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Abstracts of the used studies and articles.
to HIV illness stage and progression over one year. Ferrando SJ, Rabkin JG, Poretsky L. Department of Psychiatry, Cornell University Medical College, New York, New York, USA. This study explored associations between
serum dehydroepiandrosterone sulfate (DHEAS), free
and total testosterone levels, and HIV illness markers, including viral
load, and the behavioral problems of
fatigue and depressed mood. Subjects were 169 HIV-positive men evaluated
at baseline, 6, and 12 months for levels of DHEAS, total and free
testosterone, HIV RNA, CD4, HIV
symptoms, opportunistic illnesses, fatigue, and depression. Men with
AIDS (N = 105), compared with men
with less advanced illness, had lower mean levels of DHEAS. Baseline
DHEAS was positively correlated with CD4 count, HIV symptom severity,
and was inversely correlated with HIV
RNA. Baseline DHEAS below the laboratory reference range (96 microg/dl)
was associated with history of opportunistic infections and malignancies
(adjusted odds ratio [OR], 4.4; 95%
confidence interval [CI], 1.9-10.4) and with incidence of these complications
or death over 1 year (adjusted OR, 2.6; 95% CI, 1-7.2). Initiating
protease inhibitor combination
therapy was associated with an increase in DHEAS over 6 months. Free
testosterone was inversely correlated with
HIV RNA, but there were no other significant associations
between testosterone and HIV illness markers. No hormone was related to
fatigue or depression. This study
confirms that low serum DHEAS is associated with HIV illness markers,
including viral load, and carries negative prognostic value. Further,
protease inhibitor therapy may result
in increased circulating DHEAS. Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection. Aceti A, Pasquazzi C, Zechini B, De Bac C; The LIVERHAART Group. Department of Infectious and Tropical Diseases, II Faculty of Medicine, University of Rome La Sapienza, Rome, Italy. professoraceti@tiscalinet.it To evaluate the occurrence of hepatotoxicity in patients during antiretroviral therapy (ART) that contains protease inhibitors and the role of hepatitis viruses in its development, we performed a retrospective study including 1325 HIV-infected patients treated with ART for at least 6 months. Presence or absence of hepatitis viruses, alanine aminotransferase (ALT), total bilirubin, CD4 cell count, and plasma HIV RNA levels were evaluated. Hepatotoxicity developed in a few study subjects without coinfection, whereas it was significantly higher in coinfected patients. Univariate logistic regression analysis showed that viral hepatitis coinfections are independent risk factors for hepatotoxicity. After 6 months of treatment, ritonavir was associated with higher rates of severe hepatotoxicity in the coinfected group; in fact, ritonavir seems to be the most strongly hepatotoxic agent among coinfected patients. After 12 months of therapy, hepatotoxicity occurred more frequently in patients with hepatitis C virus who did not respond to antiretroviral therapy (ART), whereas patients who did respond to ART showed decreased ALT levels. Hepatotoxicity is not exclusively an effect of drug toxicity, and the presence of hepatitis coinfection is an independent risk factor. Moreover, chronic hepatotoxicity mainly occurs in patients who did not respond to therapy. Conversely, patients who did respond to ART seemed to show improvement of chronic liver infection.
