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By Z. Jens. The Citadel. 2019.

If purchase raloxifene 60mg with amex women's health clinic in el paso tx, however order raloxifene 60 mg mastercard pregnancy ticker, the impact is sudden buy raloxifene 60mg low price menstrual flooding, as in a rear-end collision, the body is accelerated in the forward direction by the back of the seat, and the unsupported neck is then suddenly yanked back at full speed. Here the muscles do not respond fast enough and all the energy is absorbed by the neck bones, causing the well-known whiplash injury (see Fig. It was found in these cases that the body made about a 1-m-deep depression in the surface of the snow on impact. The credibility of these reports can be verified by calculating the impact force that acts on the body during the landing. It is shown in Exercise 5-6 that if the decelerating impact force acts over a distance of about 1 m, the average value of this force remains below the magnitude for serious injury even at the terminal falling velocity of 62. In the normal course of daily activities our bodies are subject mostly to smaller repetitive forces such as the impact of feet with the ground in walking and running. A still not fully resolved question is to what extent are such smaller repetitive forces particularly those encountered in exercise and sport, damaging. Osteoarthritis is the commonly suspected damage resulting from such repetitive impact. Chapter 5 Exercises 71 Osteoarthritis is a joint disease characterized by a degenerative wearing out of the components of the joint among them the synovial membrane and cartilage tissue. As a result of such wear and tear the joint loses flexibility and strength accompanied by pain and stiffness. After the age of 65, about 60% of men and 75% of women are to some extent affected by this condition. Over the past several years a number of studies have been conducted to determine the link between exercise and osteoarthritis. The emerging conclu- sion is that joint injury is most strongly correlated with subsequent develop- ment of osteoarthritis. Most likely this is the reason why people engaged in high impact injury-prone sports are at a significantly greater risk of osteo- arthritis. Further, there appears to be little risk associated with recreational running 20 to 40 km a week (∼13 to 25 miles). It is not surprising that an injured joint is more likely to be subsequently subject to wear and tear. A joint injury usually com- promises to some extent the lubricating ability of the joint leading to increased frictional wear and osteoarthritis. This simple picture would lead one to expect that the progress of osteoarthritis would be more rapidly in the joints of peo- ple who are regular runners than in a control group of non-runners. Osteoarthritis seems to progress at about the same rate in both groups, indicating that the joints possess some ability to self- repair. If the bones of one arm absorb all the kinetic energy (neglecting the energy of the fall), what is the minimum speed of the runner that will cause a fracture of the arm bone? Assume that the object is hard, that the area of contact with the skull is 1cm2, and that the duration of impact is 10−3 sec. Calculate the duration of the collision between the passenger and the inflated bag of the collision protection device discussed in this chapter. In a rear-end collision the automobile that is hit is accelerated to a veloc- ity v in 10−2/sec. What is the minimum velocity at which there is danger of neck fracture from whiplash? Use the data provided in the text, and assume that the area of the cervical vertebra is 1 cm2 and the mass of the head is 5 kg. Calculate the average decelerating impact force if a person falling with a terminal velocity of 62. Assume that the person’s mass is 70 kg and that she lands flat on her back so that the area of impact is 0. Assuming that the moving part of his hand weighs 5 kg, calculate the rebound velocity and kinetic energy of the bag. In particular, we will consider the hovering flight of insects, using in our calculations many of the concepts introduced in the previous chapters. The parameters required for the computations were in most cases obtained from the literature, but some had to be estimated because they were not readily available. A complete discussion of flight would take into account aerodynamics as well as the changing shape of the wings at the various stages of flight. Differences in wing movements between large and small insects have only recently been demonstrated. The following discussion is highly simplified but nevertheless illustrates some of the basic physics of flight. The wings are required to provide sideways stabi- lization as well as the lifting force necessary to overcome the force of gravity. As the wings push down on the surrounding air, the resulting reaction force of the air on the wings forces the insect up. The wings of most insects are designed so that during the upward stroke the force on the wings is small. During the upward movement of the wings, the gravitational force causes the insect to drop. The downward wing movement then produces an upward force that restores the insect to its original position. The vertical position of the insect thus oscillates up and down at the frequency of the wingbeat. The distance the insect falls between wingbeats depends on how rapidly its wings are beating. If the insect flaps its wings at a slow rate, the time interval during which the lifting force is zero is longer, and therefore the insect falls farther than if its wings were beating rapidly. We can easily compute the wingbeat frequency necessary for the insect to maintain a given stability in its amplitude. To simplify the calculations, let us assume that the lifting force is at a finite constant value while the wings are moving down and that it is zero while the wings are moving up. During the time interval t of the upward wingbeat, the insect drops a distance h under the action of gravity. Typically, it may be required that the vertical position of the insect change by no more Section 6. This is a typical insect wingbeat frequency, although some insects such as butterflies fly at much lower frequency, about 10 wingbeats per second (they cannot hover), and other small insects produce as many as 1000 wingbeats per second. To restore the vertical position of the insect during the downward wing stroke, the average upward force, Fav on the body of the insect must be equal to twice the weight of the insect (see Exercise 6-1). Note that since the upward force on the insect body is applied only for half the time, the average upward force on the insect is simply its weight. The wing movement is controlled by many muscles, which are here repre- sented by muscles A and B.

