The British leprologists Colin Crawford has been doing a survey of alternatives in the management of ENL. It has been the view of several leprologists that lowering the dose of the chemotherapeutic MDT therapy will lessen the severity of ENL Management with low doses of 10-25 mg dapsone weekly was the rule in northern Nigeria in the 1960s where ENL could be successfully managed, although not completely suppressed, with the addition of 5-10 mg prednisone daily.
High dapsone doses unnecessary
Since the 1960s, dapsone resistance has increased and considered to be in part due to low doses of the drug. Hence it has been mandatory to give full doses of dapsone — up to 700 mg of dapsone weekly — for lepromatous leprosy and also for those patients with ENL. In western countries like the USA there is no spread of the disease, drug resistance to dapsone is not a public health risk and such high dosages is not recommendable.
There is also evidence that low doses do not cause dapsone resistance. According to Colin Crawford found a study found that 8% of patients given low dose sulphones as sulphetrone (solapsone) developed resistance compared to2% given sulphones in larger doses as dapsone. In Karamui , New Guinea lepromatous leprosy has only been treated with sulphones. Reactions occurred in 13 of 38 lepromatous patients but did not seem severe enough to warrant additional treatment. Unfortunately, the type of reaction was not defined but merely called “lepra reactions” so it is unclear whether this was ENL. Nevertheless, neither corticosteroids nor thalidomide were given because it was not possible to provide medical supervision. The follow up of these patients from the bacteriological view was closely monitored with good progress for at least six years. It is therefore possible to treat lepromatous leprosy, in a highly endemic area to good effect without using thalidomide.
There are other alternatives in the management of ENL then thalidomide, like Clofazimine and Fucidic acid.
A Colin Crawford gives example of other drugs that is effective against ENL. Clofazimine has a
chemotherapeutic effect as well as suppressing ENL. It causes hyper pigmentation, which can be a
problem in light-skinned patients, and some recent phenazine analogues could be used instead.
No steroidal anti-inflammatory drugs have also shown some effect against ENL Fucidic acid has been shown to have a chemotherapeutic activity against the leprosy germ and also it appears to suppress the lepra reaction. Fucidic acid is an antibacterial agent, produced by the fungus Fusidium coccineum and is mostly used against Staphylococcus bacteria infections, but also appears to have an anti-inflammatory effect and hence its use in ENL; taken by mouth, not rubbed on skin.
It can be seen that alternative forms of management of ENL are feasible and it should be possible to avoid the use of thalidomide. These regimens have drawbacks but are surely preferable to the teratogenic effects of thalidomide, recently demonstrated in Brazil .
No comparison made
Although thalidomide has been demonstrated to be effective in suppressing ENL, trials have not been carried out comparing the benefit of thalidomide against clofazimine or low doses of corticosteroids. One obvious trial would be to assess morbidity and mortality between males, and females in the reproductive age group. If thalidomide is so beneficial, then this group of females should be at a serious disadvantage. Some countries such as South Africa have continued to ban thalidomide so that leprosy patients here should be at greater risk
A very small study in Tanzania, reported by Colin Crawford, demonstrates that it possible to prevent attacks of ENL if chemotherapy is stopped. With the introduction of multidrug therapy, WHO has recommended that the duration of chemotherapy for uncomplicated lepromatous leprosy can been reduced to one year? It would be rational to restrict the duration of chemotherapy in lepromatous leprosy complicated with ENL even further. By ceasing chemotherapy the ENL will also stop or be greatly reduced. This policy could be tried out in well-supervised leprosy centres, initially in Europe and the USA . Any relapse is easily detected by taking skin smears and determining if there has been a rise in the amount of the germ. Without a relapse the need for thalidomide both in the short term and for prolonged use
would not be necessary.
Lots of research concentrates on finding drugs that reduces the body's production of TNF-alpha, overproduced during HIV infection.
Thalidomide has come into the spotlight again as an experimental treatment for people with late-stage symptoms of AIDS. Some evidence from studies suggests that thalidomide may be very effective in treating HIV-related wasting; apthous ulcers (canker sores which can form in the mouth, esophagus, and rectum). Thalidomide has inhibitory effect on tumour necrosis factor (TNF-alpha), a chemical messenger or cytokine that facilitates communication between cells. Balanced block of TNF-alpha believes to be critical to the contact tune of the human system. During HIV infection, cytokines including TNF-alpha are overproduced.
But not only thalidomide reduces the body's production of TNF-alpha, several other agents have the same effect; sulphasalazine, cyclosporine, ketotifen, N-acetyl-cysteine and pentoxifylline.
An antidepressant drug known as rolipram has been found to be a potent inhibitor of TNF-alpha in the blood. Rolipram was first developed as an antidepressant and marketed in Europe by Schering AG. It is also being investigated as possible treatment for multiple sclerosis. Rolipram is available and used now in Japan ; it has also been used extensively in Europe . Rolipram is at least 10 and perhaps 600 times more powerful then pentoxifylline at inhibiting TNF-alpha. Rolipram is also known to cross the blood-brain barrier, which is an important criterion for any HIV treatment. It is considered an essentially safe drug, the main side effect being mild gastrointestinal distress at doses approaching 15 mg a day. The dose prescribed for antidepressant use ranges between 0.5 to 1 mg taken three times daily. The development rights to rolipram in the U.S. and Japan were licensed to Berlex Laboratories and Meiji Seika Kaisha, respectively unfortunately, the drug may not reach clinical trials because the companies that control rights to it are not inclined to support further development. Schering had submitted an Investigational New Drug application to the FDA some years ago (presumably for a non-HIV related indication), and does not now want to
pursue the research necessary to bring the IND up to date.
In addition to its other uses, thalidomide also inhibits angiogenesis, or the development of new blood vessels that can feed tumours and cancerous lesions — this is the exact property which obstructed the normal growth of fetal limbs in the 1950s. TNF-alpha stimulates the growth of new blood vessels; therefore, the inhibition of TNF-alpha may have applications against Kaposi's sarcoma and cancers.
Rolipram, an antidepressant was developed by the German pharmaceutical company Schering. The agent can become a potent inhibitor of TNF-alpha in the blood.
EntreMed, the U.S. pharmaceutical company that also studies thalidomide, do have other drug
candidates on their shelves like EndostatinTM protein, and 2-Methoxyestradiol.
Antiangiogenic therapies inhibit the growth of new blood vessels, thus blocking the growth of primary and metastatic cancers. If successful, the drug could reduce the size of tumours and potentially maintain them in a dormant state.
The company's hottest candidate is AngiostatinTM protein. The advantage of AngiostatinTM protein is that it's supports the human body's way of dealing with disease. The body attempts to block the growth of diseased tissue on its own, but isn't always successful. When enhanced with additional AngiostatinTM protein,
however, this naturally occurring antiangiogenic agent could block the growth of tumours by depriving them of their blood supply.
The use of AngiostatinTM protein could be particularly critical in the case of multiple tumours. When a patient has multiple tumours, the primary tumour suppresses the growth of other tumours in the body. When that primary tumour is removed, secondary metastatic tumours grow rapidly. Angiostatin TM protein could treat all tumours in a patient effectively and simultaneously. EntreMed state that AngiostatinTM does not affect normal tissue growth as radiation and chemotherapy do. Tillbaka till toppenTillbaka till toppen