Damaging effects of nucleoside analog drugs, protease inhibitors and antibiotics Effects of nucleoside analog drugs CHANGE IN GUIDELINES FOR HIV U.S. officials to tout new treatment policy By Laurie Garrett Newsday 17 Jan. '01
U.S. officials will announce a significant change in treatment guidelines for HIV disease when top AIDS scientists gather for their annual meeting next month. Instead of telling American physicians to "hit early, hit hard," a policy in effect since 1996 that calls for giving HIV-positive patients powerful drug cocktails before the patients actually experience any symptoms of illness, the new National Institutes of Health guidelines will call for caution and delay in treatment. The shift, NIH scientists will explain at the annual Conference on Human Retroviruses in Chicago, is prompted by an emerging consensus on three factors. First, the cocktails-called highly active anti- retroviral therapy, or HAART-can't wipe out all the viruses in a person's body, so patients must take these drugs every day, probably for the rest of their lives. That prompts the second and third factors: toxicity and resistance. The longer people take the HAART cocktails, the greater the number of side effects they experience. And there is greater the likelihood that the efficacy of the drugs will diminish, as drug-resistant forms of HIV swarm into a patient's bloodstream. In practical terms, the new guidelines say physicians should hold off on using HAART until a patient's vital CD4 immune system cell count drops below 350 per milliliter of blood; guidelines now in use set a level of 500. A healthy, uninfected individual has a CD4 count of more than 800. In terms of viral levels, the soon-to-be-replaced guidelines say patients should go on HAART when tests show 10,000 HIVs per milliliter of blood. The new guidelines call for waiting until the viral load tops 30,000 (as detected with branch DNA analysis) per milliliter of blood. In a speech to the Royal Society of Medicine in London last month, prominent AIDS physician Charles Carpenter of Brown University, a member of the AIDS advisory committee to the NIH, signaled plans to change the treatment guidelines. "In retrospect," he said, "we now realize the risk of drug toxicity is greatly enhanced by taking these drugs early." Yesterday, in an interview with Newsday, Dr. Anthony Fauci, director of the National Institute ofAllergy and Infectious Diseases, confirmed details of the new guidelines. "It's clear we're not going to eradicate the virus with the drugs we have now," Fauci said. "And we're starting to see a greater and greater realization of the accumulation of toxic side effects." Among the most troubling side effects seen in people taking the HAART cocktails are death of hip bone tissue, increase in blood cholesterol levels, neuropathy or loss of nerve sensations, kidney failure, radical alterations of liver metabolism, diabetes, skin rashes, pancreas failure, severe anemia, liver dysfunctions so acute as to require transplants and near-instantaneous death due to buildup of lactic acid. Mark Harrington, leader of the activist Treatment Action Group in Manhattan, was infected 11 years ago. He held off on taking any drugs until 1996, when his CD4 count hit a low of 150. In retrospect, Harrington thinks he made the right decision because, unlike so many of his HIV-positive friends, he has been able to stay on the same drug cocktail for five years without witnessing emergence of drug-resistant strains. Since starting the drug regimen, "I have had two kidney stone episodes" that required hospitalization, "one serious case of peripheral neuropathy, one chemical hepatitis bout, some nasty fat redistribution and a host of minor problems. And I'm lucky." Dr. Michael Saag handles hundreds of HIV-positive patients in his clinic at the University of Alabama in Birmingham. He's worried about the rising tide of drug toxicities he sees, coupled with a change in patients' attitudes. "I've got a lot of patients coming to me after three or four years on HAART saying, 'I just can't take it anymore,' or 'I'm tired of taking all these pills.' I think we need to keep in mind that this is a marathon, not a sprint." Saag tells his patients that once they commence HAART, they must be prepared to live with the drugs for 20 or 30 years, or even longer. And there will be complications. He calculates that among typical, nonsmoking 35-year-old males, the odds they will have serious hypertension by age 45 are about six out of 100. But for a nonsmoking man on HAART the odds of serious hypertension by age 45 more than double to 16 per 100, largely because one group of the anti-HIV drugs boosts cholesterol counts. New research indicates that completely effective HAART would take 70 years to kill off all HIVs in a patient's body. And few patients experience such effectiveness. Most are overcome by drug-resistant forms of the virus. The ranks of such patients have swelled, and the FDA is considering weakening drug-testing requirements in an effort to speed more agents onto the roster of HAART drugs. That makes activists like Harrington and Gregg Gonsalves, policy analyst for Gay Men's Health Crisis in New York City, angry. "I would argue that the drug
companies and the Food and Drug Administration have been negligent,
retrospectively, in not conducting or requiring long- term studies of
the effects of these drugs so we can
answer basic questions like these about their use," Gonsalves said.
