VIEWS & REVIEWS

From a tree to vitamin E - th late t . ~ •• ",U' re earch

-Amanda Hunt-

Tropical rainforest trees, vitamin E and a new class of antihypertensive drugs are three diverse sources being investigated by different laboratories in the fight against AIDS. Several of these groups presented their findings at the recent Experimental Biology '93 Conference in New Orleans, US.

From the rainforests of Malaysia ••• An extract from a common Malaysian rainforest

plant species has shown inhibition of zidovudine­resistant strains of HIV-1, and could represent a new class of anti-HIV drugs.

The novel calonide drug class is being investigated by scientists at the National Cancer Institute (NCI) in Maryland, US. Calonide A is the most potent reverse transcriptase inhibitor of the series discovered so far, said Dr Michael Currens of the NCI. It is active against zidovudine-resistant strains of HIV-1, and also against the A 17 strain of the virus, which is resistant to non-nucleoside inhi bi tors 1 •

The calonides were isolated from Calophyllum species, discovered in conjunction with the National Products Programme of the NCI. They were initially thought to belong to the non­nucleoside reverse transcriptase inhibitors, a diverse group of compounds which bind to a highly hydrophobic 'pocket' of the reverse transcriptase molecule. But subsequent analysis has shown that the calonides do not bind to this site, suggesting that they represent a distinct new class.

Calonide A has shown synergistic activity against HIV-1 with nevirapine and zidovudine in enzyme assays. It is less potent than zidovudine, but has potency comparable to that of TIBO derivatives, such as nevirapine.

But before in vivo studies can be performed, a number of investigations need to be completed. While the Calophyllum species is reasonably common and the drug appears to be easy to extract, currently available quantities are small. Structural chemists are to be consulted, and Dr Currens hopes that modifications may lead to the synthesis of a compound which is even more potent.

Adenosine receptor agonists limit zidovudine toxicity

A class of drugs originally developed as antihypertensives could have potential for alleviating zidovudine-induced anaemia.

Doctors from Tulane University School of Medicine, New Orleans, US, have found that adenosine2 (A2) receptor agonists reverse anaemia induced by zidovudine in rats2. So far, the group has demonstrated the effect with NECA and DPMA, and believes that it may be a general property of A2 agonists.

Haematocrit and red cell volume in rats treated with zidovudine and NECA were similar to those in control animals, and significantly higher than

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levels in animals receiving zidovudine alone. No additional benefits were obtained by adding epoetin to the A2 agonists, reported Dr Sudhir Gogu and colleagues.

The mechanism by which the agonists exert their effect is still unknown. Changes in plasma epoetin were not observed in either treatment or control animals. Dr Gogu et a1. believe that the agonists may act by stimulating production of other growth factors, leading to an elevation of red blood cell production.

The Tulane group is looking for pharmaceutical companies interested in advancing the research further. In addition to treating zidovudine recipients, A2 agonists could have a role in reversing anaemia induced by antineoplastics and other agents.

A2 agonists are not yet approved for therapy; most are still in the preclinical stages of development [see table].

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Toa EJyo Ltd; PI8CinicaI Yamasa Shoyu

VItamin E slows p~on of murine AIDS In exciting developments, vitamin E [tocopherol]

has been shown to halt or slow the progression of a murine form of AIDS which closely resembles the syndrome in humans.

Dr Y Wang and colleagues at the University of Arizona believe that nutrient supplements such as vitamin E could ultimately be used in AIDS patients, in addition to antiviral therapy3. Giving adjunctive vitamin E could decrease the doses of zidovudine and other antiviral agents needed, limiting toxicity and reducing costs.

In mice with murine AIDS, hepatic levels of vitamin E were found to be decreased compared with normal mice. Dietary vitamin E had many beneficial effects when administered to the infected mice, including: • reversal of suppressed natural killer cell activity • enhancement of mitogen-stimulated proliferation

of splenocytes • elevations in IL-2 and IFN-y (suppressed in HIV

infection) • decreases in levels ofIL-4, IL-5 and IL-6

(abnormally elevated by retrovirus infection). Previous authors have speculated that vitamin E

may be useful in the treatment of HIV infection. Levels of vitamin E are low in HIV infection, perhaps as a result of malabsorption. Earlier research has shown that zidovudine and vitamin E act synergistically to inhibit the HIV-1 virus, and that vitamin E reduces the toxicity of zidovudine4.

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4 VIEWS & REVIEWS

However, despite describing the technique as 'promising', Dr Wang does not anticipate beginning investigations in humans for another 2 years. The group wishes to refine the technique in the murine model, to perform dosing studies, and also to study the effects of other nutrients, including copper and zinc. I. Currens MJ. et al. Biological characterization of the anti-HIV activity of calanolide A. FASEB Journal 7: 691. Part 11.19 Feb 19932. Gogu SR. et aI. Proiectiun of zidovudine (AZ1)-induccd murine bone marrow toxicity with an adenosine A2 receptor agonist. FASEB Journal 7: 688. Part II. 23 Feb 1993 3. Wang Y. et al. Vitamin E supplementation assists in the restoration of imbalanced immune functions induced by murine LP·BM5 retrovirus causing murine AIDS (MAIDS). FASEB Journal 7: 285. Part I. 19 Feb 1993 4. Coodley G. et al. Vitamins and minerals in HIV infection. Journal of General Internal Medicine 6: 472-479. Sep-Oct 1991 800191699

10 Apr 1993 INPHARMA~ ISSN 0156·2703/93/041 0·004/$1.00<i:> Adls International Ltd