Ambrisentan avoids sildenafil drug interaction in PAH patients

Sildenafil may be better given to pulmonary arterial hypertension patients in combination with ambrisentan than with bosentan, study findings suggest.

 (Ambrisentan)   (Sildenafil)

Sildenafil may be better given to pulmonary arterial hypertension (PAH) patients in combination with ambrisentan than with bosentan, study findings suggest.Researcher Keiichi Odagiri (Hamamatsu University School of Medicine, Japan) and team found that patients’ plasma concentration of sildenafil was significantly lower if given with bosentan, compared with ambrisentan.

They say this is because bosentan induces the expression of cytochrome P450 3A4, thus interfering with the pharmacokinetics of sildenafil. Ambrisentan has no such effect, so when the seven study patients, who were all taking sildenafil, were switched from bosentan to ambrisentan, their plasma concentrations of sildenafil were significantly higher.

The patients attained maximum sildenafil concentration in 1.0 hours when they took it with ambrisentan, compared with 0.5 hours with bosentan, and their respective maximum plasma concentrations were 120.2 versus 58.3 ng/mL.And the corresponding areas under the plasma concentration–time curve, representing plasma concentrations across 8 hours, were 396.8 versus 165.8 ng/h per mL.

The team notes that the patients received bosentan 62.5 mg twice daily, rather than the usually recommended 125.0 mg twice daily. They explain that Japanese physicians often use this dose “because of concerns about dose-dependent hepatic toxicity, even though the pharmacokinetics of bosentan and its metabolites are broadly comparable in Japanese and Caucasian individuals.”

Patients’ exercise tolerance improved in line with the higher sildenafil levels achieved with ambrisentan versus bosentan, the researchers report in Clinical and Translational Science.

The median distance achieved in the externally paced 10-metre shuttle walking test was significantly greater during 4–5 weeks of ambrisentan treatment than during the equivalent time on bosentan, at 340 versus 280 metres. The corresponding median 6-minute walking distances were not significantly different, at 503.0 versus 454.0 metres, but peak oxygen consumption and oxygen consumption at anaerobic threshold were significantly greater during the ambrisentan versus bosentan treatment periods.

The researchers caution, however, that they did not use invasive haemodynamic measures to definitively measure treatment response.

Ambrisentan avoids sildenafil drug interaction in PAH patients:

Sildenafil drug improves insulin sensitivity in people at risk for diabetes

Sildenafil inhibits an enzyme called phosphodiesterase 5 (PDE5), resulting in relaxation of smooth muscle, vasodilation and increased blood flow. Sildenafil is used to treat erectile dysfunction and pulmonary arterial hypertension.

Animal studies suggest that sildenafil also can improve insulin sensitivity, the uptake of glucose from the bloodstream by muscle. This action can lower the level of circulating glucose, and potentially reduce the risk of diabetes.

In the current study, overweight individuals with prediabetes were randomly assigned to receive sildenafil or placebo (inactive drug) for three months. Of the 42 subjects who completed the study, those treated with sildenafil were significantly more sensitive to insulin, the researchers reported in today's Journal of Clinical Endocrinology and Metabolism.

Sildenafil drug improves insulin sensitivity in people at risk for diabetes

Vardenafil (PDE5 inhibitor) as antiulcer agent?

Vardenafil, (Levitra, Bayer) is a PDE5 inhibitor used for treating impotence (erectile dysfunction). Vardenafil's indications and contra-indications are the same as with other PDE5 inhibitors; it is closely related in function to sildenafil citrate (Viagra) and tadalafil (Cialis). Structurally, the difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom's position and the change of sildenafil's piperazine ring methyl group to an ethyl group. Tadalafil is structurally different from both sildenafil and vardenafil. Vardenafil's relatively short effective time is comparable to but somewhat longer than sildenafil's.

We know that most of the NSAIDs are associated with ulcerogenecity. Though there are many compounds with different mode of action have been tested (and some of them are being used) to treat the peptic ulcer, compounds with phosphodiesterase 5 inhibitor were not tested before Dr. Karakaya of Zonguldak Karaelmas University-who have reported that Vardenafil can be used to treat the NSAID-induced gastric ulcer. As per the claim by the researchers the activity is dose dependent.

Ref : http://www.wjgnet.com/1007-9327/abstract_en.asp?f=5091&v=15

Sildenafil drug may effectively relieve nerve damage in men with long-term diabetes

New animal studies at Henry Ford Hospital found that sildenafil, a drug commonly used to treat erectile dysfunction, may be effective in relieving painful and potentially life-threatening nerve damage in men with long-term diabetes.   

The research targeted diabetic peripheral neuropathy, the most common complication of diabetes, affecting as many as 70 percent of patients.

The study was recently published online in PLOS ONE. Lei Wang, M.D., the Henry Ford neuroscientist who led the research, said that although numerous drugs have been shown to be effective in earlier animal experiments, most have not provided benefits in clinical trials.

"Generally, young diabetic animals with an early stage of peripheral neuropathy are used to investigate various drug treatments," Dr. Wang explains. "But patients with diabetes who are enrolled in clinical trials often are older and have advanced peripheral neuropathy.

"Failure to develop and properly evaluate treatments in the laboratory that properly reflect the target clinical population with diabetic peripheral neuropathy may contribute to the failure of clinical trials."

To mimic clinical trials in which diabetes patients have advanced peripheral neuropathy, the Henry Ford researchers chose male mice with type II diabetes that were 36 weeks old, roughly equivalent to middle age in humans.