"Thousands of patients like me
don't have the data to make an informed decision about when to use these
agents, and the drug companies are laughing
all the way to the bank." 1: N Engl J Med 1990 Apr 19;322(16):1098-105
Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Both infection with the human immunodeficiency virus type 1 (HIV) and zidovudine (formerly called azidothymidine [AZT]) cause myopathy. To identify criteria for distinguishing zidovudine-induced myopathy from that caused by primary HIV infection, we reviewed the histochemical, immunocytochemical, and electron-microscopical features of muscle-biopsy specimens from 20 HIV-positive patients with myopathy (15 of whom had been treated with zidovudine) and compared the findings with the patients' clinical course and response to various therapies. Among the zidovudine-treated patients, the myopathy responded to prednisone in four, to the discontinuation of zidovudine in eight, and to nonsteroidal anti-inflammatory drugs in two. Numerous "ragged-red" fibers, indicative of abnormal mitochondria with paracrystalline inclusions, were found in the biopsy specimens from the zidovudine-treated patients but not in those from the other patients. The number of these fibers appeared to correlate with the severity of the myopathy. All the patients, regardless of whether they had been treated with zidovudine, had inflammatory myopathy characterized by degenerating fibers, cytoplasmic bodies, and endomysial infiltrates consisting of CD8+ cells (mean +/- SD, 60.7 +/- 6.4 percent) and macrophages (39.2 +/- 6.4 percent) associated with Class I major histocompatibility complex (MHC-I) antigens (HLA-A, -B, and -C antigens) in the muscle fibers. The numbers and percentages of CD8+ cells and macrophages were similar in both the zidovudine-treated and the untreated HIV-positive patients. Specimens obtained on repeat muscle biopsy from two patients in whom the myopathy responded to the discontinuation of zidovudine showed remarkable histologic improvement. We conclude that long-term therapy with zidovudine can cause a toxic mitochondrial myopathy, which coexists with a T-cell-mediated inflammatory myopathy that is restricted to MHC-I antigen, and is indistinguishable from the myopathy associated with primary HIV infection or polymyositis in HIV-seronegative patients. Comment in: 1: Ital J Neurol Sci 1992 Dec;13(9):723-8 AZT-induced mitochondrial myopathy. Tomelleri G, Tonin P, Spadaro M, Tilia G, Orrico D, Barelli A, Bonetti B, Monaco S, Salviati A, Morocutti C, et al Istituto di Neurologia, Universita di Verona. Histochemical, electron microscopy and biochemical studies were performed on muscle biopsy specimens from 11 AIDS patients treated with zidovudine. A peculiar association of structural abnormalities and mitochondrial dysfunction was found. Focal cytochrome c oxidase (COX) deficiency was evident in muscle sections from 9 patients, 8 of whom had received long-term treatment while one had been treated for 1 month only. Electron microscopy showed changes in number, size and structure of mitochondria. Biochemical studies proved partial COX and succinate cytochrome c reductase (SCR) deficiency in 4 patients; one patient had only reduced SCR activity. Our data confirm that AZT therapy can cause toxic myopathy with mitochondrial dysfunction. PMID: 1336487 1: Lancet 1991 Mar 2;337(8740):508-10 Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA Department of Neurology, Columbia University College of Physicians and Surgeons, New York. Long-term zidovudine therapy in patients with human immunodeficiency virus (HIV) infection can cause a destructive mitochondrial myopathy with histological features of ragged-red fibres (RRF) and proliferation of abnormal mitochondria. In 9 zidovudine-treated patients with this myopathy we found severely reduced amounts (up to 78% reduction vs normal adult controls) of mitochondrial DNA (mtDNA) in muscle biopsy specimens by means of Southern blotting. In 2 HIV-positive patients who had not received zidovudine, muscle mtDNA content did not differ from that in the 4 controls. Depletion of mtDNA seems to be reversible, since 1 patient showed a substantial reduction in RRF and a concomitant pronounced increase in muscle mtDNA content after zidovudine therapy was discontinued. Depletion of muscle mtDNA is probably due to zidovudine-induced inhibition of mtDNA replication by DNA polymerase gamma and is not a secondary effect of HIV infection. 1: Lancet 1999 Sep 25;354(9184):1112-5
Brinkman K, Smeitink JA, Romijn JA, Reiss P Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. K.Brinkman@OLVG.nl Highly active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome of peripheral fat wasting and central adiposity. HIV-1 protease inhibitors are generally believed to be the causal agents, although the syndrome has also been observed with protease-inhibitor-sparing regimens. Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy, similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis. 1: N Engl J Med 1994 Mar 17;330(11):738-43
