What Is Roflumilast? And What Are Its Possible Health Impacts?

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What Is Roflumilast? And What Are Its Possible Health Impacts?

Roflumilast, also known as Texas, is a drug that acts as a selective, long-acting inhibitor of the enzyme phosphodiesterase-4 (PDE-4).

It has anti-inflammatory properties and is an orally administered drug to treat inflammatory lung conditions such as chronic obstructive pulmonary disease (COPD).

It was approved in the European Union in June 2010 for severe COPD associated with chronic bronchitis.

It received FDA approval in the United States in February 2011 for reducing COPD exacerbations.

What Is Roflumilast? Structure And Properties Of Roflumilast

what is roflumilast

It is a an organic compound with moleculr formula C17H14Cl2F2N2O31. Its molecular weight is  406.2g/mol and IUPAC name isN-(3,5-dichloropyridin-4-yl)-3-[dideuterio-(1-deuteriocyclopropyl)methoxy]-4-(difluoromethoxy)benzamide.

Roflumilast is an orally available, long-acting phosphodiesterase (PDE) type 4 inhibitor (PDE4). Roflumilast is a benzamide derived from the carboxy group of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid and the amino group of 3,5-dichloropyridin-4-amine.

It is a benzamide2, a chloropyridine, an aromatic ether, an organofluorine compound, and a cyclopropanes member.

The medication is a non-hygroscopic white to off-white powder with a melting point of 159.7°C. Water and hexane are completely insoluble, ethanol is sparingly soluble, and acetone is readily soluble.

This medication is used to treat bronchial asthma and chronic obstructive pulmonary disease. It functions as a phosphodiesterase IV inhibitor as well as an anti-asthmatic medication. 

Synthesis Of Roflumilast

what is roflumilast

Although Roflumilast is synthesized from many procedures, many of them are obsolete.

Here is an advanced method3 of synthesis using O-alkylation, oxidation, and N-acylation procedure for synthesizing roflumilast from 4-difluoromethoxy 3-hydroxybenzaldehyde and bromomethyl cyclopropane.

The overall yield of roflumilast may be increased to 68.3 percent by optimizing the reaction conditions, and the purity of the product can be increased to 99.2 percent.

The results showed that using sodium hydroxide as the alkali in the N-acylation procedure, the optimum yield of 89.2 percent of roflumilast can be produced.

The current method offers advantages over prior methods, including convenience, cheap cost, and ease of set-up, allowing for quick scale-up.

What is Daliresp, and How is It Used?

DALIRESP4 is available as round white to off-white tablets with a “D” on one side and “250” or “500” on the other. Roflumilast is present in each tablet in 250 mcg or 500 mcg doses.

daliresp pills contain the active component roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective PDE4 inhibitors.

N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide is the chemical name for roflumilast. The molecular weight is 403.22, and the empirical formula is C17H14Cl2F2N2O3.

Daliresp is a prescription medication used to treat the symptoms of Chronic Obstructive Pulmonary Disease(COPD). Daliresp can be taken on its own or in combination with other drugs.

What Are Uses Of Roflumilast

Roflumilast cream is a nonsteroidal anti-inflammatory medication. Roflumilast is used to treat and prevent symptoms of chronic lung disease (wheezing and shortness of breath). It works by reducing airway irritation and swelling.

The PDE(4) isoenzyme is inhibited by roflumilast, increasing cyclic adenosine monophosphate.

Roflumilast has several pharmacological effects5, including anti-inflammatory, anti-emphysema, and antibiotic properties.

Controlling the symptoms of breathing problems can reduce time spent away from work or school. This medication must be taken regularly.

It does not take effect immediately and should not be used to treat sudden shortness of breath or wheezing.

Is Roflumilast Effective In Asthma And Chronic Obstructive Pulmonary Disease (COPD)?

Roflumilast is used to reduce the number of episodes or worsening of COPD symptoms in people with severe chronic obstructive pulmonary disease6(COPD; a group of diseases that affect the lungs and airways). It works by reducing pulmonary swelling.

Exacerbations7 of chronic obstructive pulmonary disease (COPD) are acute events characterized by worsening respiratory symptoms that necessitate a change in medication and hospitalization.

