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Biomedical subjects

G Mathé

Publications and source records attributed to G Mathé.

At least 37 records · Page 2Linked to original sources
PubMed1999

Human obesity and thinness, hyperlipidemia, hyperglycemia, and insulin resistance associated with HIV1 protease inhibitors. Prevention by alternating several antiproteases in short sequences.

In 1997, and mainly in 1998 and 1999, a lipodystrophic syndrome with central obesity, peripheral fat loss, hyperlipidemia, hyperglycemia and insulin-resistant-diabetes II, was described as the most frequent manifestation of toxicity of HIV1 virostatic therapy, associated with protease inhibitors (PI) in 83% of the patients who used them for 10 months. Almost similar syndromes had been published before the latter, due, for example, to graft vs host reaction, or autoimmunity against insulin receptors, or to caloric excess in the presence of androgens (the mediator being hyperinsulinemia). Carr and Cooper have presented an original pathophysiological mechanism for the PI-associated syndrome, residing in 63% homology between HIV1-protease and the 3-low-density-lipoprotein-receptor-related protein (LRP), and in 53% homology between this virus enzyme and retinoid-binding-protein type 1 (CRAB1). The treatment should be more subtle than those of common obesity and/or type II diabetes. This HIV1-protease inhibitor toxicity can be prevented by alternating several antiproteases in short sequences of the different ones.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Why have ten or so nontoxic, retrovirus integrase inhibitors not been made available for AIDS treatment? A ten-year experience [correction of experiment] must liberate them.

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.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Combinations of four virostatics applied in rotational sequences induce an exponential VL regression curve, the first part of which is rapidly decreasing to a PCR-undetectable level, while the last part is insensitive to the model. Indications for virostatic and immunotherapeutic reinforcements?

Between 1992 and 1995, we have had five virostatics available: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) (as retrotranscriptase nucleosidic antagonists, RTNA), acriflavine (ACF), and hydroxy-methyl-ellipticine (HEL), as respectively a DNA synthesis and structure antagonist, and a topoisomerase II inhibitor. Between 1995 and now, we have had ten virostatics the same, plus lamivudine (3TC), stavudine (d4T) as RTNA, and indinavir (IDV), ritonavir (RTV) and saquinavir (SQV) as protease inhibitors. We first conducted a phase I-like study concerning the ratios of the drug numbers in combinations over the numbers available. The optimal model for the study was that of four virostatics selected out of the ten. The four virostatic combinations were applied in short (3 week) sequences, differing each others by drug rotation. The patients were, before treatment, nine at the phase of AIDS, one at the A3 stage. They presented a very rapid decrease of viral load (VL) which became undetectable at PCR, being first below 200 RNA copies/mL, then below 20. We call this condition 'minimum residual disease' as HIV1 persistence is revealed by virus rebounds, reversible, and probably induced by cofactors. The frequency of the latter selection is due to the very frequent (each 3 weeks) VL evaluations. The last part of the VL exponential curve which the minimum residual disease represents, is almost horizontal and quasi insensitive to the powerful virostatic model described above, though no resistance has appeared at the combination or sequence levels. Thus we propose to add phases of: a) reinforcements by virostatics, adding two more ones to the four of the model; and b) treatment complement by active immunotherapy phases: the most adapted immunomodulator is the combination of the peptidic cytokine, tuftsine, and of its antipeptidase, bestatine If they are not available, another interleukine, able to help restoring the AIDS disturbed immunologic system, interleukin 2, could be tried, as it has induced beneficial effects at very small doses by subcutaneous injections.

Anti-HIV Agents↗
PubMed1998

Possible respect of patient quality of life--without reducing survival expectancy--in breast cancer treatment.