Lenderking WR, Gelber RD, Cotton DJ, Cole BF, Goldhirsch A, Volberding PA, Testa MA Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA 02115. BACKGROUND. Zidovudine therapy is recommended for asymptomatic patients infected with the human immunodeficiency virus (HIV) who have fewer than 500 CD4+ cells per cubic millimeter. An analysis of the quality of life associated with therapy that integrated both the effects of adverse events and the benefits of delayed disease progression might influence this recommendation. METHODS. We applied a survival analysis adjusted for the quality of life to data from a randomized trial conducted by the AIDS Clinical Trials Group. The trial compared treatment with 500 mg of zidovudine per day, 1500 mg of zidovudine per day, and placebo (Protocol 019) in 1338 asymptomatic HIV-infected patients. RESULTS. The average time with neither a progression of disease nor an adverse event (symptom or laboratory finding) was 15.7, 15.6, and 14.8 months for patients receiving placebo, 500 mg of zidovudine, and 1500 mg of zidovudine, respectively. The incidence of severe symptoms was 13.8 percent in the placebo group, 15.2 percent in the 500-mg group, and 19.9 percent in the 1500-mg group (P = 0.038). After 18 months, the 500-mg group gained an average of 0.5 months without disease progression, as compared with the placebo group, but had severe adverse events an average of 0.6 months sooner. The 500-mg group had more quality-of-life--adjusted time than the placebo group only if the time lived after the progression of disease was considered by a patient to have less value than the time after the occurrence of a severe symptom. CONCLUSIONS. For asymptomatic patients treated with 500 mg of zidovudine, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease. 1: Nat Med 1995 May;1(5):417-22 Mitochondrial toxicity of antiviral drugs. Lewis W, Dalakas MC Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Ohio 45267-0529, USA. Long-term treatment with antiviral nucleoside analogue drugs, such as AZT, can give rise to delayed and at times severe mitochondrial toxicity. Although these toxic effects are manifest in many tissues, a common disease mechanism can explain the diverse clinical events. A better understanding of these disorders will shed light on genetic mitochondrial diseases and lead to the design of safer and more effective antiviral drugs. 1: J Neurol Sci 1997 Jul;149(1):19-25
Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. Benbrik E, Chariot P, Bonavaud S, Ammi-Said M, Frisdal E, Rey C, Gherardi R, Barlovatz-Meimon G Groupe d'Etudes et de Recherches sur le Muscle et le Nerf (GERMEN: ER 269 et 315, Universite Paris XII), Faculte de Medecine, Creteil, France. Zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) are the reference antiretroviral therapy in patients with AIDS. A toxic mitochondrial myopathy can be observed in patients treated with AZT, but not with ddI and ddC. All 3 compounds can inhibit mitochondrial (mt)DNA polymerase and cause termination of synthesis of growing mtDNA strands and mtDNA depletion. The propensity to injure particular target tissues is unexplained. In our work, cultured muscle cells prepared from human muscle biopsies, were exposed to various concentrations of AZT (4-5000 micromol/l), ddI (5-1000 micromol/l) and ddC (1-1000 micromol/l) for 10 days. We evaluated cell proliferation and differentiation and measured lipid droplet accumulation, lactate production and respiratory chain enzyme activities. All 3 compounds induced a dose-related decrease of cell proliferation and differentiation. AZT seemed to be the most potent inhibitor of cell proliferation. AZT, ddI and ddC induced cytoplasmic lipid droplet accumulations, increased lactate production and decreased activities of COX (complex IV) and SDH (part of complex II). NADHR (complex I) and citrate sinthase activities were unchanged. Zalcitabine (ddC) and, to a lesser extent, ddI, were the most potent inhibitors of mitochondrial function. In conclusion, AZT, ddI and ddC all exert cytotoxic effects on human muscle cells and induce functional alterations of mitochondria possibly due to mechanisms other than the sole mtDNA depletion. Our results provide only a partial explanation of the fact that AZT, but not ddI and ddC, can induce a myopathy in HIV-infected patients. AZT myopathy might not simply result from a direct mitochondrial toxic effect of crude AZT. PMID: 9168161 Geoffrey Cannon: Superbugs, Nature's Revenge Virgin Publishing Ltd., London 1995 Part Four: Apocalypse Now: How Antibiotics Breed Disease Chapter 15: Nature's Most Malicious Trick? Reasons to be careful- Immunosuppression - a link with AIDS? -Increasing risk of colon cancer. Reasons to be careful Once you know, that you need the resident bacteria in your gut to protect your health, and that antibiotics especially when overused may eventually not only devaste these friendly flora but also may strip away the outer immune defences in your gut, it is easy to see that prolonged course of antibiotics can in time lay you open to all sorts of infections and also non-infectious diseases. Many diseases, some serious, have evidently become more common in countries like UK and the USA in the last 50 years. They may in part be caused by medical treatment. Infants and children are vulnerable to repeated ear, nose and throat infections. Girls and women are vulnerable to repeated cysteitis and to fungal superinfection, which can become invasive. Antibiotics