FR2715303A1 - Riboflavin for treating human immunodeficiency virus related diseases - Google Patents

Abstract

Riboflavin (I) is used to prepare pharmaceuticals for treatment or prevention of HIV-related diseases, herpes, retinitis pigmentosa; malaria and generally any disease related to light. Pref. (I) may be combined with Vitamin PP (esp. in synergistic amts.) or with AZT.

Description

 The present invention relates to the discovery of new therapeutic indications for a drug based on vitamin B2 or ri bonavine; this remedy prescribed parenterally to patients with AIDS has been shown to present immediate, surprising and very favorable clinical effects. The remedy used, Beflavin, has so far been used for other indications; it was particularly indicated in the treatment of certain skin conditions.

 According to the state of the prior art, many molecules have been recognized to be effective in vitro against HIV, but their use in vivo is not possible due to their toxicity.

 The main molecules currently in use or in the process of being used belong to four distinct therapeutic families.

 The first family comprises reverse transcriptase inhibitor drugs which are themselves subdivided into two categories consisting of nucleoside inhibitors and non-nucleoside inhibitors.

 Among the nucleoside inhibitors, three molecules are currently in use or under test, these are AZT, DDI, DDC.

 AZT or zidovudine is the first and only remedy used so far on a large scale on sick HIV-positive subjects. Its indication has just been extended to non-sick HIV-positive subjects but this remedy is likely to cause hematopoietic complications.

 DDI or dideoxy-inosine is undergoing phase II and III trials.

It would present a certain neurological and pancreatic toxicity.

 SDC or dideoxy-cytidine is under study. It is planned to use it as a third line after AZT and DDI and possibly as a second line after AZT.

 A new non-nucleoside molecule that inhibits reverse transcriptase is currently under study; it is BI-RG-587 which belongs to the family of dipyridodiazepinones.

 The second therapeutic class consists of protease inhibitors and more particularly the molecule U81749 active in vitro on HIV.

 The third therapeutic family consists of soluble CD4 or r.CD4, under study; it is the viral receptor at the level of the membrane of T4 lymphocytes. It would be used as an HIV decoy.

 The ditiocarb or Imuthiol constitutes the fourth therapeutic anti-HIV family. It is under industrial development. It would have a major antioxidant, anti-radical action.

 In addition to the four types of remedy previously mentioned, it should be noted that certain molecules, such as quinolones and tetracyclines, have shown certain effects in vitro on the replication of HIV.

 They would act on the mycoplasmas currently considered by Professor MONTAGNIER as a co-factor of 'HIV. It will be seen later the interest of these observations.

 Finally vaccination is under study. The various results observed so far are controversial.

 If we take stock of the technique used so far, an observation can be made; at present the molecules used against HIV, if they bring a certain remission to the disease, do not seem to prevent the fatal evolution. In addition, their activity is often marred by sometimes very serious side effects.

The applicant had the idea of using riboflavin on patients with AIDS because of certain skin lesions presented by them, and especially as a result of the research he carried out on the human body and light, which led him to formulate the hypothesis:
photosynthesis is universal; the AIDS virus is subjected to photosynthesis, it is activated by ultraviolet; yellow products, highly pigmented, absorb ultraviolet and are therefore likely to protect the organism from excessive ultraviolet irradiation.

 The results obtained were immediately spectacular and surprising, seeming to confirm the initial hypothesis.

The hypotheses that led to the development of the protein photosynthesis theory on an animal scale are far too vast and complex to be explained below. We can however point out that in 1988 the price
Nobel Prize in Chemistry has been awarded to three researchers who have demonstrated photosynthesis at the level of bacteriorhodopsin, a membrane protein of the bacterium rhodo pseudomonas viridans.

With regard to viruses, it is well known that Herpes viruses
HSV1 and HSV2 are activated by ultraviolet rays: the recurrence of herpes infection linked to HSE'1 during significant sunshine is well known.

 HSV2 with genital tropism also seems to respond to ultraviolet irradiation "HSV2 irradiated by ultraviolet rays produces cancer in the hamster and transforms rat cells in vitro" (A.Mammette, medical virology, p .45).

 As for the HIV viruses, in addition to their very evocative structure vis-à-vis photocaptation, if they are capable of being destroyed by different physical methods, they resist very well against ultra-violet irradiation.

 Substances pigmented in yellow and yellow-orange absorb ultraviolet and blue radiation.

The riboflavin molecule is yellow-orange in color in crystallized form. In solution it gives a yellow-green fluorescence; its exposure, even a few minutes, to ultraviolet light causes its irreversible decomposition into its antagonistic derivative lumiflavin which gives a blue fluorescence in solution;
moreover, nearly 85X of the riboflavin in milk is destroyed by exposure to the sun.