The treatment of breast cancer by some doctors in all countries and all in some does not concern itself with quality of life considerations. Partial breast cancer surgery is possible in cases of neither voluminous nor central tumors, and surgery can also be partial after pre-surgical chemotherapy reduction. The apoptotic test for cytostatic choice should assist in obviating toxicities which are minor for the physician, i.e., alopecia, cardiac lesion, etc, but which are major for the patient. Cytostatics will be useless in treatment if they are not apoptogenic. Hormonal treatment may, when there are estrogen receptors involved, be advantageously combined with chemotherapy. In estrogen receptors absence, growth factor receptors should be considered, as there is a possible indication of somatostatin analogs (instead of hormones, which are useless). Quality of life is mainly determined by the partial character of the surgery, hence by the volume and localization of the tumor. Cancer screening allows diagnosis when tumors are smaller as opposed to those which are the object of spontaneous diagnosis. We even propose screening of dysplasias and their biological treatment between 40 and 50 years--hormonal if the specific cells carry hormone receptors, and based on somatostatin analogs if they carry growth factor receptors.

Antineoplastic Agents↗
PubMed1998

Data of pre-clinical and early clinical trials of acriflavine and hydroxy-methyl-ellipticine reviewed, enriched by the experience of their use for 18 months to 6 years in combinations with other HIV1 virostatics.

Two virostatics which we discovered in 1990, acriflavine (ACF) and hydroxy-methyl-ellipticine (HEL) and shown active on HIV1 resistant to AZT have been introduced into combinations of four virostatics selected among ten available: themselves, plus zidovudine, zalcitabine, didanosine, lamivudine, stavudine, saquinavir, ritonavir, indinavir, the combinations were applied in 3-week sequences, differing from each other by drug rotation. Those which contained ACF may have more often a CD34 decrease than those containing neither ACF nor HEL, and they present more often a CD4 increase. No significant difference as far as side effects or beneficial effects could be detected after 18 months to 6 years, between sequences containing ACF or HEL or both, and sequences not containing any one of them.

Acriflavine↗
PubMed1998

The kinetics of cancer cells and of HIV1: the problems of cell and virus rebounds and of latency.

The kinetics of non treated and especially of treated HIV1 is compared to that of non treated and of treated cancer cells. Contrary to Skipper's scheme, based on constancy of cancer cell proliferation or post-chemotherapy decrease slope, the same chemotherapy successive cycles decrease in fact less and less the proportion of cell number reduction, and the hope of killing the "last cell" is a utopian concept. Hence, the very poor global benefit in cancer medicine registered in the last 50 years. The only cures are seen in child tumors and young adults testis cancer: the immunity reaction being stronger before 40 years of age than after 40 may explain this difference with age. The a priori systematic opposition to active immunotherapy of cancer from some authorities has been a grave fault. Such fault should not be committed for the treatment of HIV1-AIDS complex. The continuous HIV1 so called intensive virostatic chemotherapy is complicated by severe toxicities, and resistances of relapses and virus re-activation when it must be discontinued. The widely accepted triple therapy only affects two virus targets (retro-transcriptase and virus protease), which is insufficient, as we have shown. We have also observed that the constant and most rapid VL decrease to < 200 or < 20 RNA copies/mL is obtained when four virus targets are affected, including some concerning DNA provirus (which is the case of acriflavine and methylhydroxy-ellipticine). As in acute lymphoid leukemia, two treatment phases can be distinguished: a) the VL reduction to 20 copies; b) the maintenance of the residual < 20 copies of viruses. Excellent results as far as VL decrease and maintenance at < 20 copies have been obtained with a follow-up between 1 1/2 and 6 years, without any toxicity nor global resistance, with combinations of four drugs affecting four viral targets, applied in short (3 week) sequences, different from each others owing to drug rotation. This can be compared with the 65% remission rate obtained with alternative different cycles of cancer chemotherapy in tumors resistant to conventional modalities. The possibility of repeating for ten patients the evaluation of viral load and of immunologic parameters has allowed us to discover that some VL decrease curves are fractal. As well, maintenance 20 copies are not rarely interrupted by short and reversible HIV1 rebounds as those we had described in "cured" acute lymphoid leukemia patients. Of utmost importance, all HIV1 rebounds were associated with the presence of one cofactor: chimerism, chronic hepatitis, CMV, herpes 8, herpes 6, and influenza are those we observed. The problem today is not to "kill the last tumor cell in cancer" or "the last HIV1 particle" in HIV1-AIDS complex. It is to keep the residual cells or virus in latency. Active immunotherapy and other biologic interventions, such as hypermethylation, should be studied in this aim, as they are also able to do so.