are certainly one cause of this diseases and may be one cause of a variety of bowel diseases and some forms of arthritis. And the serious general malaise known as chronic fatique syndrome may be in part a complication of invasive fungal infection. Young children and old people are especially at risk, as are the chronically ill. This in addition to the known immediate or acurate ill-effects of antibiotics already described. Once again, these are not reasons to always avoid antibiotics. To repeat, they are a presicous resource: in case of reliably diagnosed serious invasive bacterial infetions their benefits far outweight their risks. But risks there are: and many of the ill-effects of antibiotics are insidious, quite likely not to be linked with the drug either by victims or their doctors. Immunosuppression Our resident gut flora have another vital function not mentioned so far. They stimulate the production of immunoglobulins, proteins in the blood integral to the body's inner immune defences. Experiments show that animals with all their gut flora removed, make only about one-fiftieth as much immunoglobuline as normal animals. Commenting on this finding, the standard textbook 'Immunology' states: "If the commensal organisms of the gut are removed by antibiotics, pathogenic organisms can readily gain a foothold", and emphasises the importance of not disturbing the relationship between the host and its indigenous flora. Does this mean that antibiotics are immunosuppressant drugs? This is an explosive question. Drugs generally classified as immunosuppressants are very dangerous. They are used only on people with cancer, and also after organ-transplants. They greatly increase the risk of serious bacterial and viral infection, and also of cancer, and are used only when patients are otherwise likely to die. In ordinary circumstances, antibiotics are nothing like as dangerous as these drugs. As already stated, one course of antibiotics destroys the bacteria in the gut but not utterly, and a healthy balance of resident bacteria is usually restored soon after antibiotic therapy. The only class of antibiotic that is commonly identified as immunosuppressive is tetracycline, because of its profound destruction of so many species of resident gut flora. And in a sense allergic reactions are reassuring because as mentioned, they show, that the body's inner immune defences are beeing irritated, and therefore obviously in working order. Basically healthy people are very unlikely to disrupt their inner immune defences by taking just one course of antibiotics. Nevertheless, antibiotics do have a suppressive effect on our defences against infection. Given that our outer defences, including resident bacteria and the mucosal lining of the body's inner passages, are an integral part of our immune system, it follows inescapably that all antibiotics are by their nature immunosuppressants -mildly so, no doubt, compared with the drugs used on cancer and organtransplant patients, but immunosuppressive none the less. How much this matters depends on the general state of the health of the individual, the type of antibiotic and the strength and length of the course. As ever, babies and little children, old people, hospital patients and anybody else who is generally weak or ill are at greatest risk, and this includes many, if not most people on the antibiotic treadmill, taking more and more courses for recurrent infections. Most vulneralbe of all are people who are already immunosuppressed. But which came first; immunosuppression or antibiotics? Here ist the view of Professor Sandy Raeburn, head of the departement of clinical genetics at Nottingham University, a specialist in disease of young children. In 1972 he wrote a paper for the Lancet, on "Antibiotics and Immunodeficiency": "Immunological-deficiency syndromes were not observed before 1952. A possible explanation is that some of these conditions are produced by administration of antibiotics to certain individuals at a critical point in the development of immune responses." Dr Raeburn gave examples of immunodeficiency diseases suffered mostly by babies and young children. Combined immunodeficiency (DIC) lays infants open to diarrhoea, thrush, pneumonia and other infections, and may increase the chance of cancer. Chronic granulomatous disease (CGD) also makes babies more vulnerable to bacterial infections. "This diseases were not described before the antibiotic era" said Dr. Raeburn, "and the usual view is that modern therapy has enabled affected patients to survive longer. An alternative explanation, however, is that antibiotics have actually led to immunodeficiency states -diseases which did not previously exist". He supports this proposal by three lines of argument. First, since one of the main purposes of the immune system (including the bacteria that have evolved with us) is to protect the body against invading micro-organisms, 'removal of bacteria by other means, such as rapidly effective antibacterial therapy, could have profound effects -for exaple, in infancy, during immunological development.' Later in life, antibiotics might provoke bacteria, even the friendly flora, into producing poisons that the immune system cannot handle. "The rarest clinical effects will emerge sooner