Sildenafil drug may effectively relieve nerve damage in men with long-term diabetes

Drug trio of rapamycin, sildenafil and doxorubicin improved effectiveness of cancer treatment, protected heart

Combining cancer medication with a drug for erectile dysfunction and one for heart transplants helped kill cancer cells and protected the heart from damage. For decades, doxorubicin has been a powerful anti-cancer treatment for various human cancers, including breast, ovarian, colon and prostate. But its use has been limited due to harmful, possibly irreversible effects on the heart.

In this study, using cell and animal models, researchers found that sildenafil alone or in combination with rapamycin (an immunosuppressant used to prevent post-transplant organ rejection) significantly improved the anti-cancer effects of doxorubicin while protecting the heart. The combination of all three medications showed the most powerful effect, researchers said.

"Because sildenafil and rapamycin are clinically approved drugs that both protect heart muscle, we thought that combining these drugs with doxorubicin would be a unique strategy to eliminate the cardiac side effects of doxorubicin while further improving its cancer-killing ability," said Rakesh Kukreja, Ph.D., study co-author and professor of internal medicine and cardiology, Virginia Commonwealth University (VCU) School of Medicine in Richmond.

"The drug combination led to a dramatic protection of heart muscle from apoptosis (cellular self-destruction) and, to a lesser extent, necrosis (cell death from disease)," said David E. Durrant, study lead author and Ph.D. candidate at the VCU School of Medicine. "We think this combination therapy may have excellent potential to move forward into clinical trials and eventually improve life expectancy of cancer patients."

Drug trio improved effectiveness of cancer treatment, protected heart

FDA Approves Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria

PTC Therapeutics, Inc. (NASDAQ: PTCT) announced   U.S. Food and Drug Administration (FDA)  approval of Sephience™ (sepiapterin) for the treatment of children and adults living with phenylketonuria (PKU). The approval includes broad labeling for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive PKU.

"We are excited to have reached this important milestone for those affected by PKU," said Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics. "The broad labeling reflects the potential of Sephience to meet the significant unmet need of PKU patients. The Sephience clinical data along with our expertise in launching rare disease therapies position Sephience to become the future standard of care. Our experienced customer facing teams are ready to bring this therapy to children and adults with PKU in the United States as quickly as possible."

The FDA approval is based on the evidence of significant efficacy and safety from the

Phase 3 APHENITY trial as well as durability of treatment effect in the APHENITY long-term extension study.

"The approval marks an exciting milestone for the PKU community," said Catherine Warren, Executive Director of the National PKU Alliance. "This progress brings renewed hope, and we are eager to see the positive impact this new treatment option will have on advancing care and potentially improving quality of life for individuals of all ages and PKU subtypes that respond to this therapy."

Sephience was recently granted marketing authorization by the European Commission. Review of approval applications is ongoing in several other countries including Japan and Brazil.

About Sephience (sepiapterin)

Sephience is indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients with phenylketonuria (PKU). Sephience is a natural precursor of the enzymatic co-factor BH4, a critical co-factor for phenylalanine hydroxylase (PAH). Through its mechanism of action, Sephience is able to effectively reduce blood phenylalanine (Phe) levels and has the potential to treat a broad range of PKU patients. Sephience is approved in the European Economic Area and the United States.

Indication and Important Safety Information

Indication

Sephience is indicated for the treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). Sephience is to be used in conjunction with a phenylalanine (Phe)-restricted diet.

Contraindications

None

Important Safety Information

Treatment with Sephience should be directed by physicians knowledgeable in the management of PKU. Biochemical response to Sephience can only be determined by a therapeutic trial with careful monitoring of ongoing dietary and nutritional balance to ensure adequate Phe control.

Warnings and Precautions

Increased Bleeding: Sephience may increase the risk of bleeding. Bleeding events, including superficial hematomas, prolonged bleeding, and heavy menstrual bleeding have occurred in patients treated with Sephience. Inform patients about the risk of bleeding associated with Sephience and have patients follow up with their healthcare provider should such a bleeding event occur. Consider treatment interruption with Sephience in patients with active bleeding.

Hypophenylalaninemia: Some pediatric patients receiving Sephience experienced hypophenylalaninemia. Monitor blood Phe levels during treatment and modify the dosage of Sephience and/or dietary protein and Phe intake as needed to ensure adequate blood Phe level control. Frequent blood monitoring is recommended in the pediatric population.

Interaction with Levodopa: In a 10-year post-marketing safety surveillance program for a non-PKU indication using another drug that is a phenylalanine hydroxylase (PAH) activator, 3 patients with underlying neurological disorders experienced seizures, exacerbation of seizures, over-stimulation, and irritability during co-administration with levodopa. Monitor patients who are receiving levodopa for changes in neurological status during treatment with Sephience.

Adverse Reactions

Most common adverse reactions with Sephience (≥2% and > placebo) were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain.

Drug Interactions

Avoid concomitant use of drugs known to inhibit folate synthesis dihydrofolate reductase (DHFR) (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate, raltitrexed, and piritrexim) while taking Sephience. Concomitant administration of such drugs may reduce sepiapterin metabolism to BH4. If concomitant use is not avoidable, monitor blood Phe levels.

Sephience and PDE-5 inhibitors (e.g., sildenafil, vardenafil, or tadalafil) induce vasorelaxation and may reduce blood pressure. Monitor for signs and symptoms of hypotension.

For medical information, product complaints, or to report an adverse event, please call 1–866–562–4620 or email at usmedinfo@ptcbio.com.

https://en.wikipedia.org/wiki/Sepiapterin

FDA Approves Sephience (sepiapterin) for the Treatment of Children and Adults Living with Phenylketonuria