By L. Rasarus. Queens College. 2019.
They also point to the misuse of dose by female patients lasix 100 mg online, a phenomenon seen in science (ultrasound or amniocentesis) for sex deter- both sexes and probably much more common mination cheap 100 mg lasix amex. While these are extreme examples of societal atti- It has also been claimed (because gender data are tudes purchase 100mg lasix with visa, it is true that women have been excluded from rarely mentioned in clinical studies, papers or many large, well-published studies, such as the reports) that gender differences are not sought. Nonetheless, after many years It is also frequently mentioned that fear of em- and millions of prescriptions, it is of reassurance bryonic malformation, whether or not drug- that few have shown significant clinically import- related, and subsequent litigation is the major de- ant gender-related differences. This overly simple explanation covers up other difficulties, Differences in Disease Presentations such as methodology, lack of relevant baseline in- formation, and biochemical variables, both hormo- A report from the National, Heart, Lung and Blood nal and gender-related. The signature symptom of a heart attack, severe chest pain, is Do women respond to medications differently to often absent in women, and pain in the upper men? The American Heart Association states tween the sexes in drug handling, particularly with that 44% of women are likely to die in the first year certain classes of drugs. It must be recognized that, despite careful and those on contraceptive hormones will have animal testing, the full potential for teratogenic even greater changes, added to a possible basic activity of any drugs in humans will only come to gender difference, either amplifying or even sup- light once the drug is in the marketplace, and then pressing effects. It is already represented in regulatory drug testing extremely unlikely that deliberate drug testing in guidelines in the elderly Federal Register (1990), pregnant women will ever become routine. The latter from animal screening; many agents have been option will increase the risk of potential fetal eliminated from further development, and only exposure. The commonest abnormalities most on a Trial Drug frequently associated with drug exposure in the first trimester are neural tube defects, cardiac and What is the risk of pregnancy occurring in a study renal anomalies, shortening of limbs and digits, participant while a new drug is being developed? Thus, over 27 years in industry, an average of two chil- it comes as no surprise that industry and other dren are born exposed to a new chemical entity. The incidence of neonatal abnormalities in The Potential for Teratogenic Damage during mothers taking anticonvulsant treatment is 70/ Drug Study Programs 1000 live births (Frederick, 1973). What is the across therapeutic classes, some of which, with likelihood of detecting low-incidence, drug-induced meta-analysis, will provide data which individual congenital effects in a drug development program? Thus, on a surgical procedures are obvious examples, but single-case basis, the abnormalities will be indistin- the clear-cut risks involved are usually deemed guishable for drug causality. It has been estimated that Wilson has estimated that both drugs and envir- exposure of pregnant women to normal thera- onmental chemical exposures only account for 2± peutic doses of valproic acid may give rise to 1% 3% of developmental defects in man (Wilson, fetal abnormality rate involving the neural tube 1972). Thus, a product-label reference of such an (Lindhaut and Schmidt 1986)Ð10 times the occurrence will be undeserved at least 97% of the natural incidence. They may also Medical journalist Paul Cotton (1990) asked, in a alter the genetic make-up of either spermatozoa or thought-provoking article, is there still too much ovum. If it could be shown that the synthetic and the development of a final report can take as chemicals are incorporated into the blastocyst, the long as 2 years. In general, only some of the muta- field of male Phase I testing would be transformed, genicity studies are completed, and perhaps 1±3 as would that of genetic counseling. Some, such as postexposure weaning and subsequent second-gen- Largely because early testing of drugs occurred in eration drug effect studies will be time-consuming males rather than females, for reasons discussed and expensive. The logistics of running Phase I single-dose and multiple-dose It has been stated that large numbers of mature ranging studies while controlling for a natural men- women are volunteering for the new lipid, heart strual cycle are truly horrendous, both for the risk, osteoporosis and arthritis studies, due to Phase I testing units and for the volunteer. It will readily be appreci- together, single, multiple, and multiple-dose ated that most drugs or devices are not unique or ranging studies, with food effect studies and extra life saving but hopefully an improvement on staff costs, could add $1 million to development existing agents, and indeed this applies to most costs and very rarely show a difference which basic research experiments. Some studies have shown that women demonstrate greater duration in the gastric residence time of The Weight/Dose Problem medications, which is reflected in an increased lag time of absorption, compared to men. This effect is A casual appraisal of ideal weight-for-height tables increased when medication is taken with food, even for males and females (Metropolitan Life Insur- when adjusted for the timing of the menstrual cycle ance, 1999) shows clear differences between males (Majaverian et al, 1987). Miaskiewicz et al (1982) showed that, from 50 at 106 pounds to 6 80 00 at 226 pounds; in after a single dose of sodium salicylate, absorption females, it varies from 85 pounds at 4 90 00 to 185 was slower and achieved a lower level in women. For both sexes this represents a was observed to be more than 54 min in females, 46% differential in healthy weight while taking the compared to a Tmax of 31. First, the majority of the binding capacity have been