Animals↗
PubMed1997

Pilot study for preoperative administration of l-OHP to patients with advanced scirrhous type gastric cancer.

A new DACH platinum complex, l-OHP, was developed by Kidani as an anticancer agent. A clinical trial took place in Europe which demonstrated its therapeutic efficacy for colorectal cancer. An effective treatment, especially chemotherapy for patients with a advanced scirrhous type gastric cancer, has not yet been established. An in vitro study showed that l-HOP inhibited cell growth in human gastric cancer cell lines. Our pilot study determined the efficacy of preoperative administration of l-OHP, 67 mg/m2 to 100 mg/m2, every 2-3 weeks, for two to three cycles, in five patients with this disease (Stage III and IV) roentogenoscopically and histologically. The platinum concentration in the tissues was also measured. By X-ray examination of the stomach at the time of pre- and post-administration of l-OHP, extension of the lesional gastric wall was observed. Histologically three Grade 2 responses and two Grade 1a responses were obtained according to the criteria presented by Japanese Research Society for Gastric Cancer. The mean platinum concentrations in the lesional tissues were 0.98 ppm and 0.5 ppm in the patients administered l-OHP for three and two cycles respectively. There was no toxicity that prevented surgery. These preliminary results showed the possibility that 1-OHP would be effective for patients with advanced scirrhous type gastric cancer as a neoadjuvant therapy.

Adenocarcinoma, Scirrhous↗
PubMed1997

Hypothetical reasons of the HIV1-AIDS "tritherapy" failure. A challenging model.

Daily journals in France recently published a declaration of eight AIDS-assistance associations stating, because of already established resistance of most of types of HIV1 to the so called "tritherapies" 8,000 subjects in France will soon be "in condition of treatment failure". This tritherapeutic "flat note" is a double flat, for relative and absolute reasons: a) relative indeed was the case of well-known results: the tritherapies initially performed better than bitherapies, which had done better than monotherapies; b) absolute is their failure, which induce, as the other types, toxicity, resistance and relapses. Toxicity and resistance are due to the fact that, as the T1/2 of the virus is very short, virostatics must be applied continuously. But in AIDS groups tritherapies are applied not only in a continuous fashion, but in an identical form and for an undefined time, the process which is used in experimental cancer chemotherapy to induce resistant cell lines. Applying them in sequences of 3 weeks (a duration chosen with the knowledge that resistance may occur in about 12 weeks), we have shown in AIDS not only an absence of toxicity, but also an absence of resistance in patients treated with four drugs affecting four different targets. There is indeed another point to underline: AIDS group tritherapies are comprised of three drugs, but whatever the choices of these drugs they affect only two targets: retrotranscriptase and HIV1-protease. We had obtained in the best murine model of HIV1-infection (Friend's virus infection) eradication with a combination of three drugs, AZT, acriflavine (ACF) and the ellipticine analogue methyl-hydroxy-ellipticine (MHE); (the two last were discovered to be rather more efficient that AZT in our virostatic screening). This combination affects three virus targets (AZT, retrotranscriptase; MHE, topoisomerase 2; and ACF, integrated and proviral DNA). The next article will show that sequential drug combinations of three virostatics chosen from ten drugs available, affecting four targets, are more efficient in HIV1-AIDS than three drug combinations affecting three targets because they were chosen from a pool of only five drugs. It will, however, be shown that the same type of sequential combinations with four drug rotations chosen among the ten available ones affecting four targets rapidly reduced, and for years maintained, the viral load at undetectable levels. This level has been < 200 RNA copies/mL during the trial and is, at the end of the study, < 20 RNA copies/mL.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.

AIDS-Related Complex↗