I simply believe that they’re overused buy discount raloxifene 60mg line womens health quickie, few patients get full informed consent order raloxifene 60 mg visa pregnancy 7 weeks symptoms, and the root cause—often neuroendocrine imbalance—is sometimes overlooked purchase raloxifene 60mg otc women's health clinic flinders. We want to avoid the either/or thinking that polarizes women—that makes women feel damned if they do take an antidepressant given the risks and loss of sexual interest, and damned if they don’t. Women need more choices, preferably choices that are natural and address the root cause of their discontent. Some conventional clinicians might even be resistant to considering any other options, such as looking at your cortisol levels, despite the documentation I’ve provided in this chapter (and on my webpage specifically for practitioners: http://thehormonecurebook. I believe that with a closer look, many burned-out women would show adrenal dysregulation, given the telltale signs of insulin resistance, decreased immunity, midsection weight gain, fatigue, tension, and low mood. This is when you need to find a doctor who will work with you, in a partnership that feels aligned with your goals and belief system. It’s also important to develop tools to dance with stress and to deal with a frantic lifestyle. In Appendix D, I’ve included a checklist for how to find a practitioner who is an ally in your health goals. But just because you might not recognize its name, pregnenolone is still important. In fact, pregnenolone is considered the mother of all the sex hormones, because it is the prehormone (the necessary precursor) to all the others. Women have a rapid decline of pregnenolone beginning in their thirties, while men reach their peak in their twenties, with only a minor decline 37 through their sixties. We all worry about high cholesterol, but a certain level of cholesterol is needed to create pregnenolone. This could cause you to run low in cortisol and other hormones, as described in chapter 10. That’s easy: it hasn’t gotten the same research attention as the others, likely because there is no financial incentive for pharmaceutical manufacturers. Despite all my medical training, I knew nothing about it until I took an advanced hormonal seminar with a European endocrinologist. Indeed, pregnenolone is largely unknown in the United States, although that’s beginning to change. The Solution Stress is your response to change, such as external or internal factors that knock us out of homeostasis. Negative stressors, especially the emotional type, lead to excess glucocorticoids. A common pattern in women after age thirty-five is to have low cortisol during the day and high cortisol at night, which may make it hard to fall asleep and/or stay asleep. Although The Gottfried Protocol solutions below are separated into algorithms for high and low cortisol, remember that balancing cortisol is related to stress reduction. So whether your cortisol is high or low, always start with the lifestyle changes that you can make to mitigate stress in your life, both real and perceived. Here’s a recap of the aim of The Gottfried Protocol: • Start with lifestyle redesign: optimize nutrition, exercise, and mental retraining. No need for testing or consulting with a practitioner before beginning these strategies. Testing may also be helpful to identify and fix efficiently your missing vitamins, minerals, and amino acids (the building blocks of protein). Part A: The Gottfried Protocol for High