reported (Miaskiewicz population falls towards the middle of the height± et al, 1982) and, for other agents (Allen and Green- weight levels, rather than the extremes. Second, blatt, 1981), g-globulin transport systems have most drugs have a wide range where which they been reported to be altered with the menstrual exert therapeutic effect before efficacy levels off. Third, the level of unacceptable adverse events Some effects on absorption can be subtle, such as generally occurs at much higher doses than the the greater absorption of alcohol in women due to therapeutic level for most drugs (there are some their reduced gastric mucosal and liver alcohol notable exceptions, e. Propranolol is still one of the most frequently used In animals, estrogen has been shown to influence b blockers (National Prescription Audit, 1989), but the effect of antidepressants on the brain. Wilson Walle et al (1985) reported that women had higher showed that estradiol increased the binding of imi- plasma levels of propranolol than men following pramine to the uptake of serotonin at membrane single oral dosing and, in an additional study, sites. Estrone had no effect, but the addition of showed that on multiple dosing, propranolol progesterone to low doses of estrogen increased steady-state (trough) plasma levels were 80% this effect. It is of interest that men, used as westa et al, 1986) and antimigraine medications, a control, only sustained levels at the level of day seen with the fluctuation of the menstrual cycle 1 in women (Wilson et al 1982). Differences between males and females in the Young women appear to be the group most at risk amount of free drug found in plasma, and of pro- of developing extrapyramidal reactions when taking tein binding, have been reported for diazepam the antinausea drug metoclopramide. Another age/gender-related effect is seen stance, a direct correlation was found with differ- in older women who have become newly postme- ences in lipoprotein and orosomucoid protein nopausal and who are still taking antipsychotic (1-a-acid glycoprotein) fractions (Greenblatt et al, medications, because the symptoms of tardative 1980). In women, oxazepam has been found to be dyskinesia may appear or even worsen (Smith eliminated at a slower rate, about (10%), and for and Baldossarini, 1973). Twice as many Circulating hormones, such as aldosterone and women are treated for depression and anxiety neur- renin have long been known to fluctuate with the osis than men, first described by Raskin (1974), and menstrual luteal phase. If oral contraceptives are given, then chemical differences, for women are more likely to an increase of these hormones is also seen in the seek help than men. In women of all ages, Tran et al (1998) also ible contraceptive precautions and those with reported that, in findings from records of 2367 vasectomized partners. More than one 1993), perhaps spurred by its own findings in 1989, agent was reported to be responsible in 50% of and confirmed by the General Accounting Office female patients vs. It is possible that bare arms and exposed population, and young women in large numbers legs in women may cause more phototoxic reac- (Bush et al, 1993). Clearly, these two classes adequately discuss gender difference, which would of agents need special gender exploration in clinical be addressed in the new amended guideline. It called for all research on human sub- All 33 responding companies collect gender-related jects concerning drugs, devices, epidemiology, non- data on the participant patients in clinical studies. By December 1999, there were study ought to be undertaken, and then a shorter 348 medicines in development for diseases only in duration efficacy and safety study in women. Of those who saw differences, only larger, because a difference in low-incidence ad- one-third found these differences to be clinically verse events will not show up until the drug is on significant 5% of the time, while 17% of respond- the market. Subjects Indeed, diseases such as endometriosis can only be studied in such a population, whereas drugs to treat Women should be and, indeed, are included into urinary incontinence would be better undertaken in new drug and device development programs when older patients. While possible, this is not gen- The Potential Child-bearing Population erally a widely applicable solution, because geo- graphic, environmental and volunteer numbers The probability of potential early embryonic ex- now become added variables. When a woman of childbearing age participates in a research procedure in which there is a risk to the fetus, the nature of the risk being either known or unknown, she should be advised that, if she wishes Liabilities for Fetal Damage to be a subject, she should avoid becoming preg- nant. Such research may expose the insti- tution to risk of liability for damage to subjects; example of the National Vaccine Injury Act of however, that is inherent in research involving October 1988, where a trust fund was set up derived human subjects anyway, and there are many from an excise tax imposed on each vaccine. Not to do such funds, through an arbitration panel, are used to research, while it may serve to protect the interests compensate persons injured by vaccination. Data in women are needed and the possibility is suggested of an Gender-related differences do exist in drug hand- expanded National Register along the lines of the ling, but in general are relatively clinically insignifi- International Clearing House for Birth Defects cant. Theoretically, because of weight differences, Monitoring to follow up the expected small number women may receive more medication than men of embryos exposed and a Compensation Panel in for a standard dose when converted to mg/kg.