Severe exacerbations (those resulting in hospitalization and death) are associated with a poor prognosis, decreased quality of life, and increased mortality.

Roflumilast is used once daily, an oral, selective phosphodiesterase-4 inhibitor that targets COPD’s systemic and pulmonary inflammation.

A clinical research8 has shown that adding roflumilast to inhaled therapies reduces COPD exacerbations in patients with severe COPD, chronic bronchitis, and a history of exacerbations.

On the other hand, the adverse events associated with systemic therapies often necessitate that these therapies be used to treat specific patient populations in whom they are likely to have the greatest clinical benefit.

Is Roflumilast Effective In The Treatment Of Psoriasis?

According to the National Psoriasis Foundation, Psoriasis is a chronic skin condition that affects more than 8 million Americans. The disease develops due to an abnormal immune response that causes a rapid turnover of skin cells, causing them to accumulate on the skin’s surface.

Psoriasis9 is a skin condition that causes red, itchy, scaly patches on the knees, elbows, trunk, and scalp. Psoriasis is a common, long-term (chronic) disease for which there is currently no cure. It tends to be flared up for a few weeks or months, then subside for a while or go into remission.

The new study10 tested an experimental cream medication that may avoid the side effects of current psoriasis topical treatments. The cream contains roflumilast, a drug that inhibits an enzyme that causes inflammation.

 The researchers discovered that roughly one-quarter of patients randomly assigned to use the cream once a day saw their skin clear up within six weeks. This compares to 8% of those who received an inactive (“placebo”) cream.

Systemic oral PDE-4 inhibitors are effective in treating Psoriasis. Roflumilast cream contains a PDE-4 inhibitor studied for topical psoriasis treatment.

Adults with plaque psoriasis were randomly assigned in a 1:1:1 ratio to use roflumilast 0.3 percent cream, roflumilast 0.15 percent cream, or vehicle (placebo) cream once daily for 12 weeks in a random phase study, double-blind trial.

Roflumilast cream, applied once daily to psoriasis-affected areas, outperformed11 vehicle cream to achieve clear or nearly clear skin after six weeks. Longer trials are needed to determine roflumilast’s durability and safety in Psoriasis.

Can Roflumilast Be Used As an Anticancer Drug?

A few types of research have shown that Roflumilast is quite effective in its anti-cancer properties. It has been tested for its role in lung and ovarian cancer.

In a research study12 roflumilast, alone and in combination with inhaled budesonide, was tested in mice. Research showed that it could inhibit lung carcinogenesis induced by carcinogen B(a)P in mice. A single dose of benzo(a)pyrene was administered to female A/J mice.

High-dose roflumilast can inhibit lung carcinogenesis in a B(a)P-induced murine lung cancer model.

The chemopreventive effect of roflumilast may be related to the inhibition of increased cAMP-mediated inflammatory processes and angiogenesis markers in tumor tissues.

Meanwhile, it is reported to be effective in curing ovarian cancer. With an incidence of 6.1 cases per 100,000 women and a mortality rate of 4.3 deaths per 100,000 women, ovarian cancer is the leading cause of gynecologic cancer death in developed countries.

To investigate Roflumilast’s direct anti-tumor effects on ovarian cancer, two ovarian cancer cell lines, OVCAR3 and SKOV3, were used.

A series of Roflumilast concentrations were administered to two cell lines for 24 hours, and the results indicated that Roflumilast significantly inhibited cell vitality in a dose-dependent manner.

The anti-tumor role of Roflumilast13 in vivo was also demonstrated; the treatment of roflumilast effectively inhibited tumor proliferation and increased FtMt expression to limit tumor growth via the activation of cAMP/PKA/CREB signals in ovarian cancer.

Is Roflumilst Helpful In Covid-19 Treatment?

The coronavirus disease 2019 (COVID-19) is the world’s most serious inflammatory respiratory disease. Despite numerous proposed treatments, no effective medication has yet to be approved.

Neutrophils appear to be the primary mediators of COVID-19-related inflammatory immunopathologic, thromboembolic, and fibrotic complications. As a result, for any therapeutic agent to be effective, it must significantly inhibit the neutrophilic component of COVID-19.

The suppression of the neutrophilic component that compels to increased systemic inflammation and coagulopathy associated with COVID-19 infection is thought to be biologically linked to lowering the patient’s risk of COVID-19 progression.