Cortisol Although it may be appealing to treat excess stress with sugar and coffee, I consider these “fake” energy boosts that ultimately undermine your hormonal progress. My preference is that we make the necessary tweaks so that you wake up each morning feeling restored, and coffee is not necessary. Start with Step 1 and the interventions that are easiest to integrate into your life, since you’ll be more likely to sustain habits that fit into your day. Of course, talk to your doctor about what supplements and dosages might be best for you. Excess stress also can cause you to excrete magnesium, a mineral key to calcium absorption. If you are suffering with five or more symptoms of low cortisol, and your low progesterone is confirmed through testing with your doctor, I recommend taking all of them. If you are suffering from fewer than three symptoms, and are a minimalist who wants to see how few supplements it takes to optimize your adrenal function, I recommend starting first with lifestyle adjustments. If you need more adrenal healing after four to six weeks, move on to the B vitamins. In what may be the most popular study ever performed on cortisol, dark chocolate (40 grams per day for two weeks) lowered urine cortisol levels. But take the results with a grain of salt (perhaps combined with the square of chocolate)—the study was sponsored by Nestlé. Alcohol raises cortisol, and the effect persists for twenty-four hours in men—probably longer for women. Caffeine, the world’s most popular psychoactive substance, directly induces the adrenocortical cells to produce more cortisol, as well as more epinephrine, norepinephrine, and insulin. Advocates of coffee point to the studies of the antioxidant benefits and longevity. If you suffer from insomnia, anxiety, or bruxism, which is clenching or grinding your teeth at night, I suggest you wean yourself off caffeine. What is the smallest dose of caffeine that supports your productivity yet doesn’t undermine your health? Massage of the pressure receptors in and under the skin stimulates vagal activity, which is one reason massages are so relaxing. One study compared people who had a single forty-five-minute session of either Swedish “light” massage or deep tissue massage. The deep-tissue massage lowered cortisol and raised oxytocin, the hormone of affiliation and bonding. A pilot study of traditional acupuncture, three times a week for twelve weeks, versus sham or no acupuncture, showed a decrease in hot flashes and night sweats, lower twenty-four-hour urinary-cortisol levels, and improved quality of life in menopausal women. Another way of observing yourself, if you need more external accountability, is to purchase a gizmo called an emWave HeartMath. Briefly, HeartMath methodology is based on the fact that the time between each beat of your heart varies according to emotional arousal, heart-rate variability. Loss of variability is a sign of inner emotional stress and waning adaptive suppleness, as well as of heart disease. If a patient rolls her eyes at my prescription of yoga or meditation, I whip out my emWave, which is smaller than a smartphone. While this has been documented in healthy men, but not women, forgiveness training has been shown to lower stress and anger. If you think it sounds fringy, consider that stroking of the clitoris was once used as therapy for women with hysteria, though the more sanitized term was “medical massage. Within sixty seconds of orgasm, oxytocin, the hormone of love and bonding, floods your system.