His use of “shot treatments” or hypodermic treatments that induced vomiting was a precursor to later aversion therapies and his introduction of clubs for addicted individuals to receive social support to maintain sobriety was a precursor to the mutual support programs that remain prominent today cheap lasix 40 mg overnight delivery. His focus on helping people 141 quit smoking in the 1920s was prescient in its characterization of nicotine as a harmful and addicting drug generic lasix 40 mg with amex. Addiction treatment tactics that are based more on the personal charisma of the founders buy lasix with visa, catchy phrases and simplistic approaches than on the science of what works in addiction continue to proliferate and show no sign of waning. A simple Google search produces an abundance of “rehabilitation” approaches and facilities with slogans such as: Learn how to heal 142 the underlying causes of dependency--and be free of addiction forever! A recent study examining treatments that a panel * of experts believes qualifies as quackery in addiction treatment found such treatments as electrical stimulation of the head, past-life therapy, electric shock therapy, psychedelic medication and neuro-linguistic programming to be “certainly 143 discredited. In the late 1930s and early 1940s, many hospitals would not admit patients for the treatment of addiction involving alcohol, 144 so lay approaches became an important option. While the mutual support/self-help approach maintained the perspective of addiction as a disease--formalized in the development of the principles underlying the Minnesota Model in the 1950s--the “rehabilitative model” of treatment was seen as distinct from “the medical model. This model remains the dominant approach to addressing addiction in the United States. Yet, its limitations and failure to address addiction the way other diseases are addressed have led to a call to integrate addiction treatment into mainstream medical care. And a lot or qualifications to implement the existing of medical people like and want it that way; they range of evidence-based practices and face do not want to deal with addiction; they do not many organizational and structural barriers like to deal with the people and they do not feel 148 to providing services; effective addressing the problem. Other highly-trained and intervention, treatment and disease credentialed health professionals may be part of management is inadequate. Motivated and experienced non-professionals Because of the vast chasm between the health may serve additional vital functions--such as care system and approaches to preventing risky providing social support to encourage adherence substance use or treating addiction, medical to a treatment plan and help patients maintain professionals fail to address risky substance use important lifestyle changes that can reduce the or addiction or take responsibility for risk of relapse--but their roles and services do intervention or treatment, risky substance use is not supersede or replace those of the medical addressed primarily in terms of its consequences team. Degree * Among those who responded that the educational qualification is "very Further, most treatment providers see important". Program Staff Directors Providers Despite this variability in perceptions regarding High volume of paperwork/reporting what the treatment system should look like, requirements 76. While limited education and training of most providers and a provide treatment for co-morbid conditions treatment culture largely steeped in the self-help Insufficient number of trained master’s- 28. We haven’t inadequate education and training of treatment 161 effectively brought practical research results to providers in evidence-based practices, the 168 individual providers…so they can use it. Janes implementing many evidence-based practices Former Director and the qualifications that the majority of the Florida Office of Drug Control 162 treatment workforce currently possesses. Office of the Governor Because most treatment providers are not adequately trained, they are not capable of Evidence from research findings is not generally performing health assessments, prescribing accessible and understandable to providers; 169 we’re failing miserably at that. National Association of Lesbian and Gay Most also are not trained in the scientific method Addiction Professionals or clinical research, further impeding their (now Vice President, and association now called ability to integrate clinical research findings into The Association of Lesbian, Gay, Bisexual, 164 Transgender Addiction Professionals treatment practice. They also were more likely to have * Evidence-based practice involves the use of current staff with advanced degrees and less likely to have evidence in making decisions about patient care. The authors of this study speculate Evidence-based practices aim to combine the best that programs with managed care contracts might be available research and clinical judgment while taking likelier than those without such contracts to be into account patient characteristics and needs. For example, based practices tended to be more highly while numerous guidelines have been produced 172 †† 178 educated. In contrast, specialists is essential to help educate and train providers with a strong 12-step orientation to other physicians, serve as equal partners in treatment tend to perceive evidence-based regular medical practice and provide specialty 175 183 practices as less acceptable. For many recovering paraprofessional Efforts also must be made to translate physician counselors, their counseling “trump card” is training into practice. A lack of time and that their personal experience is exemplary of resources make it difficult for physicians to 177 how recovery works. Poor training in the care of patients fourth-year medical students in New York City with addiction relates to low confidence among found that the majority (85 percent) did not physicians in their ability or competence to treat know of local smoking cessation programs to 193 such patients, negative attitudes toward patients which to refer patients. And a national survey with addiction, pessimism about the of directors and assistant directors of U. They may assess, but they don’t and inhibit the acceptance of biological models 187 195 intervene. Curriculum time and the number of faculty with Only a small proportion of primary care expertise in addiction education pale in physicians feel “very