 This fact is essential for two reasons: the first is that despite the greater stability of riboflavin in acid solution, it seems that a yellow packaging, opaque to light and ultraviolet, would be an additional guarantee for the good conservation of remedies based on vitamin B2.

 The second notable reason is that exposure destroying a major part of riboflavin, it is possible to suppose that in very sunny countries the human organisms can present in the same way a relative deficiency in vitamin B2 following an accelerated destruction .

Some examples of photoprotection with products or substances pigmented in yellow are well known: thus beta-carotenes by stimulating skin pigmentation protect the skin against UV rays;
patients with retinitis pigmentosa wear yellow-orange glasses to slow the progression of the disease. Their colored vision is then amputated of its blue color; it is remarkable to note that riboflavin exists in a physiological state in an appreciable quantity in the retina. It is then safe to assume that in the event of a vitamin B2 deficiency, the retina which is no longer protected by this photoprotective molecule would be attacked by the ultraviolet rays and the free radicals they generate, this aggression causing or aggravating lesions. at the level of the visual cells.

 The corollary is that the use of riboflavin-based drugs appears to represent the preventive and curative treatment of choice for pigmentary retinitis.

 Vitamin D in solution, for example ergocalciferol or Stérogyl from Laboratoires Roussel is packaged in yellow-brown bottles to avoid inactivation of the molecule by light and ultraviolet light.

Quinine and its derivatives are extracted from yellow cinchona bark. Among the multiple indications of quinine two of them are particularly interesting; the main one of course is its action against malaria. However, it was noted that the endemic areas of AIDS and malaria are very significantly geographically superimposable.

 Assuming that AIDS presents a certain relationship with an excess of sunshine and / or a relative deficit in photoprotective molecules normally present in the physiological state in the organism, we come to the conclusion that the administration of vitamin B2 as preventive and curative would constitute a simple and logical treatment of AIDS infection. The joint administration of vitamin PP which acts in symbiosis with riboflavin at the level of the cellular respiratory chain and which is known for its photoprotective effects, could be interesting.

 If we suppose in the same way that malaria can have a relationship with a strong ambient sunshine, it would not be then surprising that molecules like quinine or its derivatives, sometimes prescribed in lucites, can cure or prevent malaria . based on the same therapeutic effects.

 In recent years, there has been a resurgence of morbidity and mortality from malaria which is becoming more and more resistant to standard treatments.

If quinine inhibited the development of d = protozoan by its photoprotective effect, it would be safe to assume that another photoprotective remedy of the same color such as a vitamin-based drug
B2 could be a therapeutic solution to malaria infestation with the advantage of the recognized non-toxicity of such a remedy.

 Quinolones are apgurenrEtffls antibiotic substances to the quinone nucleus. They would have demonstrated certain effects on HIV in vitro.

 The same is true for tetracyclines. These, like quinolones, are known for their photosensitization effects when administered in vivo.

On the other hand the tetracyclines, which have a yellow coloring
in solution, are likely to cause tissue pigmentation
abnormal, of the same color, for example at the level of dental buds, which contraindicates them in pregnant women and children up to seven years.

your morbidity from AIDS infection compared to ethnic groups shows
a decreasing predominance according to the races, black, then white,
and finally yellow; the pigmentation of the skin would therefore seem to confer a certain protective effect vis-à-vis the AIDS infection in the subjects
yellow.

Finally, to finish with this paragraph on products and sub
pigmented tances, it should be remembered that DDI in solution is yellow and that bile salts, which inhibit HIV in vitro, have a yellow-green coloration.

 It follows from all these considerations that the substances and products pigmented in yellow absorb ultraviolet radiation and would therefore have a photoprotective effect.

 In addition, various yellow-colored substances have an inhibitory effect on the replication of HIV.

 A more extensive literature search on vitamin B2 shows that in addition to its colorimetric properties riboflavin has other properties capable of confirming its inhibitory action on the replication of HIV.

 First of all, it is interesting to note that in its metabolic becoming, riboflavin goes through two active metabolites, FMN and FAD or flavin-mononucleotide and flavin-adenine-dinucleotide; it is useful to recall here that a dinucleotide corresponds to a phosphorylated dinucleoside. Therefore, in its transfer to the FAD, the riboflavin molecule probably passes through a dinucleoside intermediate before being phosphorylated.

 However, it has been seen previously that certain dinucleoside molecules such as AZT, DDI, DDC are inhibitors of HIV reverse transcriptase.

Warburg riboflavin or yellow ferment plays an essential rattle in the cellular respiratory chain where it acts in symbiosis with vitamin PP itself known for certain photoprotective effects since it is prescribed in lucites. These two vitamins are carriers of hydrogen; this transfer action between hydrogen and oxygen at the level of the cell and mitochondrial membranes suggests an anti-radical, that is to say antioxidant, effect of the vitamins
B2 and PP; such an antioxidant effect can be verified on a macroscopic scale by a simple experiment, a rusty nail soaked in a solution of riboflavin is released from its rust after a few hours.