or later because antibiotics are so widely used". Second -and here Dr. Raeburn draws on his own clinical experience -while antibiotics work well for previous healthy people with an acute infection, they usually don't work for patients who are immunodeficient. "Failures of antibiotic therapy are often excused by an assumption that host resistance was impaired. Could it be that infection persisted because the antibiotics interfered with host resistance in a susceptible patient? I have seen several patients whose infections progressed while they were receiving seeminly appropriate antibiotics. Third, he cited the laboratory evidence showing that antibiotics make experimental animals more vulneralbe to infections by suppressing their immune responses -some very much mor than others. Those at greatest risk of immunodeficiency diseases caused by antibiotics will include: those born vulnerable; babies and young children; people who are suffering from other diseases; and anybody taking regular heavy doses of antibiotics. He concluded: "If this theory is substantiated, it follows that antibiotics shoud be reserved for life-threatening infections, until the risk of immunotoxicity ist excluded in each patient". I wrote to Dr. Raeburn asking him if, in the twenty years since he had published tha Lancet paper, he had changed his view. He wrote back saying: "Since I published that paper, there has been a vast amount of work on the interaction between antibiotics and the immune system. Much of it bears my own original hypothesis... When a patient receives antibiotic treatment, the beneficial effects due to antibacterial activity could be reduced or even negated by deleterious effects on the immune system". Overall, he said, antibiotics are beneficial, "but in my special area of medical genetics, we might well see patients in which the balance is set differently -for exaple in cystic fibrosis". In 1984, a dozen years after Dr. Raeburn's Lancet paper., Dr William Hauser of the Bosten University Medical Center and Dr. Jack Remington of the Palo Alto Medical Foundation, both specialists in infectious disease, published a review of the scientific literature on the "Effect of Antimicrobial Agents on the Immune Response" in the textbook Antimicrobial Therapy. Antibiotics listed as having ill-effects on the human immune response include: some aminoglycosides (gentamicin, tobramycin); a cephalosoprin (cephalotin); chloramphenicol; a lincosamide (clindamycin), ;various sulphonamides, and co-trimoxazole; various tetracyclines; sodium fusidate; and a number of anti-fungal and ant-tubercular drugs. Penicillins are not included, and evidently do not have ill-effects on the body's inner immune defences. Hauser and Remington comment: There is clearly a need for a better understanding of the potentail beneficial and deleterious effects of antibiotic therapy on the host's immune defences, especially in the immunosuppressed patient. Indeed there is. But when antibiotics suppress our immune defences against disease, as evidently they may do, then people given constant courses of antibiotics to drive out infection will be not so much on a drug treadmill as caught in vortes pulling them down deeper into disease. Here is an appalling prospekt. A child suffers middle-ear inflammation, treated with antibiotics, which then recurs because of antibiotics. A woman suffers cystitis, which is cleared up with antibiotics, but which then recurs in a more invasive form because of antibiotics. These infections occured in the first place because of antibiotics taken in infancy and childhood. Then people of all ages and both sexes suffer a cascade of diseases of the gut, each stage accelerated by antibiotics, which eventually cause irreversible infections carried by bacteria and by viruses that easily break thrugh weakened immune defences. At some stage in this cascade, the victims become chronically immunosuppressed, vulneralbe to invasion by any infectious agend around.. The idea that medicine can cure illness immediately and yet cause illness later may seem strange. But in other areas of life we know that gain now can mean loss later -this, after all, is one of the tenets of the Christian religion. Or, to take two familiar analogies, we knwo we can drive to destinations faster by breaking the speed limit, and we know we can spend our way out of immediate trouble by running up and overdraft. We also know we are running the risk of wrecking our car or our finances. A friendly garage mechanic or bank manager will advise us to be careful. A link with AIDS When Professor Raeburn wrote his paper, chronic fatigue syndrome was obscure, and AIDS was unknown. When Drs Hauser and Remington wrote their review, neither disease was common. While AIDS kills and CFS does not, the two diseases are in some ways rather similar. Both are new, epidemic, afflict young people, have no known cure, take many clinical forms and cause profound debility. In the case of AIDS it is generally but not universally agreed that the infectious agent ist the HIV retrovirus. In the case of CFS there is a growing belief, that an enterovirus is involved. As Professor James Mowbray has said of CFS, why has the immunity of people who suffer AIDS broken down?What is it that some people who are