prepared” to detect comparison to curriculum time and the number particular types of risky use (alcohol--19. A students and I feel that too many of our attending state-based 2006 survey of primary care physicians have not demonstrated to us that they physicians found that the vast majority (88 believe that addiction can and should be percent) screen for diabetes in adults with risk addressed and that attitude affects patient care factors such as obesity, hypertension and a 198 189 for the worse. Another national study found that 199 established, yet there often are more addiction only half of psychiatry residency programs offer -217- 205 psychiatry residency positions available than ability to provide psychosocial therapies. For example, overwhelming evidence has percent); and “smoking patients are not proven that smoking cessation interventions are interested in smoking cessation counseling” 206 clinically effective and cost effective and that a (19. Yet many medical schools do not training in caring for patients with risky 202 207 require clinical training in smoking cessation. Only about half of dental * schools and dental hygienist programs have My relapse was in part due to ignorance in the tobacco cessation clinical activities integrated in medical profession and lack of medical 210 their student clinics. This is despite the fact addiction understanding during a life- threatening illness. Yet, nurses are not clinical psychologists are highly trained in adequately prepared to perform these services, psychosocial therapies, many of which can be particularly tobacco cessation for which applied effectively to addressing addiction in the research indicates they can be particularly 215 significant proportion of their patient population effective. Barriers to the implementation of that has co-occurring addiction and mental smoking interventions include a reported lack of 204 motivation, self- efficacy, institutional support, health disorders. Nursing school curricula screening and intervention for risky substance have little tobacco control content; there is a users and in diagnosing, treating or referring lack of tested curricula, nurse educators are not patients with addiction, some fail to identify * risky use or addiction or lack confidence in their Forty-seven percent of dental schools and 55 percent of dental hygienist programs. Specifically, cessation interventions are effective in providing although it is well understood that dosages 218 those services, and despite the important role between 60-100 mg per day promote retention in 225 pharmacists can play in preventing the misuse of treatment and reduction of opioid use, 34 219 controlled prescription drugs, most are not percent of patients are given doses of less than well trained to perform these functions, have 60 mg per day and 17 percent are given doses of * 226 little confidence to do so and believe that most less than 40 mg per day. Treatment patients are not interested in having them programs more likely to give suboptimal doses 220 intervene. A study of pharmacists in Florida involving opioids be integrated into mainstream found that 29. The underutilization of pharmaceutical therapies in addiction treatment is another example of the Furthermore, despite the potentially vast market disconnect between addiction treatment services for pharmaceutical treatments for addiction, the and medical care. Many addiction treatment pharmaceutical industry has not made providers are unable to prescribe pharmaceutical substantial investments in the development of therapies and medical professionals who could new and effective addiction treatment 231 prescribe such therapies fail to address medications. A related problem is that some contributing factors to the increased medical medical professionals appear to have a treatment of mental health disorders, such as disproportionate concern about the safety risks depression and anxiety, in the past two decades of addiction medications relative to medications has been the development and marketing of aimed at treating other medical conditions. For pharmaceutical treatments for these 232 example, although side effects for some conditions. However in recent years, the addiction medications have been noted and pharmaceutical industry has cut back safety concerns raised--particularly with regard dramatically on investments in the development 223 of new pharmaceutical therapies for these and to smoking cessation treatments, side effects 233 exist for many medications aimed at treating other mental health conditions. The large other health conditions and typically are profits that pharmaceutical companies were able acknowledged as an acceptable risk of treatment. Addiction treatment providers do not speak with Coupled with the rising cost of research and clarity or consistency about what the goals of development, the fact that pharmaceutical treatment are, what counts as quality treatment, companies face dramatic losses once the patents how performance and outcomes should be on many of their largest money-making drugs measured and what practices should be expire makes the current climate for the implemented to improve treatment and achieve development of new innovative medications * 239 measurable outcomes. For example, transporters that underlie addiction and that are organizations like the Council on Graduate promising targets for the development of Medical Education and the National Advisory 235 medications to prevent and treat addiction. Council on Nurse Education and Practice are public-private partnerships with Congressional Aside from economic concerns, other factors mandates to provide sustained assessment of the inhibiting investments in new pharmaceutical 241 needs of the medical and nursing fields. Even for which states that every physician must assume smoking cessation, which offers a huge clinical responsibility for the diagnosis and potential market, investments are negligible referral of patients with addiction and explicates compared with the costs associated with the particular competencies needed to fulfill that developing medications to treat the responsibility. Despite these and other efforts by government and professional Translating the rapidly-evolving science of organizations to put forth guidelines and addiction into science-based treatments will principles aimed at ensuring proper training in require dramatic changes in incentives for the risky substance use and addiction, physicians pharmaceutical industry to invest in innovative continue to be insufficiently equipped to address medications, increased public understanding that 242 the needs of their substance-involved patients.
