved selective estrogen receptor modulator (SERM) indicated to treat anovulatory or oligo-ovulatory infertility to induce ovulation for women desiring to conceive. In men, clomiphene causes an increase in FSH and LH secretion. This leads to an increase in both sperm production and testosterone secretion. Men may need to take clomiphene for at least 3-4 months to see the optimal effect.

3. Anastrozole: Anastrozole is in a class of medications called nonsteroidal aromatase inhibitors. It works by decreasing the amount of estrogen the body makes. In females, this can slow or stop the growth of many types of breast cancer cells that need estrogen to grow. In men, studies have shown that daily treatment with anastrozole significantly increased sperm production. Similarly, a 2004 study involving 37 older adult men with hypogonadism (or low testosterone) found that anastrozole helped restore testosterone levels to the normal range typically seen in younger, healthy men.

4. Calcium Dobesilate: Calcium dobesilate, a calcium salt of dobesilic acid, is a medication used to treat hemorrhoids (piles) and varicose veins. Calcium dobesilate works by reducing capillary leakage, thickening blood, and enhancing fluid removal through the lymphatic system.

Recent research suggests calcium dobesilate might stimulate the production of nitric oxide (NO) in the endothelium, the inner lining of blood vessels. NO acts as a vasodilator, promoting relaxation of blood vessel walls and potentially improving circulation in hemorrhoidal tissue.

Results also suggest that dobesilate may be of help to treat diabetic erectile dysfunction. Co-administration with phosphodiesterase (PDE 5) inhibitors warrants further investigation.

Vascular lesions from microvascular involvement leads to impaired blood flow and contribute to damage and dysfunction of one or more target organs, that is, the heart, kidneys, eyes, and nervous system. Calcium dobesilate, due to its vasoactive and angio-protective properties, has shown a unique, multi target mode of action in several experimental studies and in different animal models, for the treatment of diabetic microvascular complications.

5. Nebivolol: Nebivolol is a beta blocker used to treat high blood pressure and heart failure. It may be used by itself or with other blood pressure medication. Nebivolol has the highest β1-receptor affinity among β-blockers and, most interestingly, it substantially improves endothelial dysfunction via its strong stimulatory effects on the activity of the endothelial nitric oxide synthase and via its antioxidative properties.

Nebivolol, unlike other β-blockers, may not cause erectile dysfunction since it increases NO release which is the main mediator of erection. Nebivolol may be advantageous in terms of preserving sexual functions in eligible hypertensive male patients.

Nebivolol is just as effective as other beta blockers at assisting with anxiety symptoms, perhaps better in some cases due to the drugs slight nitric oxide effect.

6. SGLT-2 Inhibitors: SGLT2 inhibitors are a class of prescription medicines that are approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.

According to AHA/ACC/HFSA (2022) guidelines, guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) includes sodium-glucose cotransporter-2 inhibitors.

According to the 2023 ACC Expert Consensus, SGLT2 inhibitors are indicated in all HFpEF (Heart Failure with preserved ejection fraction) patients.

According to a joint consensus from KDIGO and ADA (2022), SGLT2 inhibitors with established kidney benefits are suggested for patients with type 2 diabetes mellitus and chronic kidney disease (CKD).

SGLT2 inhibitors directly cause body weight loss via glucose excretion (calorie loss) in the kidneys, therefore, SGLT2 inhibitors may prove to be an effective weight loss therapy in patients with obesity without diabetes.

7. GLP-1 agonists: Glucagon-like peptide-1 (GLP-1) agonists are a class of medications utilized to treat type 2 diabetes mellitus.

Studies have found that the most-effective agent for weight loss overall was an investigational combination of semaglutide and the amylin analog cagrilintide, which yielded a mean 14.0 kg lower body weight than placebo.

A recent study found that weekly treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduced the risk of a combination of stroke, heart attack, and death from cardiovascular causes by 20% compared with placebo.

