In the Journals

Angina drug activity reveals possible new treatment strategy against cryptococcosis

Recent research suggested that calcium-channel blockers may serve as a new treatment strategy for cryptococcosis after determining that fendiline hydrochloride, a drug widely used to treat angina, facilitated activity against Cryptococcus neoformans.

The researchers’ findings, published in the International Journal of Antimicrobial Agents, indicate that fendiline hydrochloride can stimulate white blood cells to fight cryptococcosis, which may be more effective than using drugs to directly kill the fungus.

“Fungi are intrinsically more difficult to target than bacteria, because they are much more closely related, evolutionarily, to humans. Finding an essential pathway in a fungus that you could inhibit, which doesn’t exist in humans, is very difficult,” Robin C. May, PhD, of the University of Birmingham in the United Kingdom, said in a press release. “Therefore, the approach of stimulating your own immune system to kill the fungus, instead of killing it directly through treatment, is potentially more powerful.”

Pulmonary infections caused by C. neoformans occur in patients, particularly those who are immunocompromised, who inhale the pathogens. The infections may spread to the central nervous system, causing meningitis. According to the researchers, patients with HIV are especially prone to cryptococcal infections. Approximately 1 million cases of cryptococcal meningitis (CM) are reported annually among patients with HIV. The highest incidence of CM-related deaths in this group occurs in Sub-Saharan Africa, which reports a CM mortality rate of 70%.

Current treatment options for cryptococcosis involving intravenous dosing and clinical toxicity require therapeutic monitoring, which has hindered treatment deployment in resource-limited settings, May and colleagues wrote. Therefore, novel alternative therapies are needed.

In response, the researchers screened 1,200 FDA-approved drugs to identify effective compounds that may stimulate white blood cells to recognize and kill C. neoformans living in the cells, the release said. During a preliminary screening, 19 compounds were found to significantly inhibit intracellular growth of C. neoformans. After additional screening processes ruling out compounds with host cell toxicity, the researchers found that fendiline hydrochloride, dosed at 5 µM, significantly enhanced phagosomal acidification without exhibiting a direct antifungal effect against C. neoformans.

“Although calcium channel blockers have not previously been identified as a potential anticryptococcal agent, their ability to work in this way makes sense,” May said in the release. “We have previously shown that Cryptococcus perturbs calcium signaling when living inside human cells, probably in order to trick the cell into not killing it. Consequently, it’s possible that fendiline hydrochloride works by overcoming this perturbation and restoring normal calcium dynamics, helping the host to kill the fungus.”

Despite its efficacy, a lower dose (1 µM) of fendiline hydrochloride ideal for clinical use failed to prevent C. neoformans growth.

The researchers further assessed the efficacy of fendiline hydrochloride against C. gattii, the other main cryptococcal species. Similarly, they found the drug triggered activity against the pathogen; however, the effect significantly dropped with the reduced dose.

“Though the relatively high dose of fendiline hydrochloride required renders it unfit for clinical deployment against cryptococcosis in itself, our study presents an opportunity to approach treatment of this much neglected disease in a new way,” Rebecca A. Hall, PhD, also from the University of Birmingham, said in the release.

In light of these findings, the researchers concluded that calcium-channel blockers may represent a “promising” new strategy for designing future anticryptococcal agents. – by Stephanie Viguers

Disclosure: The researchers report no relevant financial disclosures.

Recent research suggested that calcium-channel blockers may serve as a new treatment strategy for cryptococcosis after determining that fendiline hydrochloride, a drug widely used to treat angina, facilitated activity against Cryptococcus neoformans.

The researchers’ findings, published in the International Journal of Antimicrobial Agents, indicate that fendiline hydrochloride can stimulate white blood cells to fight cryptococcosis, which may be more effective than using drugs to directly kill the fungus.

“Fungi are intrinsically more difficult to target than bacteria, because they are much more closely related, evolutionarily, to humans. Finding an essential pathway in a fungus that you could inhibit, which doesn’t exist in humans, is very difficult,” Robin C. May, PhD, of the University of Birmingham in the United Kingdom, said in a press release. “Therefore, the approach of stimulating your own immune system to kill the fungus, instead of killing it directly through treatment, is potentially more powerful.”

Pulmonary infections caused by C. neoformans occur in patients, particularly those who are immunocompromised, who inhale the pathogens. The infections may spread to the central nervous system, causing meningitis. According to the researchers, patients with HIV are especially prone to cryptococcal infections. Approximately 1 million cases of cryptococcal meningitis (CM) are reported annually among patients with HIV. The highest incidence of CM-related deaths in this group occurs in Sub-Saharan Africa, which reports a CM mortality rate of 70%.

Current treatment options for cryptococcosis involving intravenous dosing and clinical toxicity require therapeutic monitoring, which has hindered treatment deployment in resource-limited settings, May and colleagues wrote. Therefore, novel alternative therapies are needed.

In response, the researchers screened 1,200 FDA-approved drugs to identify effective compounds that may stimulate white blood cells to recognize and kill C. neoformans living in the cells, the release said. During a preliminary screening, 19 compounds were found to significantly inhibit intracellular growth of C. neoformans. After additional screening processes ruling out compounds with host cell toxicity, the researchers found that fendiline hydrochloride, dosed at 5 µM, significantly enhanced phagosomal acidification without exhibiting a direct antifungal effect against C. neoformans.

“Although calcium channel blockers have not previously been identified as a potential anticryptococcal agent, their ability to work in this way makes sense,” May said in the release. “We have previously shown that Cryptococcus perturbs calcium signaling when living inside human cells, probably in order to trick the cell into not killing it. Consequently, it’s possible that fendiline hydrochloride works by overcoming this perturbation and restoring normal calcium dynamics, helping the host to kill the fungus.”

Despite its efficacy, a lower dose (1 µM) of fendiline hydrochloride ideal for clinical use failed to prevent C. neoformans growth.

The researchers further assessed the efficacy of fendiline hydrochloride against C. gattii, the other main cryptococcal species. Similarly, they found the drug triggered activity against the pathogen; however, the effect significantly dropped with the reduced dose.

“Though the relatively high dose of fendiline hydrochloride required renders it unfit for clinical deployment against cryptococcosis in itself, our study presents an opportunity to approach treatment of this much neglected disease in a new way,” Rebecca A. Hall, PhD, also from the University of Birmingham, said in the release.

In light of these findings, the researchers concluded that calcium-channel blockers may represent a “promising” new strategy for designing future anticryptococcal agents. – by Stephanie Viguers

Disclosure: The researchers report no relevant financial disclosures.