Gastrin is a linear peptide hormone produced by G cells of the duodenum and in the pyloric antrum of the stomach buy 100 mg lasix with amex. Gastrin is released in response to certain stimuli discount lasix generic, including stomach distension order lasix in united states online, vagal stimulation, the presence of partially digested proteins (amino acids) and hypercalcaemia. Two cell types in the mucosa of the corpus of stomach are principally responsible for secretion of acid. Bicarbonate ion (production catalysed by carbonic anhydrase) exits the cell on the basolateral surface, in exchange for chloride. The outﬂow of bicarbonate into blood results in a slight alkalinity of the blood, known as the ‘alkaline tide’. Chloride and potassium ions are transported into the lumen of the cannaliculi by conductance channels. Hydrogen ions are pumped out of the cell, into the gut lumen, in exchange for potassium, through the action of the proton pump; potassium is thus effectively recycled (Figure 4. Cell surface polarity The apical membrane of a polarised cell is that part of the plasma membrane that forms its luminal surface, particularly so in the case of epithelial and endothelial cells. The basolateral membrane of a polarised cell refers to that part of the plasma membrane that forms its basal and lateral surfaces. Proteins are free to move from the basal to lateral surfaces, but not to the apical surface; tight junctions, which join epithelial cells near their apical surfaces, prevent migration of proteins to the apical surface. The highly acidic environment causes denaturation of proteins, making them susceptible to proteolysis by pepsin (which is itself acid-stable). Gastrin and vagus nerve stimulation trigger the release of pepsinogen from chief cells in the gastric glands. Pepsinogen (inactive) is a zymogen which under acidic conditions autocatalytically cleaves itself to form pepsin (active), an enzyme with a pH optimum of 1. It cleaves peptide bonds on the N-terminal side of aromatic amino acids; peptides are further digested by proteases in the duodenum. Safe and effective inhibition of gastric acid secretion is a goal of clinicians in treatments of gastro-oesophageal reﬂux disease and peptic ulcer. Omeprazole and lansoprazole are effective in the treatment of the Zollinger–Ellison syndrome. Zollinger–Ellison syndrome is characterised by increased levels of the hormone gastrin, causing the stomach to produce excess hydrochloric acid. Additional mediators of gastric acid secretion include calcium, gastrin-releasing hormone and enkephalin, while opiate receptors have also been identiﬁed on parietal cells. Gastrin-releasing hormone stimulates gastrin release through G-protein-coupled recep- tors. Together with cholecystokinin, it is the major source of negative-feedback signals that suppress feeding. Another group of G-protein receptors (opioid receptors) are affected by enkephalins. Adhesins are produced by the bacterium, which binds to membrane-associated lipids and carbohydrates to maintain its attachment to epithelial cells. Large amounts of the enzyme urease are produced, both inside and outside of the bacterium. Urease metabolises urea (which is normally secreted into the stomach) to carbon dioxide and ammonia (which neutralises gastric acid), and is instrumental in the survival of the bacterium in the acidic environment. Pylori, including protease, catalase and certain phospholipases, causes damage to these cells. Some strains of the bacterium ‘inject’ the inﬂammatory inducing agent peptidoglycan from their own cell wall into epithelial stomach cells. The risk of developing stomach cancer is thought to be increased with long-term infection with H. It consists of the duo- denum, a short section that receives secretions from the pancreas and liver via the pancreatic and common bile ducts, the jejunum and the ileum. Two other major cell types are present: enteroendocrine cells, which secrete hormones such as cholecystokinin and gastrin into blood, and goblet cells, which secrete lubri- cating mucus. Crypts (of Lieberkuhn) are moat-like invaginations of the epithelium around the villi, and are lined largely with younger epithelial cells, which are involved primarily in secretion. Toward the base of the crypts are stem cells, which continually divide and provide the source of all the epithelial cells in the crypts and on the villi. Gastric parietal cells and chief cells have Reduces shear stress on the epithelium. Cells have rapid turnover rates, usually a Abundant carbohydrates in mucin bind bacteria, few days. Stem cells, in the middle of gastric pits and The effects of toxins are minimised by their crypts, provide continual replenishment. Gastric and duodenal epithelial cells secrete bicarbonate to their apical faces to maintain a neutral pH along the epithelial plasma membrane. Their location, adjacent to crypt stem cells, suggests they have a role in defending epithelial cell renewal. The gastrointestinal tract is the largest endocrine organ in the body and the endocrine cells within it are referred to collectively as the enteric endocrine system. Three of the best-studied enteric hormones are gastrin, secreted from the stomach, which plays an important role in control of gastric acid secretion, cholecystokinin, which stimulates secretion of pancreatic enzymes and bile, and secretin, which stimulates secretion of bicarbonate-rich ﬂuids from the pancreas and liver. Normal proliferation of gastric and intestinal epithelial cells, as well as proliferation in response to such injury as ulceration, is known to be affected