GLP-1 agonists have recently demonstrated efficacy in reducing BP and improving cardiovascular (CV) outcomes in individuals with overweight or obesity.  Moreover, GLP-1 can control B-cell sensitivity and improve glycemic and cholesterol homeostasis.

8. Clonidine: Clonidine is in a class of medications called centrally acting alpha-agonist hypotensive agents. Clonidine treats high blood pressure by decreasing your heart rate and relaxing the blood vessels so that blood can flow more easily through the body.

Clonidine is also used off-label for the treatment of alcohol withdrawal, smoking cessation, restless leg syndrome, Tourette's syndrome, and opioid withdrawal.

Clonidine is also known for stimulating Human Growth Hormone (HGH) release from the anterior pituitary and causes elevation of serum HGH levels. It increases growth hormone releasing hormone (GHRH) secretion and inhibits somatostatin.

9. Baclofen: Baclofen is used to help relax certain muscles in your body. It relieves the spasms, cramping, and tightness of muscles caused by medical problems, including multiple sclerosis or certain injuries to the spine.

Baclofen is sometimes used off-label as a treatment for alcohol use disorder to reduce the risk of relapse and to increase the number of days that a person can go without drinking alcohol (abstinence days).

Among the studies in which the anxiety and depression levels of participants were evaluated, baclofen administration reduced anxiety but not depression levels.

Baclofen decreases acid reflux and improves sleep quality in individuals with nighttime heartburn. Most recently in healthy humans, baclofen was observed to reduce the rate of gastroesophageal reflux episodes by 60%.

Baclofen can lower the seizure threshold in patients with epilepsy and decrease alertness in elderly patients with acquired brain injury.

Baclofen therapy has been also found effective in treating both the PTSD (Post Traumatic Stress Disorder) symptoms and accompanying depression and anxiety in patients with chronic PTSD due to combat.

It is also found that baclofen increases human growth hormone (HGH) release by inhibition of hypothalamic somatostatin release and/or by dopaminergic control.

10. Pyridostigmine: Pyridostigmine is a medication that treats myasthenia gravis. This condition causes muscle weakness that worsens throughout the day. Pyridostigmine helps strengthen your muscles. Pyridostigmine sometimes is used to treat orthostatic hypotension. It may also be of benefit in chronic axonal polyneuropathy.

It is also being prescribed off-label for postural orthostatic tachycardia syndrome (POTS) as well as complications resulting from Ehlers–Danlos syndrome.

In diabetics and pre-diabetics, it has shown to decrease blood glucose levels.

Intravenous injection of physostigmine has shown to produce a dose-dependent fall in blood pressure and heart rate.

Pyridostigmine has been shown to elicit human growth hormone (HGH) release when given alone and to potentiate the HGH response to GH-releasing hormone (GHRH) in man. Numerous experiments have indirectly indicated that somatostatin (SS) inhibition is its likely mechanism of action.

11. Dipyridamole: Dipyridamole is an antiplatelet agent used in secondary prophylaxis against stroke and as an adjunctive agent with warfarin post mechanical valve replacement. Being a vasodilator, it is also used off-label to prevent stroke; however, it is not FDA approved for this indication. Dipyridamole has both PDE3 and PDE5 inhibiting properties. PDE3 inhibitors, namely milrinone, have been used in the management of acute and chronic heart failure, whereas cilostazol inhibits phosphodiesterase-3 in various cell types including platelets, vascular cells, myocytes, and adipocytes, which affects several pathways resulting in vasodilation and enhanced blood perfusion. PDE5 inhibitors like sildenafil, tadalafil and vardenafil are used to treat erectile dysfunction in men.

Low dose dipyridamole (ranging from 0.25 mg – 10 mg) is being studied for the treatment of viral infections (such as, for example, sore throat, SARS, flu with or without influenza), erectile dysfunction, sleep disorders (e.g., insomnia, lack of REM sleep, The treatment of pain, the treatment of conditions such as dry mouth, dry eye syndrome, hair loss and cancer treatment.