 This symbiotic action of vitamins B2 and PP also makes it possible to envisage the possibility of a therapeutic synergy in the treatment of AIDS and certain diseases related to light, if the photosynthetic hypotheses previously expressed prove to be correct.

 In the context of AIDS, therapeutic synergy would be all the more interesting as many of the known symptoms of vitamin B2 deficiency as well as vitamin PP deficiency are found in patients with AIDS.

Among other properties of riboflavin, it is necessary to specify the interferential relationships existing between this vitamin and the bile salts, glutathione, erythropoietin;
bile salts are necessary for the food absorption of vitamin B2. they can therefore in a way serve as the vehicle "for riboflavin; vitamin B2 is then secreted by the bile before being reabsorbed and then excreted mainly in the urine; bile salts which present a coloring of the same nature as the vitamin
B2, as seen above, have an in vitro inhibitory effect on HIV. This therefore suggests that vitamin B2 is very likely to have the same properties.

 Glutathione, too, has been shown to be able to inhibit HIV in vitro; glutathione is a molecule made up of three amino acids, glutamic acid, cysteine and glycocolle; it should be emphasized here that the biogenesis of vitamin B2 takes place from glycine, formic acid and C02, and that, moreover, FAD, by its ability to reoxidize NADPH, stimulates the activity of lagluttbion Erythrocyte reductase. It is also recognized that cysteine has photocaptricative properties compared to ultraviolet.

 According to these considerations, there is therefore an obvious relationship between vitamin B2, vitamin PP and glutathione as well as ultra-violet.

 Finally, it is written in the reference manuals that ribofla vine is likely to initiate erythropoetin which, itself, would stimulate the synthesis of the theme; However, it has recently been found that heme, alone or associated with AZT, would inhibit the replication of HIV in vitro.

So bile salts, glutathione and heme have been shown to be active in vitro against HIV, but their use in vivo is not without drawbacks, which is not the case with vitamin
B2.

 In conclusion, vitamin B2, by its colorimetric, biological and physiological properties, seems to be a treatment of choice for AIDS infection, and this all the more so since there could be a deficiency of this vitamin due to excessive sunlight and / or by imbalance in the food ration with excess lipids and carbohydrates at the expense of the protein ration; this nutritional imbalance, common in underdeveloped countries, causes excessive elimination of vitamin B2 in the urine.

 It seems that other photoprotective remedies and more particularly vitamin PP could be added to it in order to seek a synergistic action.

 This new therapeutic approach to AIDS with a riboflavin-based remedy, that is to say Beflavin, used by intravenous parenteral route at a daily injection of 20 mg. showed dramatic clinical improvement; The National AIDS Research Agency, to which the name of the remedy has not been disclosed, has agreed in principle to carry out in vitro tests as well as clinical trials.

 The advantages of AIDS therapy through the use of a remedy composed of vitamin B2: seem essential compared to already existing treatments, due first of all to the absence of contraindications and side effects known to the eye. therapeutic use of vitamin B2.

 It is moreover well known that an overdose is accompanied by the immediate elimination of urine from excess Vitamin B2.

 The second advantage is linked to the industrial manufacture of remedies based on vitamin B2, for oral or parenteral use and for preventive or therapeutic use. This manufacturing method is simple and inexpensive; however, it should be emphasized that a yellow-brown or yellow-orange packaging, opaque to light and to ultra-violet appears to be essential.

 The third advantage, finally, is constituted by the fact that according to the numerous references and hypotheses cited above, it would seem that vitamin B2 represents the etiopathogeqic treatment par excellence of AIDS infection.

Claims (8)

 1. Use of FAD, a metabolite of riboflavin, and / or NAD or their derivatives to obtain a drug intended for the preventive and curative treatment of AIDS.  2. Use of FAD, a metabolite of riboflavin, and / or NAD or their derivatives for obtaining a medicament intended for the preventive and curative treatment of retinitis pigmentosa.  3. Use of FAD, a metabolite of riboflavin, and / or NAD or their derivatives to obtain a drug for the preventive and curative treatment of malaria.  4. Use of FAD, a metabolite of riboflavin, and / or NAD or their derivatives for obtaining a medicament intended for the preventive and curative treatment of diseases related to light.  5. Use according to one of claims 1 to 4 characterized in that riboflavin and / or vitamin PP are associated in synergistic amounts with FAD and / or NAD.  6. Use according to one of claims 1 to 5 characterized in that said drug is for oral or parenteral use.  7. Use according to one of claims 1 to 6 characterized in that said medicament is in opaque conditioning to light and to ultra-violet.  8. Use according to one of claims 1 to 7 characterized in that the derivatives are salts or esters of FAD or NAD.