by a large number of endocrine and paracrine factors. Prostaglandins, particularly prostaglandin E2 and prostacyclin, have ‘cytoprotective’ effects on the gastrointestinal epithelium. Prostaglandins are synthesised within the mucosa from arachidonic acid through the action of cyclooxygenases. Their cytoprotective effect appears to result from stimulation of mucosal mucus and bicarbonate secretion, increasing mucosal blood ﬂow and, particularly in the stomach, limiting back-diffusion of acid into the epithelium. Both peptides bind to a common receptor and stimulate epithelial cell proliferation. Cytokines, such as ﬁbroblast growth factor and hepatocyte growth factor, have been shown to enhance healing of gastrointestinal ulcers in experimental models. Trefoil proteins are a family of small peptides that are secreted by goblet cells in the gastric and intestinal mucosa, and coat the apical face of the epithelial cells. Their distinctive molecular structure appears to render them resistant to proteolytic destruction. They appear to play an important role in mucosal integrity, repair of lesions and limiting epithelial cell proliferation, as well as in protecting the epithelium from a broad range of toxic chemicals and drugs. Trefoil proteins also appear to be central players in the restitution phase of epithelial damage repair, where epithelial cells ﬂatten and migrate from the wound edge to cover denuded areas. Mice with targeted deletions in trefoil genes showed exaggerated responses to mild chemical injury and delayed mucosal healing.
On top of all this lasix 40 mg low price, we have to understand that generic 40mg lasix amex, as Kurtz does not have a training in medicine discount 40mg lasix with amex, it is possible he knows nothing about the subject. They promote the view that not only are vulnerable people being parted from their cash, but that people are being philosophically duped: they are thinking wrong thoughts! If you cone to France with your dog, you have to tell the dog to bark in English or American. His work was internationally labelled as fraudulent and he was held up to ridicule. Jacques Benveniste is a well-respected French scientist He will tell you that he is an immunologist, and that is all he is; this though is to undervalue him. He is an entertaining and charismatic man who has a considerable history as a medical research scientist. He is committed to one of the most exciting areas of biological research: the communication between cells, especially the cells which make up the human immune system. He has devoted his life to trying to discover the pathways between a select group of cells which are activated when foreign substances enter the human body. He has a good track A but like many immunologists who have strayed from orthodox pharmaceutical research and become involved with alternatives, he feels that the American, British and French scientific establishments have deprived him of deserved accolades. After training as a doctor and working with cancer patients for twenty years, Benveniste began research into allergic conditions. On this subject he speaks with the common bitterness which many allergists feel about their governments and the orthodox medical establishment. At the same time, 2 one billion francs are spent on pharmaceuticals for allergy each year. The amount of money which the population spends on pharmaceutical preparations for allergy would be irrelevant if such preparations helped to resolve the problem. Benveniste believes, as do many others both inside and outside orthodox medicine, that drug solutions to allergy do nothing more than alleviate a minority of the symptoms; moreover Benveniste believes that chemicals generally take an increasing toll on health, creating more immune system illnesses. Despite all the Nobel prizes given for work in this area, more people die today of asthma than did twenty years ago. On occasions, the dilution is so great that orthodox scientists say that the original substance cannot be detected in the solution. Throughout these conflicts he has made a name for himself as a scientist who will fight his corner. He sees himself now isolated to some extent because of this consistent opposition. When there was a large conference on allergy in the beginning of the eighties in Britain, I sent a public letter to everyone. I was at that time leading the most productive French allergy research group and I was not even invited. As the biggest drug companies moved into immunology and the kudos and money attached to finding cures for asthma and allergy grew, so did the anger and resentment against Jacques Benveniste. He found that his discoveries were often deprecated by the scientific establishment and he was not recognised for them. For example, in asthma research, during the seventies, medical research workers promoted very heavily in papers all over the place, that leukotrienesf were the molecules that did the job. There was enormous interest from the drug companies, who all wanted to get involved. Ten years later, it is clear that leukotrienes have only a modest importance in asthma treatment. Benveniste feels that throughout the eighties he was excluded and isolated from the discussions around his own work and discoveries. According to Maddox, the conclusions of the paper struck at the roots of two centuries of observation and rationalization of physical phenomena. While he was working for Boiron, Benveniste was also working on contracts for mainstream pharmaceutical companies. In 1989, two other homoeopathic companies took over from Boiron, one French, Dolisos, and the other, Homint, half-German and half-Dutch. The first problem that Benveniste encountered with his work came in 1985, when interim results were leaked and then taken up in a full-page article in Le Monde. Although he had no means of knowing it, this attack was the first skirmish in a war declared upon him by a then unknown enemy. The question stripped him of his experience, his advanced knowledge in the field and his status as an internationally renowned scientist. Benveniste was not able within the parameters of the discussion to