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I believe that with a closer look generic raloxifene 60 mg overnight delivery menstrual related migraines, many burned-out women would show adrenal dysregulation purchase 60mg raloxifene visa menstrual type cramps during pregnancy, given the telltale signs of insulin resistance cheap 60mg raloxifene mastercard women's health clinic north adelaide, decreased immunity, midsection weight gain, fatigue, tension, and low mood. This is when you need to find a doctor who will work with you, in a partnership that feels aligned with your goals and belief system. It’s also important to develop tools to dance with stress and to deal with a frantic lifestyle. In Appendix D, I’ve included a checklist for how to find a practitioner who is an ally in your health goals. But just because you might not recognize its name, pregnenolone is still important. In fact, pregnenolone is considered the mother of all the sex hormones, because it is the prehormone (the necessary precursor) to all the others. Women have a rapid decline of pregnenolone beginning in their thirties, while men reach their peak in their twenties, with only a minor decline 37 through their sixties. We all worry about high cholesterol, but a certain level of cholesterol is needed to create pregnenolone. This could cause you to run low in cortisol and other hormones, as described in chapter 10. That’s easy: it hasn’t gotten the same research attention as the others, likely because there is no financial incentive for pharmaceutical manufacturers. Despite all my medical training, I knew nothing about it until I took an advanced hormonal seminar with a European endocrinologist. Indeed, pregnenolone is largely unknown in the United States, although that’s beginning to change. The Solution Stress is your response to change, such as external or internal factors that knock us out of homeostasis. Negative stressors, especially the emotional type, lead to excess glucocorticoids. A common pattern in women after age thirty-five is to have low cortisol during the day and high cortisol at night, which may make it hard to fall asleep and/or stay asleep. Although The Gottfried Protocol solutions below are separated into algorithms for high and low cortisol, remember that balancing cortisol is related to stress reduction. So whether your cortisol is high or low, always start with the lifestyle changes that you can make to mitigate stress in your life, both real and perceived. Here’s a recap of the aim of The Gottfried Protocol: • Start with lifestyle redesign: optimize nutrition, exercise, and mental retraining. No need for testing or consulting with a practitioner before beginning these strategies. Testing may also be helpful to identify and fix efficiently your missing vitamins, minerals, and amino acids (the building blocks of protein). Part A: The Gottfried Protocol for High Cortisol Although it may be appealing to treat excess stress with sugar and coffee, I consider these “fake” energy boosts that ultimately undermine your hormonal progress. My preference is that we make the necessary tweaks so that you wake up each morning feeling restored, and coffee is not necessary. Start with Step 1 and the interventions that are easiest to integrate into your life, since you’ll be more likely to sustain habits that fit into your day. Of course, talk to your doctor about what supplements and dosages might be best for you. Excess stress also can cause you to excrete magnesium, a mineral key to calcium absorption. If you are suffering with five or more symptoms of low cortisol, and your low progesterone is confirmed through testing with your doctor, I recommend taking all of them. If you are suffering from fewer than three symptoms, and are a minimalist who wants to see how few supplements it takes to optimize your adrenal function, I recommend starting first with lifestyle adjustments. If you need more adrenal healing after four to six weeks, move on to the B vitamins. In what may be the most popular study ever performed on cortisol, dark chocolate (40 grams per day for two weeks) lowered urine cortisol levels. But take the results with a grain of salt (perhaps combined with the square of chocolate)—the study was sponsored by Nestlé. Alcohol raises cortisol, and the effect persists for twenty-four hours in men—probably longer for women. Caffeine, the world’s most popular psychoactive substance, directly induces the adrenocortical cells to produce more cortisol, as well as more epinephrine, norepinephrine, and insulin. Advocates of coffee point to the studies of the antioxidant benefits and longevity. If you suffer from insomnia, anxiety, or bruxism, which is clenching or grinding your teeth at night, I suggest you wean yourself off caffeine. What is the smallest dose of caffeine that supports your productivity yet doesn’t undermine your health? Massage of the pressure receptors in and under the skin stimulates vagal activity, which is one reason massages are so relaxing. One study compared people who had a single forty-five-minute session of either Swedish “light” massage or deep tissue massage. The deep-tissue massage lowered cortisol and raised oxytocin, the hormone of affiliation and bonding. A pilot study of traditional acupuncture, three times a week for twelve weeks, versus sham or no acupuncture, showed a decrease in hot flashes and night sweats, lower twenty-four-hour urinary-cortisol levels, and improved quality of life in menopausal women. Another way of observing yourself, if you need more external accountability, is to purchase a gizmo called an emWave HeartMath. Briefly, HeartMath methodology is based on the fact that the time between each beat of your heart varies according to emotional arousal, heart-rate variability. Loss of variability is a sign of inner emotional stress and waning adaptive suppleness, as well as of heart disease. If a patient rolls her eyes at my prescription of yoga or meditation, I whip out my emWave, which is smaller than a smartphone. While this has been documented in healthy men, but not women, forgiveness training has been shown to lower stress and anger. If you think it sounds fringy, consider that stroking of the clitoris was once used as therapy for women with hysteria, though the more sanitized term was “medical massage. Within sixty seconds of orgasm, oxytocin, the hormone of love and bonding, floods your system. Oxytocin lowers cortisol, and women are designed, physiologically and neurologically, to generate far more oxytocin than men. Direct your anxiety toward your health: use your concerns about your high cortisol and elevated blood pressure to motivate you to stay positive and appreciate what you do have, not what you lack. Pantethine (B5) appears to reduce the hypersecretion of cortisol in humans under high stress.