exposed to the disease remain untouched while other become infected with HIV? Why is it that some pople who test HIV positive remain in good health for many years, perhaps never suffering full blown AIDS, while others die rapidly? Because AIDS is a new disease, is deadly and is an accelerating epidemic with in 1990 alone an estimated one million new cases of people worldwide infected with the HIV virus, other sexually transmitted diseases seem less important now. But at the end of 1990, the World Health Organisation announced that more than 250 million new cases of sexually transmitted diseases are reported every year. According to WHO Director-General Dr. Hiroshi Nakajima, "they have reached epidemic proportion globally, and if sexual behaviour is not modified and effectiv new prevention programmes are not implemented immediately the resulting disease and mortality rates will be even more staggering". In 1990, 25 million new cases of gonorrhoea and 3,5 million new cases of syphilis were reported worldwide. Gonorrhoea is now often very resistant to penicillin, the original durg of choice, in which case, treatment is either with massive doses of penicillin, or other antibiotics including aminoglycosides, sulphonamides or co-trimoxazole. Penicillin usually still works on symphilis; an alteernative drug is tetracycline. In the last half-century, other sexually transmitted diseases have become more common. These include genital ulcers, treated with sulphonamides or tetracyclines; chlamydia, with tetracyclines, chancroid, with co-trimoxazole, trichomoniasis, with metronidazole; and genital herpes, a viral disease. More than any other community, people whose lifestyle involves very many sexual partners are almost certain to suffer combinations and permutations of sexuelly transmitted diseases, which when bacterial are treated with constant courses of antibiotics, often broad-spectrum and/or cocktails. Such treatment over time provokes superinfection and drug-resistant superbugs -so more antibiotics are used, often more toxic in their effect. On such a drug treadmill, people who have constantly quenched their sexually transmitted diseaes with antimicrobial drugs are more vulneralbe to any infection, whether bacterial, fungal or viral, and once infected, are more likely to be overwhelmed. In his book "The Plague Maker, Dr. Jeffrey Fisher states that Dr. Luc Montagnier of the Pasteur Institute in Paris, co-discoverer of HIV, believes that gross overuse of antibitocs may be a co-factor with HIV development of full-blown AIDS. This theory, sensation only because AIDS is the great deadly plague of our time, is also believed by some homoeopaths. Can it be true? It makes microbiological sense: there is some experimental evidence suggesting that tetracycline has a side-effect of mutating mycoplasmas, including M. pirium and M. fermetans, into virus-type micro-organisms that can invade T-lymphocyte cells, whose function is crucial to the body's inner immunity against infectious diseases. The Theory goes on to propose that if these cells are also already invaded by HIV, the mutated mycoplasmas effectively feed the HIV, activating them and enabling them to destroy T-lymphocyte function, thus laying the victim open to a great range of infections identified as full-blown AIDS. On a separate point, Dr. Fisher quotes other research scientists who confirm the findings of Drs. Hauser and Remington, and who state that various antimicrobial drugs, including sulphonamides, cephalosporins, antifungals and antiparastics are directly immunosuppressive in different ways and, when overused, themselves increase vulnerability to infectious diseases. If the mycoplasma theory is ture, it would follow that pople who test positive for presence of the HIV virus in their bodies, but whose lifestyles have not led them to gross overuse of antibiotics, will be less likely to develop full-blown AIDS. And indeed, haemophiliacs and others frequently show no signs of illness for ten or fifteen years after beeing accidentally treated or transfused with clotting factors or blood infected with HIV. If the mycoplasma theory turns out not to be supported by evidence from other researchers, it remains true that destruction of gut flora and damge to the body's immunological defences by continual courses of antibiotics lays the body open to all sorts of bacterial, fungal and viral infections, including those most commonly associated with AIDS. For men, the dream of sexual liberation began in the 1940ies. American Gis believed that because of penicillin they could go on the rampage with European and Asian women during World War II, and then during the Korean and Vietnam wars, without risk to themselves. The result is multi drug-resitant gonorrhoea. But antibiotics retained their reputation as magic bullets throughout the 1970s and 1980s, enabling incresingly wild liefestyles. In the USA and other rich countries, this is the context of AIDS. It can be said, that AIDS is a disease that was waiting to happen. 