outline his expert experience. Most scientists consider the control to be one of the essential components of correct research method. It was during that programme that Benveniste realised that he was going to meet some hard opposition to his work. More than anything, he was amazed by the vehemence of the argument used against him. Being a reasonable man and an intellectual, he had expected a debate, not the kind of anger which was now hurled at him. He felt, he says, like a European intellectual who, on visiting a Muslim country, had denied the existence of God. To Benveniste, this attitude was antipathetic to science or any kind of intellectual discourse. I can not understand that scientific data is important enough for everyone to get on their feet and start a bloody war. At the same time he submitted papers to the British Journal of Clinical Pharmacology and the European Journal of Pharmacology. Both the latter articles were eventually accepted and published in 1988 and 5 1987. There were a few questions before publication about the way the statistics were handled. Benveniste got no answer from Nature until a year after he had submitted the paper. The next communication from Nature was a demand that he should arrange for the work upon which the paper was based to be reproduced in other laboratories before publication. Such a principle, if it were put into effect universally, would make the whole scientific process unworkable. Believing that he had become involved against his will in a struggle not only to preserve his own good name, but to defend the objective basis of scientific research, Benveniste agreed to the demand. He found two laboratories, one in Israel and one in Canada, which willingly replicated his work and his results. A team from Italy also replicated the work, doing eight experiments, of which they were happy with seven. All the results were then sent to Nature in the summer of 1987, with the revised paper signed by all the scientists who had carried out the work.
Emily Martin has noted that scientists confronted with this new evidence in the late 1980s vacillated between a model that emphasized the egg as seductress and the more mutual paradigm of sperm–egg fusion (Martin buy cheap lasix, 1991) buy lasix us. The fusion model is devoid of (most of) the human agency imparted to eggs and sperm in traditional descriptions discount lasix 40mg otc, opting instead for a characterization that relies on a simple chemical process. Changing characterizations of the process of fertilization thus created a new context (valid or not) for research supporting the link between paternal exposures and fetal harm. The evidence of male-mediated developmental toxicology Male reproductive exposures are now strongly suspected of causing not only infertility but also miscarriage, low birth weight, congenital abnormalities, cancer, neurological illness and other childhood health problems (Davis et al. Studies of male reproductive health and toxicity have Between fathers and fetuses 121 concentrated primarily on the eVects of occupational and environmental exposures of men and less on the eVects of what scientists refer to as men’s ‘lifestyle factors’, such as drinking, smoking, or drug use (Davis et al. Because adult males continuously produce sperm throughout their lives, the germ cells from which sperm originate are continuously dividing and developing. Sperm take approximately 72 days to develop to maturity, and then move for another 12 days through the duct called the epididymis, where they acquire the ability to fertilize an egg. During this developmental process, sperm may be particularly susceptible to damage from toxins because cells that are dividing are more vulnerable to toxicity than cells that are fully developed and at rest, as are eggs in the female reproductive system. Abnor- mal sperm may still be capable of fertilizing an egg because speed may be more important than size or shape, as was suggested in the earliest article on this subject (Moore, 1989). Some of the earliest epidemiological research studied the eVects of radi- ation exposures on the children born to men who survived the atomic bombs at Nagasaki and Hiroshima. However, few associations were found between paternal exposures and childhood health problems, possibly due to the fact that so few men conceived children in the six months after the bombing, when the exposure eVects of radiation were at their strongest (Yoshimoto, 1990; Olshan and Faustman, 1993). Vietnam veterans concerned about the eVects of the herbicide Agent Orange called for studies on links between male exposures during the war and childhood diseases of their oVspring. Other studies also showed increased rates of spinal malformation, spina biWda, congenital heart defects and facial clefting in the children of Vietnam veterans. Seventeen studies have now evaluated the impact of pesticides and herbicides on male reproduction and paternal–fetal health (Olshan and Faustman, 1993: p. Other studies have analysed the eVects of occupational exposures on paternal–fetal health, with many Wnding signiWcant associations between paternal exposures and fetal health problems. Paints, solvents, metals, dyes and hydrocarbons have been asso- ciated with childhood leukaemia and childhood brain tumours (summarized in Olshan and Faustman, 1993: p. In analyses by occupation, janitors, mechanics, farm workers and metal workers have been reported to have an excess number of children with Down’s syndrome (Olshan and Faustman, 1993: p. Painters and workers exposed to hydrocarbons have also been shown to have higher rates of children with childhood leukaemia and brain tumours (Savitz and Chen, 1990). And, as in all epidemiological studies, it is diYcult to control for confounding factors, such as the eVects of multiple chemical exposures and alcohol or drug use. However, whilst the problem of confounding variables is common to all epidemiological studies of reproduc- tive toxicity, for cultural reasons scientists are more acutely aware of method- ological caveats when studying men. For instance, studies of paternal eVects are routinely criticized