In one study, five subjects with erectile dysfunction were treated with the low dose oral dipyridamole, to measure the effect of low dose oral dipyridamole on the treatment of erectile dysfunction.

- Subject 1: 2 mg was found to be the optimal dose for complete recovery of erectile function that did not exist for 6 years, including the absence of nighttime erection for 12 years.

- Subject 2: 3 mg was found to be the optimal dose to obtain satisfactory erectile function. Subject 2 was unable to achieve erection for 3 years without the use of sildenafil, tadalafil or vardenafil. Additional effects included improved sleep.

- Subject 3: Starting with 2 mg of dipyridamole, the erectile function was restored to user satisfaction within 10 days. Over a period of time, the subject increased the dose up to twice a day and still had satisfactory results. When the subject increased the dose to 10 mg / day, the beneficial effect was lost.

- Subject 4: The eradication of erectile dysfunction was achieved within 5 days, starting with 2 mg of low dose oral dipyridamole. No dose adjustment was attempted because the subject was satisfied with the results.

- Subject 5: Erectile dysfunction was resolved within 2 weeks of starting low dose oral dipyridamole 2 mg. The subject found that 2 mg is not effective and 5 mg is effective when taken with food. However, 10 mg did not produce the same gain as 5 mg.

(Source: https://patents.google.com/patent/KR20180074707A/en)

12. Modafinil: Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. It is used in the treatment of conditions that cause excessive daytime sleepiness. Although it has never been studied in Alzheimer's patients, it slightly improves certain aspects of cognition in healthy adults and elderly. Modafinil is the world’s first safe “smart drug”, researchers at Harvard and Oxford universities have said, after performing a comprehensive review of the drug. They concluded that the drug, when taken by healthy people, including elderly, can improve decision- making, problem-solving and possibly even make people think more creatively.

13. Clenbuterol: Clenbuterol is a sympathomimetic amine used by sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders such as asthma use this as a bronchodilator to make breathing easier. But it is abused generally by bodybuilders and athletes for its ability to increase lean muscle mass and reduce body fat. Clenbuterol has shown to dramatically increase the skeletal muscle mass in young animals and humans, and partially prevent or restore muscle loss in experimental models of muscle wasting. Clenbuterol isn't a steroid, but it has some properties similar to those of anabolic steroids, such as promoting an increase in muscle mass. Clenbuterol increases the rate of lipolysis (the process of breakdown of fats to release energy) by inducing hormone-mediated lipolysis. This is one way to reduce fat deposits in the body. Side effects include include increased heart rate, nervousness, headache, muscular tremor, dizziness, nausea, vomiting, fever, and chills, typically resolved within 2 to 6 days.

14. Dapoxetine: Dapoxetine is short-acting Selective serotonin reuptake inhibitors (SSRI). SSRIs are a widely used type of antidepressant. They're mainly prescribed to treat depression, particularly persistent or severe cases, and are often used in combination with a talking therapy such as cognitive behavioural therapy (CBT). But interestingly, dapoxetine is not prescribed for managing depression, but for treating Premature Ejaculation (PE) in men, aged 18-64 years.

15. Duloxetine: Duloxetine is a serotonin–norepinephrine reuptake inhibitor (SNRI), a medication used to manage major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain. Its off-label uses include, management of osteoarthritis of the knee in adults, management of chronic lower back pain in adults, management of stress urinary incontinence in adult women, management of chemotherapy-induced peripheral neuropathy, management of stress urinary incontinence in adult men after prostatectomy until recovery is complete.

Disclaimer: The above article is for information purpose only. The above-mentioned medicines are prescription medicines, that can only be made available to a patient on the written instruction of an authorised health professional. Do not try to self-medicate yourselves with these.

Sources:

1. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label

2. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label

3. https://www.ahrq.gov/patients-consumers/patient-involvement/off-label-drug-usage.html

 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538391/