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Particularly poignant are the stories of female patients with high mercury levels and children with learning disabilities raloxifene 60 mg discount menopause and pregnancy. These women thought they were doing everything right while they were pregnant: they avoided caffeine buy raloxifene 60 mg on line women's health issues election 2012, they didn’t drink alcohol cheap raloxifene 60mg free shipping womens health zone exit health, they ate fish once a week. Hightower found her female patients had ten times more mercury in their blood than the Centers for Disease Control’s national average. For fish with less mercury, check out websites that list fish according to mercury content (for example, www. Mercury can also be found in high-fructose corn syrup, fungicides and herbicides, dental fillings, thermometers, some drugs, and some vaccinations. Mercury also acts like the aforementioned xenoestrogens by binding your estrogen receptors. High Estrogen, Breast Cancer, and Genes Science bears out the link between high estrogen and cancer. Higher estradiol levels put you at a higher risk for the type of breast cancer that involves estrogen receptors. It does not seem to put you at risk for the type of breast cancer that lacks estrogen receptors. I performed many of these preventive surgeries while undergoing my residency training at the University of California at San Francisco, where genetic counseling for breast cancer is robust and data driven. That’s where triggers and the exciting and emerging world of epigenomics come into play. Many of the genes you inherit can be expressed in one way or another, depending on triggers. The triggers can be internal (how you react to stress) and external (xenoestrogen exposure, radiation, what you eat, whether you are sedentary or active). Certain triggers may override your gene expression, silencing a bad gene or promoting a good gene. By making lifestyle changes, such as reducing your alcohol consumption, exercising more, and losing weight, you can potentially encourage a gene that tells your body to make more of the “good” estrogens instead of the “less good” estrogens. Look no further than the Amish for a good example of a trigger determining gene expression. The Bottom Line on Mammograms After being told for years that women should have annual mammograms starting at age forty, you may have read about the dramatic turnaround in recommendations for mammogram screenings that occurred in 2009. This is a congressionally mandated panel of independent experts who systematically review our best evidence in the area of primary care and prevention. Turns out that having more mammograms over the years may lead to more unnecessary biopsies (because of false positives) and perhaps increased damage to breast tissue from radiation. Another exception is women with dense breasts, in which case you may want to have your mammograms more frequently and the first mammogram done earlier. This has been shown to predict breast cancer risk better than other measures of density or risk factors alone. Recently, the New York Times reported on a new drug often prescribed to prevent breast cancer in women. Although tamoxifen and raloxifene have been shown to help prevent this kind of cancer, they are rarely used for this purpose. That’s because they can cause serious side effects, such as blood clots, uterine polyps, and even endometrial cancer. You may wonder why in the world a doctor would prescribe a pill to prevent breast cancer that actually causes another type of cancer, and I completely agree with the illogic of that practice. That’s why there’s such controversy about the prescription medications now available to help prevent the downstream effects of excess estrogen and another situation where discussing risks and benefits with your clinician is the best option. Paul Gross, the lead author of a study showing the benefit of exemestane, considers it “a very safe therapy that looks highly effective in preventing breast cancer. As a result, my patients report that while taking the drug, their skin sags, they can’t focus, their libido drops, and their memory is shot. I have found that answers rarely lie in a bottle of pills, and I follow instead my great- grandmother’s bidding to find the internal solution rather than resorting to external prescriptions. Prescription pills are often more complicated and dangerous than the drugmakers and some physicians want you to believe. And there’s more: once a prescription drug is approved for a particular purpose, such as breast- cancer prevention, it often takes five to ten years before we have a full grasp of the side effects and adverse reactions. My opinion is that when it comes to lowering excess estrogens and reducing risk of breast, endometrial, and cervical cancer, effective lifestyle and nutritional strategies are infinitely less risky than lesser-known prescription medications. The Solution: The Gottfried Protocol for Excess Estrogen Step 1: Targeted Lifestyle Changes and Nutraceuticals