 As a result, COVID-19 management should modulate neutrophil function and response. According to the underlying guidelines, the recommended anti-inflammatory therapies for COVID-19 have not provided treatment satisfaction or effectiveness.

PDE4i has been proposed as an intriguing new class of COVID-19 treatment as the search continues because inhibiting PDE4 is thought to have effective anti-inflammatory and anti-platelet activities.

Among the clinically available PDE4i, roflumilast has been reported to be the most selective and effective drug for treating a variety of neutrophil-mediated airway inflammatory disorders.

A review14 discusses the NEP-mediated therapeutic properties of roflumilast and its role in combating the inflammatory, coagulopathy, and fibrotic cascades caused by COVID-19.

It is hoped that this hypothesis will act as a stimulus for further confirmation of roflumilast’s therapeutic impact in COVID-19 management and, as a result, may provide physicians with a novel repurposed treatment option against COVID-19.

Is Roflumilast A Cause Of Weight Loss?

Roflumilast, a PDE4 inhibitor, reduces weight gain by increasing energy expenditure, which leads to improved glucose metabolism.

In a clinical trial15, Roflumilast’s metabolic effects were studied in C57BL/6J mice fed a high-fat Western-type diet to be treated with or without roflumilast for 12 weeks.

Roflumilast caused a significant decrease in body weight gain, which was noticeable in the second week after treatment initiation and was attributed to a significant increase in energy expenditure.

Furthermore, in mice, roflumilast improved glucose tolerance, decreased insulin resistance, and reduced steatohepatitis.

Roflumilast-dependent PDE4 inhibition is a novel target for weight loss strategies, particularly in the presence of chronic conditions such as insulin resistance and non-alcoholic steatohepatitis.

What Are the Most Common Roflumilast Or Daliresp Side Effects?

Diarrhea, weight loss, nausea, headache, back pain, flu-like symptoms, difficulty sleeping (insomnia), dizziness, and decreased appetite are the most common Roflumilast side effects16.

These are not the only DALIRESP side effects that could occur. Always notify your healthcare provider if you experience any side effects that bother you or do not go away.

What Are Serious Side effects Of Roflumilast?

In clinical trials, diarrhea and nausea were the two most common side effects that caused people to stop taking DALIRESP.

In these clinical trials, most people who experienced diarrhea and nausea did so at the start of their treatment, and it usually lasted less than four weeks. It lasted longer and was more severe for some.

Dairies have the potential to cause serious side effects17.

Some people who take DALIRESP may experience mood or behavior problems, such as suicidal thoughts or attempts, difficulty sleeping (insomnia), new or worse anxiety, new or worse depression, acting on dangerous impulses, or other unusual behavioral or mood changes, including suicidal thoughts.

Roflumilast has the potential to cause weight loss. It will help if you weigh yourself regularly. It’s good for you to visit your doctor regularly to check your weight.

Call your doctor if you notice you’re losing weight. If you lose too much weight, your doctor may advise you to stop taking Roflumilast.

Roflumilast may affect how other medications work, and other medications may affect how Roflumilast works.

Inform your doctor regarding all of the medications you use, including prescription and over-the-counter medications, vitamins, and herbal supplements.

What Are Precautions In Taking Roflumilast Drugs?

Some precautionary measures18 are a must while taking the Roflumilast or Delirasp medicine.

Your doctor must monitor your progress regularly. It will allow your doctor to determine whether or not the medication is working properly and whether you should continue to take it.

This medication is used to prevent acute COPD flare-ups. It is not used to stop a flare-up that has already begun. You should use an inhaled medicine that works quickly to help you breathe better for acute flare-ups.

Check with your doctor if you do not have an inhaled medicine for acute COPD flare-ups or any questions about this.

Some people may become agitated or exhibit other abnormal behaviors due to this medication, such as feeling sad or hopeless, becoming easily upset, having difficulty sleeping, or feeling nervous or hostile.

 It may lead to suicidal thoughts and tendencies in some people and an increase in depression. If you or a caregiver will notice any of these side effects, contact your doctor immediately.

You may lose weight as a result of taking this medication. While using this medication, your doctor may need to check your weight regularly.

