acriflavine and Acquired-Immunodeficiency-Syndrome

We detected in 1989, with the inhibitor test of proviral insertion into c-erb B erythroblastosis, two retrovirus integrase inhibitors: hydroxy-methyl-ellipticine and acriflavine. They have been used for ten years in AIDS patients with high efficacy and no toxicity. Since vitamin B12 and cobalt, which it contains, have been detected as HIV1-integrase inhibitors by an in-vitro test, we have also used vitamin B12 (combined with folic acid), whose clinical action has been remarkable. Ten or so other compounds have been detected by such in-vitro tests, among which there are many compounds (such as flavones) which are used in many conditions and are not toxic.

Topics: Acquired Immunodeficiency Syndrome; Acriflavine; Cobalt; Ellipticines; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Vitamin B 12

We have individually treated ten AIDS patients whose CD4 numbers were inferior to 200/mm3, with the five following HIV1 virostatics: a) azido-deoxythymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), which affect the same viral target, retrotranscriptase, b) acriflavine (ACF) and methyl-hydroxy-ellipticine (MHE) which we have discovered to be strong virostatics in vivo, in mice, against Friend's virus, and in man, against AZT resistant HIV1. We have shown that their combinations with AZT, hitting three viral targets, reduces in mice, the blood Friend's virus load below detectable level. Due to the short doubling time of HIV1, AIDS therapy must be continuous, and to allow the best tolerance, the five virostatic combinations were applied in short, three-week sequences, each differing as much as possible from the former and from the following one, due to drug rotation [1]. Among the ten patients, a) three received the two-drug combinations for 15 to 30 months, followed by the three-drug combinations, b) three received the three-drug combinations from the beginning, c) four received the four-drug combinations also from the beginning, two having less than 10 CD4/mm3 at initiation of treatment, and two having more than 100. The tolerance was remarkable: the only side-effect being macrocytosis. The application of the two-drug combination sequences maintained stable CD4 levels in two subjects whose viral load (the evaluation of which had became available) was, at the end of this period, of 4,486 and 39,238 RNA copies. The third subject who had received, an intensive UV irradiation for a psoriasis, presented an irreversible decrease in his CD4 count and a high viral load (1,352,495 RNA copies/mL) at the end of the two-drug period. Fifteen to 25 months after the shift to the three-drug combinations, the viral load decreased, from 39,328 to 13,291 in one of the non-UV irradiated subjects, and from 1,352,495 to 314,387 in the irradiated one. No subject had an increase in CD4 number. In the three patients having initially received the three-drug combinations, a very strong decrease of viral load was registered after periods of observation varying from 77 to 40 months, while the CD4 counts increased moderately in two subjects, and noticeably in the third (from 126 to 266). Out of the four subjects initially treated with four-drug combinations, the two with less than 10 CD4/mm3 had a moderate decrease in viral load in about three months, and the CD4 increase

Topics: Acquired Immunodeficiency Syndrome; Acriflavine; Adult; Anti-Infective Agents; Antiviral Agents; CD4 Lymphocyte Count; Didanosine; Drug Therapy, Combination; Ellipticines; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Zalcitabine; Zidovudine

To present the 4 to 9 years (median: 6 years) treatment follow up of 10 HIV1-AIDS patients, 9 at AIDS and 1 at A3 stages.. We have applied from 1992 to 1994, AZT combined with 2 integrase inhibitors, acriflavine and hydroxy-methyl-ellipticine. We could shift, in 1994, to combinations of 3 drugs including two more retrotranscriptase inhibitors (RTI), ddI and ddC, and, after 1995, to combinations of 4 drugs including also two other RTI, d4T and 3TC, and 3 protease inhibitors (PI), indinavir, ritonavir, and saquinavir. In 1998, as cobalamine was shown by an in vitro test, to act as integrase inhibitor, vitamin B12 was added in cycles of various lengths. Every three weeks, not only the investigations were repeated, but the virostatics were changed.. No grade 2 virostatics toxicity has been registered. The viral loads (VL) decreased according to exponential curves. Their initial parts obeyed first order kinetics. The second parts were and still are asymptotic. The first parts could be rectilinear or sinuous. The sinuosities were associated to cofactors present before treatment (chimerism, UV irradiation, hepatitis C or B and C, brain toxoplasmosis). The asymptotic parts, whose VL were below PCR detectable levels, presented discrete, reversible HIV1 rebounds, associated to other cofactors (such as herpes zoster, herpes 6, CMV, flat condyloma, and influenza). Among immunologic parameters, the monocyte and CTL numbers increased and presented, during the rapidly decreasing part of VL curve, a significant inverse correlation with it. Neither CD4+ nor suppressor T-cell (STC) numbers presented such correlation. Near 100 % of CTL were CD28+. Later, vitamin B12 applications increased monocyte and CD28+ CTL numbers, and appeared to reinforce VL stabilization.. The combinations of inhibitors affecting 3 retrovirus targets, retrotranscriptase, integrase, and protease have given to 10 out of 10 AIDS patients survivals varying today between 4 to 9 years, in excellent conditions. The UVA-pretreated patient is the only one presenting a not maximally reduced asymptotic VL, while his CD4+ and STC have been absent for 8 years. Other patient VL regressed exponentially to become asymptotic, below PCR detectable levels.

Topics: Acquired Immunodeficiency Syndrome; Acriflavine; Adult; Anti-HIV Agents; Antiviral Agents; CD4-CD8 Ratio; Didanosine; Drug Therapy, Combination; Ellipticines; Female; Follow-Up Studies; HIV-1; Humans; Integrase Inhibitors; Male; Middle Aged; Protease Inhibitors; Stavudine; Vitamin B 12; Zalcitabine; Zidovudine

While the intensive virostatic combinations applied according to the conventional models (such as HAART), based only on the attacks of two HIV-1 targets, retrotranscriptase and protease, and applied in a long and continuous fashion, a) are notably toxic, b) do not correct completely the abnormal immunologic parameters, and c) are followed by particularly severe and poorly sensitive relapses in case of discontinuation, we propose to the 'AIDS treatment headquarters' to include in their failing strategy the two original features which we have included in the treatment of a cohort of a dozen patients, treatment applied at all but one AIDS stage. We attack one more HIV-1 target than the conventional protocols do, by adding inhibitors of integrase; we apply the combinations of virostatics, comprising inhibitors of the three targets, in short sequences (of 3 weeks), between which the analogues are changed inside each series. The first patient of the cohort started his treatment 8.5 years ago, and the entries of the others into it have been at random and not randomized. All patients are alive today and in excellent condition.

Topics: Acquired Immunodeficiency Syndrome; Acriflavine; AIDS-Related Complex; Animals; Anti-Infective Agents, Local; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Drug Resistance, Viral; Ellipticines; HIV Integrase Inhibitors; HIV-1; Humans; Immunosuppressive Agents

Simultaneous administration of zidovudine, acriflavine and celliptium to Friend virus-injected mice eradicates the virus, as evidenced by the impossibility of the treated-mouse serum, when injected to virgin recipients, to induce spleen foci formation. An adapted preliminary protocol given to patients in whose p 24 antigen was present in the blood, lead to a considerable reduction of that marker. The cures lasted 3 weeks, and were repeated after 3-week intervals. Since p 24 antigen returns to pre-treatment levels at the end of the interval, research should concentrate on the maintenance of the effect during the interval.

Topics: Acquired Immunodeficiency Syndrome; Acriflavine; AIDS-Related Complex; Animals; Drug Therapy, Combination; Ellipticines; Friend murine leukemia virus; HIV Infections; Humans; Male; Mice; Mice, Inbred DBA; Zidovudine