Reduce alcohol. We know that alcohol raises your level of estrogen and can disrupt the function of the liver. If you have five or more symptoms of excess estrogen from the questionnaire in chapter 1, I recommend fewer than four servings a week. Better yet, stick to a glass of wine only on a special occasion, and you’ll be good to go. Yet Japanese women lower their estradiol levels with green tea, suggesting that race modifies your estrogen metabolism, perhaps explaining why Japanese women have a lower risk of breast cancer. As I hope I’ve shown you, endocrine disruptors such as bisphenol-A and phthalates can cause havoc. Buy organic when you can, especially fruits and vegetables that don’t have skin you have to peel. After menopause, consumption of red meat can increase your breast cancer risk by 22 percent. Perhaps the advice of your grandmother was spot on: consumption of prunes has been shown to reduce 16- alpha-hydroxy-estrone, the “less-good” estrogen associated with breast and endometrial cancer. We know that increased fiber will lower your estrogen levels and likely reduce your risk of breast cancer. Even with seven or more servings of fresh fruits and vegetables per day, most women need medicinal fiber, taken as a supplement. If you are obese or overweight, weight loss will reduce your excess estrogen levels and lower your risk of breast cancer and other conditions. Exercise decreases estrogen levels, lowers risk of breast cancer, and helps you make more of the good estrogens. Blind women have a much higher production of melatonin than women with normal eyesight do, and their risk of breast cancer is 50 percent lower. She overworks, overeats, overdrinks, overdiets, and overprovides to her two young kids and husband. Her blood pressure crept up since her first child, and she never lost the baby weight. Other symptoms of excess estrogen include mood swings, headaches, rosacea, heavy periods, and bloating. I suspected the excess estrogen was related to the high stress of grueling work combined with the demands of motherhood. She took a six- week mental health leave from her job and began an exercise regimen of Pilates and the elliptical trainer four days a week.

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Using this procedure it has been possible to show that very little [18F] fluorodopa is concentrated in the striatum of Parkinsonian patients generic raloxifene 60 mg with visa menstruation after childbirth, compared with normals (Fig buy raloxifene 60mg with amex women's health questions answered. The injection and subsequent detection of an appropriately labelled ligand can give an indication of the density of the receptors to which it is bound generic raloxifene 60 mg with mastercard women's health clinic greenville tx. As with any binding study the validity of the approach depends on the specificity of the ligand for its receptor. The difference between these two levels should in fact increase as unbound drug is lost (excreted). To determine the precise number of receptors and see if that varies from brain to brain (e. Normally the estimation of receptor number requires a measure of specific binding at two or more ligand concentrations under equilibrium conditions (see Chapter 3), which will clearly be difficult in vivo, not least because the effect of different doses may be unacceptable to the patient or subject. It must also be remembered that much of the in vivo binding can be to presynaptic receptors and uptake sites as well as postsynaptic receptors, although drugs specific for those sites can be used to label nerve terminals. Good correlations between the analgesic potency of morphine derivatives and displacement of the labelled morphine antagonist, naloxone, helped not only to formulate the concept of opioid receptors and hence of endogenous opioids to occupy them but also the actual discovery of the enkephalins. Displacement of labelled diazepam by a wide range of other benzodiazepines, in an order in keeping with their clinical efficiency as anxiolytics, led to the realisation of endogenous benzodiazepine receptors. Unfortunately a significant correlation between the clinical efficacy and a particular pharmacological effect of a range of drugs may give the impression that that is the only way in which that disorder may be treated. When drugs are evaluated for therapy in a peripheral malfunction, the tendency is to try to show that they work through different mechanisms. Indeed it is considered desirable, if not essential, to develop anti-hypertensive drugs with different actions, e. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then convulsions are a very basic form of activity common to most species and epileptic seizures that are characterised by behavioural rather than motor symptoms are more difficult to reproduce in animals. It is a statement of the obvious to say that we cannot tell when a rat is anxious or depressed, assuming that they can even experience such human reactions, but they can be subjected to conditions that would make us anxious or depressed. These problems are well known to experimental psychopharmacologists whose studies are becoming more sophisticated and, hopefully, more appropriate and predictive. This may be achieved by giving the precursor, if it crosses the blood-brain barrier. Thus if synthesis is a complicated multi- stage process or is controlled by the availability of enzymes that are already reduced or working maximally in remaining neurons, this approach may prove difficult. Many of the problems associated with the above approaches may be circumvented by administering an appropriate agonist. It would be counterproductive if the drug activated the presynaptic autoreceptors unless they happen to augment release. It may be possible to reduce the neuronal uptake of a precursor if this requires a specific transport mechanism. This is most likely to be achieved by stimulating inhibitory pre- synaptic autoreceptors (2a). As with agonists, these have the advantage that they can be designed to have a long half-life and act specifically on one type of receptor. In fact this approach has proved valuable in treating the peripheral neuro- muscular disorder of myasthenia gravis which presents as a muscle weakness caused by insufficient cholinergic activity at skeletal neuromuscular junctions. In respect of drug therapy, Parkinsonism presented with a number of advantageous features that are unlikely to be repeated in other conditions. Even so, long-term therapy with levodopa has not been without its problems and disappointments and highlights the difficulties of replacement therapy. The main features are: (1) Slowness and loss of movements known as bradykinesia or akinesia (2) Muscle stiffness and rigidity (3) Tremor of the limbs mainly at rest (but not in sleep) These result in a shuffling gait, an inability to initiate even simple movements like turning, a stooped posture and micrographia (small handwriting). It is a slowly pro- gressing degenerative disease affecting, at most, some 1% of the population above 55 years. The scheme to be outlined should, however, be regarded as a working template rather than fully proven fact but there is much evidence for it (Fig. The axons of both pathways arise from the medium spiny neurons that constitute 80% of striatal cells. The assumption is that the thalamo-cortical pathway can then function properly and movement is normal. So how can the abnormal pattern of striatal activity that causes akinesia be restored to normal? Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It is generally accepted that the improvement is very good in 35% of patients, good in 30% and moderate in 30% with some (55%) not really responding. Presumably conversion must take place in other neurons or as dopa crosses the blood-brain barrier. Unfortunately levodopa (only the levo form of dopa is active) has a very short plasma half-life (‰t) of 1‰±2 hours. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. A patient may be walking fairly well but then become suddenly akinetic and fixed before quickly moving again. These effects could result from the progression of the disease but as they are a feature of levodopa therapy a change in the central response to levodopa or changes in its peripheral kinetics are more likely. The latter does not occur since the maximum plasma concentration, the time to reach it and the plasma half-life are still similar after 10 years of treatment to those achieved initially, although continuous infusion of dopa can smooth out the swings. Attention has been given to the possibility that some of the above motor effects may arise from a metabolite of levodopa. Pathway activity: ---- low; Ð normal; high Ð less effective in combination unless given in high doses that could be inappropriate clinically (Treseder, Jackson and Jenner 2000). Since D2 (but not D1) receptors are expressed on neurons of the Ind Path, then D2 agonists will have the same effect on this pathway as levodopa and overcome the hypokinesia. Conversely, the absence of D1 receptors on the Ind Path explains why their agonists cannot influence it and so appear unable to reduce hypokinesia. There are as many D1 as D2 receptors in the striatum and it is unlikely that they are all redundant. Unfortunately few specific full D1 agonists have been available for evaluation until recently (see Hagan et al. Some show promise in both animal models and humans, although the reported absence of dyskinesias is perhaps surprising in view of the considered role of D1 receptors in their initiation (see above). Never- theless, treatment with specific D1 and D2 agonists in controlled combinations could be useful. Views are conditioned by the knowledge that the disorder is progressive, requiring long-term therapy and tempered by the cost of some agonists. Perhaps the consensus now is to start therapy as late as possible, keep it to the minimum and only increase dose or add drugs as is absolutely necessary. There is a developing consensus that since levodopa so frequently causes motor complications (e.

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