for not controlling for maternal exposures, while studies on women virtually never control for the exposures of fathers. Studies that do focus on the eVects of lifestyle factors on men’s reproduction are criticized for not controlling for men’s workplace exposures, while studies of women and drug use do not control for women’s occupational exposures. The biological processes of male-mediated teratogenicity have also been examined through clinical studies on animals and studies of the eVect of toxic exposures directly on sperm. In a study of more than 14 000 birth records in San Francisco, researchers found associations between paternal smoking and various birth defects, including cleft lip, cleft palate and hydrocephalus (Savitz, Schwingle and Keels, 1991). SigniWcant associations have also been found between paternal smoking and brain cancer in children, and between paternal smoking and low birth weight – a diVerence of up to 238 grams (c. In addition, cotinine, a meta- bolite of nicotine, has been found in seminal Xuid, although researchers are unsure what eVect this might have on fetal health (Davis et al. Bruce Ames of the University of California, Berkeley, has suggested that the link between smoking and birth defects could be due to smokers’ low levels of vitamin C. Case reports suggest an association between paternal drinking and ‘malformations and cognitive deWciencies’ in the children of alcoholic men (Little and Sing, 1987; Colie, 1993: p. Ricardo Yazigi, Randall Odem and Kenneth Polakoski discovered that cocaine could bind to sperm and thereby be transmitted to the egg during fertilization. Reports of cocaine ‘piggybacking’ on sperm have led to controversy in the scientiWc community over whether this phenomenon could contribute to birth defects (Brachen et al. In animal studies, opiates (such as morphine and methadone) administered to fathers, but not to mothers, have produced birth defects and behavioural abnormalities in the Wrst and second generations of the father’s oVspring (Friedler and Wheeling 1979; Friedler, 1985). Press coverage of male-mediated harm The scientiWc evidence on male-mediated risks has generated quite diVerent stories in popular magazines and newspapers than it has for women. Whilst images of crack babies and irresponsible mothers prevail in stories about maternal exposures to drugs, visual images in popular science magazines and news stories about male reproduction place sperm in the centre of focus as the tiniest victims of toxicity. Even in newspaper stories that address the connection between paternal exposures and fetal health, certain patterns of reporting emerge that function to reduce male culpability for fetal harm. In all of the stories that draw connections between paternal exposures and fetal harm, maternal exposure was also mentioned as a possible source of harm. Evidence of male-mediated risks are often prefaced with statements such as, ‘While doctors are well aware of the eVects that maternal smoking, drinking and exposure to certain drugs can have on the fetus, far less is known about the father’s role in producing healthy oVspring’ (Merewood, 1992: p. News and World Report began an article on paternal–fetal harm in these terms, ‘It is common wisdom that mothers-to-be should steer clear of toxic chemicals that could cause birth defects. Between fathers and fetuses 125 Fourth, paternal exposures to illegal drugs are always contextualized by reference to ‘involuntary’ environmental and workplace exposures, thereby reducing men’s culpability for harm. After reporting that children of fathers who smoke have been found to be at increased risk for leukaemia and lymphoma, the article ends with the recom- mendation of a physician that men who smoke ‘either modify their diets to include fruits and vegetables or take a vitamin C supplement each day’. While sperm ‘delivers’, ‘transports’ or ‘carries’ the drug to the egg in such stories, it never ‘assaults’ the fetus, as stories on drug use and women imply. When the sperm is not presented as itself a victim, it acts as a shield for men – deXecting or capturing the blame that might otherwise be placed on the father. One news story entitled ‘Sperm Under Siege’, presented an image of sperm at the centre of a target, menaced by bottles of alcohol and chemicals (Merewood, 1991). Another presented a cartoon image of a man and his sperm huddled under an umbrella whilst packets of cigarettes, martini glasses and canisters of toxins rained down upon them (Black and Moore, 1992). Yet of the 853 column inches dedicated to pregnancy, alcohol and drug abuse by the New York Times in one two-year period, almost 200 column inches were taken up by photographic images of crack babies and their drug-addicted mothers (Schroedel and Peretz, 1993). The biological mechanism of paternal–fetal harm have been made invisible not by science itself, but by the lens through which scientiWc evidence is perceived. As Evelyn Fox Keller has observed, un- articulated gender assumptions aVect not only the questions and methodolo- gies of scientiWc research but also ‘what counts as an acceptable answer or a satisfying explanation’ (Keller, 1992: p. For this reason, scientists who have engaged in research on paternal–fetal hazards have met with scepticism from colleagues, editors and newspaper reporters alike. Daniels Paternal effects and ‘political correctness’ Evidence of paternal–fetal harm has generated, at best, virtual silence from public health authorities and the courts, or, at worst, active hostility. An editorial in Reproductive Toxicology (Scialli, 1993) argued that the impulse to link paternal exposures with fetal eVects is a result not of science but of ‘political correctness’, ‘There has been no quarrel that testicular toxicants can produce fertility impairment, but paternally mediated eVects on conceived pregnancies is [sic]adiVerent matter altogether’. The article concedes that ‘several’ studies on paternally mediated eVects have been ‘nicely performed and reported’, but taken as a whole they are ‘diYcult to interpret’ (Scialli, 1993: p.
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