Other medications should not be taken unless discussed with your doctor. It includes prescription and nonprescription (over-the-counter [OTC]) medications and herbal and vitamin supplements.

There are no adequate studies to determine infant risk when this medication is used while breastfeeding. Before taking this medication while breastfeeding, weigh the potential benefits against the potential risks.

Conclusion

Roflumilast available as Deliresp is an effective medicine. It is proved to be most effective in chronic lung conditions and Asthma.

It has proved to be effective also in the treatment of Psoriasis and as an anticancer drug. Researchers have given a gesture for its positive role in Covid-19 treatment also.

However, Precautions are also a must while using this medicine as it causes serious behavioral implications also. You must be careful if you are a liver patient already. Care must be taken while using lactation and breastfeeding.

Always consult your doctor before using. Although Roflumilast has shown the most likely results, more research is needed.

References

1-PubChem. (n.d.). PubChem. Nih.Gov. Retrieved January 3, 2022

2-PubChem. (n.d.-b). Roflumilast. Nih.Gov. Retrieved January 3, 2022

3-Lin, Y., Huang, P., Liu, S., Sima, L., Chen, L., & Wang, D. (2013). A convenient method for the synthesis of roflumilast. Research on Chemical Intermediates, 39(5), 2107–2113.

4-Daliresp. (n.d.). RxList. Retrieved January 3, 2022

5-Cortijo Gimeno, J., & Morcillo Sánchez, E. (2010). Pharmacological profile of roflumilast. Archivos de bronconeumologia, 46 Suppl 10, 19–24

6-Roflumilast: Diarrhoea and weight loss: 2 case reports. (2016). Reactions Weekly, 1618(1), 148–148.

7-Rabe, K. F., Calverley, P. M. A., Martinez, F. J., & Fabbri, L. M. (2017). Effect of roflumilast in patients with severe COPD and a history of hospitalization. The European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology, 50(1), 1700158.

8-Martinez, F. J.,Rabe, K. F., Calverley, P. M. A., & Fabbri, L. M. (2017).

9-Psoriasis. (n.d.). Mayo Clinic. Retrieved January 3, 2022.

10-New psoriasis treatment option from skin cream with roflumilast. (n.d.). MedicineNet.

11-Lebwohl, M. G., Papp, K. A., Stein Gold, L., Gooderham, M. J., Kircik, L. H., Draelos, Z. D., Kempers, S. E., Zirwas, M., Smith, K., Osborne, D. W., Trotman, M.-L., Navale, L., Merritt, C., Berk, D. R., Welgus, H., & ARQ-151 201 Study Investigators. (2020). Trial of roflumilast cream for chronic plaque psoriasis. The New England Journal of Medicine, 383(3), 229–239

12-Yeo, C. D., Kim, Y. A., Lee, H. Y., Kim, J. W., Kim, S. J., Lee, S. H., & Kim, Y. K. (2017). Roflumilast treatment inhibits lung carcinogenesis in the benzo(a)pyrene-induced murine lung cancer model. European Journal of Pharmacology, 812, 189–195.

13-Gong, S., Chen, Y., Meng, F., Zhang, Y., Wu, H., & Wu, F. (2017). Roflumilast restores the cAMP/PKA/CREB signaling axis for FtMt-mediated tumor inhibition of ovarian cancer. Oncotarget, 8(68), 112341–112353.

14-El Tabaa, M. M., & El Tabaa, M. M. (2020). New putative insights into neprilysin (NEP)-the dependent pharmacotherapeutic role of roflumilast in treating COVID-19. European Journal of Pharmacology, 889(173615), 173615.

15-Möllmann, J., Kahles, F., Lebherz, C., Kappel, B., Baeck, C., Tacke, F., Werner, C., Federici, M., Marx, N., & Lehrke, M. (2017). The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and improving glucose metabolism. Diabetes, Obesity & Metabolism, 19(4), 496–508.

16-Roflumilast oral: Uses, side effects, interactions, pictures, warnings & dosing – WebMD. (n.d.). Webmd.Com. Retrieved January 3, 2022

17-DALIRESP® (roflumilast). (n.d.). Daliresp.Com. Retrieved January 3, 2022.

18-Roflumilast (oral route). (n.d.). Mayoclinic.Org. Retrieved January 3, 2022.

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