15) Toxicities Associated with Purine Analog Therapy Bruce D. Cheson V. Summary The nucleoside analogs have proven to be highly effective in the therapy of lymphoid malignancies. However, they have a number of associated toxicities, some of what may be severe. Of particular concern is immunosuppression wich is uniform with standard treatment programs. Each of the nucleoside analogs is associated with a profound lymphocytopenia, with a reversal of the CD4/CD8, and opportunistic infections. Whether secondary malignancies will be a long-range complication will require observation and recording of long-term follow-up resulsts. The frequency with wich many of the nonhematologic toxicities occur is difficult to estimate. Most studies contain small numbers of patients, in whom few, if any nonhematologic toxicities are reported. Whether that reflects the actual rarity of these events or the care with which those series was evaluated is not clear. As the clinical experience with these agents become more extensive, with longer follow-up, recognized toxicities will become better charatrized and new side effects ma be encountered. Anecdotal reports may serve to increase the sensitivity for identification of new and unusual complications. There are a number of unresolved issues in the use of the nucleoside analogs. The optimal schedule of administration remains unknown. A 6-month course of fludarabine has been recommnded for CLL, and a similar duration of DCF for HCL. Although a single course of CDA is generally used for HCL, repeated courses have been delivered for the other lymphoid malignancies. Nevertheless, these regiments are empiric. An accumlating body of evidence suggests that fludarabine and CdA work by a different mechnism of action, e.g., activation of apoptosis. Therefore, we may be administering more drug than is required for biological effect (199, 200). Further study of this issue is warranted to maintain efficacy while minimizing the tocicities associated with treatment with these highly effecive nucleosid analogs. As nucleosid analogs are being combined with cytotoxic and biological agents in an attempt to increase their efficacy, care must be exercised to avoid drugs with overlapping toxicities. Based on the published literature, the non-hematologic toxicities from the nucleoside analogs are relatively similar (Table 3), with the possible exception of the ocular toxicity, rash and increased severity of nausea and vomiting with DCF, and the relatively more prolonged period of immunosuppression with DCF and CdA. In general, however, they are relatively well tolerated. The decision as to which is the preferred nucleoside analog for a specific indication must be determined by their response rate, durability of responses, cost, toxicity profile and ease with wich they can be combined into effective combination regiments. 2) Induction of Apoptosis by Nucleoside Analogs Peng Huang Susan Wright V. Summary Apoptosis is a key pathway by which nucleoside analogs exert their cytotoxic action against cancer cells. Although this class of drugs acts at multiple cellular targets, the incorporation of the analogs into cellular DNA is a crtical event in triggering apoptotic response. In proliferating cell population, S-phase cells are most sensitive to apoptosis induction. Two distinct size classes of DNA fragmentation, the internucleosomal and high molecular weight DNA fragments, are associated with nuceloside analog-induced apoptosis. The two types of DNA fragmentation are distinguishable by their requirements for Ca2+ and responses to phorbol ester treatment. High molecular weight DNA fragmentation is an early event of DNA degradation that is critical for drug-induced apoptosis, wheras activation a Ca2+-dependent endonuclease to cleave DNA at internuclesomal sites is not an absolute requirement for the execution of the apoptotic cell death program. Furthermore, high molecular weight DNA fragmentation occurs in vivo and may be correlated with the therapeutic activities of nucleoside analogs. The factor responsable for high molecular weight DNA fragmentation is a protein that requires MG2+, ATP, and neutral pH for optimal activity. This activity is transferable by cell fusion and active in isolated nuclei. Thus, the enzyme responsible for clevage of DNA int HMW fragments may be considered as an execution molecule in the apoptotic process. Figure 7 illustrates a proposed model of nucleoside analog-induced apoptosis. During DNA replication, cells maintain a normal level of DNA repair activity and keep the apoptotic program inactive through the function of the proposed sensor molecule (e.g., DNA-PK/Ku). The incorporation of analogs into DNA terminates further strand elongation, resulting in the generation of an abnormal DNA end. A sensor molecule binds to the damaged DNA region and singals for repair. If repair fails, the sensor molecule triggers the apoptotic program by phosphorylating other proteins involved in the signaling and execution of the cell death pathway. This apoptotic mechanism can be regulated by a variety of regulatory molecules such as bcl-2, bcr-abl, p53, and c-myc. A comprehensive understanding of the mechanisms in drug induced apoptosis and ist regulation will provide a base for developing more effective therapeutic strategies for cancer treatment. from: Nucleoside Analogs in Cancer Therapy edited by Bruce D. Cheson, Michael J. Keating, William Plunkett Marcel Dekker Inc. New York, Basel, Hong Kong 1997
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