New production method could increase the availability of treatment for cryptococcal meningitis

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A drug vital for treating cryptococcal meningitis (CM) could become more readily available in less developed nations as a result of new research from Durham University. The study, published in Organic Process Research & Development, reports a simplified production process, which the authors hope will reduce the cost of this important drug.

CM is a leading cause of meningitis and is responsible for 20% of deaths in HIV/AIDs patients worldwide. In developed countries the mortality rate for cases of CM is approximately 9%, however this rate is higher in developing nations, for example the mortality rate in Sub-Saharan Africa is 70%. This dramatic difference is due to poor drug availability, which is partly a result of the cost of key treatment drug, flucytosine.

Currently flucytosine is produced utilizing a multi-stage process that requires four separate reactions. A 2 week course of flucytosine costs $62 per patient, making it prohibitively expensive in developing nations.  The researchers, led by Graham Sandford (Durham University, Durham, UK), have developed an innovative and simplified new method for producing this drug, which consists of a one-step continuous flow process.

Sandford explained: “We have successfully developed a method of making flucytosine from a starting material of cytosine which is a readily available, naturally occurring product.

“Our new technique continuously passes fluorine gas through a reactor tube, together with a solution of cytosine in acid. In the tube the fluorine atoms react with the cytosine molecules to make flucytosine.

“This method uses less energy, fewer raw materials and produces less waste than existing production processes and is also less expensive.”

The team hope this simpler method of production, which has a low initial capital expenditure, will allow flucytosine to be produced at a significantly reduced cost in the future, therefore increasing its availability and preventing CM deaths.

To initially assess the methods’ scalability the team worked with pharmaceutical company Sanofi and the not-for-profit organization MEPI. The researcher’s initial results demonstrated that a small scale reactor could produce up to 1 kg of raw material per day, indicating this new process could present a viable alternative to current methods.

Sandford commented: “Our research has shown that it is possible to synthesise flucytosine using an operationally simple process and inexpensive, readily available starting materials.”

Future research will look into production scale-up, with the aim of making this medication available and improving the treatment of CM across the globe. Sandford concluded:  “Our hope is that this research will raise awareness of the neglected CM health epidemic and help to provide affordable flucytosine for low income countries, something which is urgently needed.”

Source: Harsanyi A, Conte A, Pichon L et al. One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine. Org. Process Res. Dev. 21 (2), 273–276 (2017); https://www.dur.ac.uk/news/newsitem/?itemno=30675%20

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