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By L. Berek. Mississippi University for Women.

The design of drugs based on biochemical leads remains a highly sophis- ticated endeavor order viagra 25mg free shipping, light-years removed from the random screening of sulfonamide dyes in which it has its origin order 75 mg viagra free shipping. However, of the approximately 10200 “small” organic molecules that could theoretically exist in our world (1052 of which are drug- like molecules), many would be purely synthetic substances that do not occur naturally. The concept of rational drug design (in contrast to its logical counterpart, irrational drug design) implies that the disease under consideration is understood at some funda- mental molecular level and that this understanding can be exploited for purposes of drug design. Such an understanding would facilitate the design of purely synthetic mol- ecules as putative drugs. Although this ideal of rational drug design has been pursued for many years (see section 3. Recognizing its chemical similarity to iodine, French physicians immediately exploited it as an iodine alternative for the treat- ment of numerous conditions, including syphilis and thyroid goitre. Although no bene- ficial effects were reported for either bromine or its potassium salt, their widespread use persisted and eventually the depressant effect of potassium bromide on the nervous system, so-called ivresse bromurique, was recognized. However, it was a report in the German literature concerning bromide’s ability to induce impotence and hyposexuality, rather than ivresse bromurique, which lead to its discovery as an anticonvulsant. In 1857, Sir Charles Locock, the physician accoucheur to Queen Victoria, ascrib- ing to the then prevalent view that epilepsy arose from excessive sexuality, introduced bromide as an anaphrodisiac to suppress the supposed hypersexuality of epileptics. Although side effects had been considerable (and included psychoses and serious skin rashes), bromides were successful in 13 of the 14 patients treated. On 11 May 1857, at a meeting of the Royal Medical and Chirurgical Society, Locock proudly reported his success in treating “hypersexual” epilepsies with bromides. He argued that logical and rational drug development had finally been achieved for the time: epilepsy arises from excessive sexuality; potassium bromide suppresses sexual- ity; therefore, potassium bromide successfully treats epilepsy. In reality, it was little more than yet another serendipitous discovery, since hypersexuality has absolutely nothing to do with epilepsy. Regardless of the flawed reasoning, bromides were a major step forward in the treatment of epilepsy and their use persisted until the introduction of phenobarbital in 1912. Rational drug design is an iterative process, dependent upon feedback loops and new information. When the drug designer makes the first prototype molecule, this molecule becomes a probe with which to test the drug design hypotheses. The molecule can then be further designed and refined to better improve its ability to dock with the receptor site and elicit a biological response. This cycle of “design–test–redesign–retest” can go on for several iterations until the optimized molecule is achieved. The successful ratio- nal design of a drug is similar to solving a major puzzle using your wits and wisdom. The macromolecules involved in the disease have been determined; the structures of these macromolecules have been ascertained using X-ray crystallography and/or computer-aided molecular design; a small organic molecule capable of binding to the macromolecule has been cleverly designed; a synthesis for this small organic molecule has been devised; and biological testing has confirmed the bioactivity of the small organic molecule. Despite protestations from the “naysayers” who despondently claim that all drugs are discovered by serendipity, there is an increasing number of examples that exemplify the successes and practical utility of rational drug design. Perhaps one of the earliest exam- ples is the discovery of cimetidine, an H2-antagonist drug used for the treatment of peptic ulcer disease. Even though the complete structure of the receptor was not fully appreciated, the careful manipulation of the molecule’s physicochemical properties (based in part upon an understanding of the underlying histamine molecule) led to the discovery of cimetidine. These structural studies greatly facilitated the process of rational drug design, ultimately leading to six rationally designed therapeutics: amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and lopinavir. As evidenced by the aforementioned examples, structural chemistry is front and center in enabling rational drug design. Molecular modeling, also called quantum phar- macology, has been instrumental to many of the advances in rational drug design. Some cynics are quick to pontificate that there are no drugs that have been designed by com- puters. Strictly speaking, this is true; likewise, no drugs have been designed by a nuclear magnetic resonance spectrometer. However, computers are immensely valuable in advancing and progressing the art and science of rational drug design. Until the dawning of the 20th century, it was believed that all reality was eminently describable through Newton’s Laws. However, through the work of Bohr and others, it was eventually realized that classical Newtonian mechanics failed at the atomic level of reality—atoms did not behave like billiard balls. An alternative approach was needed for the quantitative evaluation of molecular phe- nomena. In the first three decades of the 20th century, there occurred many significant advances in theoretical physics and physical philosophy. Planck showed that energy is emitted in the form of discrete particles or quanta; Einstein expanded upon this theory with the proposal that an atom emits radiant energy only in quanta, and that this energy is related to the mass and to the velocity of the light; Schrödinger incorporated these evolving ideas of the new quantum theory into an equation that described the wave behavior of a particle (wave mechanics); Heisenberg formulated a complete, self- consistent theory of quantum physics, known as matrix mechanics; and Dirac showed that Schrödinger’s wave mechanics and Heisenberg’s matrix mechanics were special cases of a larger operator theory. The capacity for a robust, mathematical description of molecular-level phenomena seemed to be at hand. Since the Schrödinger equation (which lies at the mathematical heart of quantum mechanics) permitted quantitative agreement with experiment at the atomic level, the physicists of the 1930s predicted an end to the experimental sciences, including biology, suggesting that they would merely become a branch of applied physics and mathematics. Although in princi- ple the Schrödinger equation afforded a complete description of Nature, in practice it could not be solved for the large molecules of medical and pharmacological interest.

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When these are violently removed purchase viagra 25 mg with visa, the natural order viagra 50 mg without prescription, proximate effect is, that they will usually come forth again, usually to be subjected again, in vain, to a similar, painful, cruel treatment. But even if they could be rooted out in this way, it would merely have the consequence, that the figwart-disease, after having been deprived of the, local symptom which acts vicariously for the internal ailment, would appear in other and much worse ways, in secondary ailments; for the figwart-miasm, which in the whole organism, has been in no way diminished, either by the external destruction of the above-mentioned excrescences, or by the mercury which has been used internally, and which is in no way appropriate to sycosis. Besides the undermining of the general health by mercury, which in this disease can only do injury, and which is given mostly in very large doses and in the most active preparations, similar excrescent then break out in other parts of the body, either whitish, spongy, sensitive, flat elevations, in the cavity of the mouth on the tongue, the palate and the lips, or as large, raised, brown and dry tubercles in the axillae, on the neck, on the scalp, etc. They yield either to a dose of one drop of fresh parsley-juice, when this is indicated by a frequent urgency to urinate, or a small dose of cannabis, of cantharides, or of the copaiva balm, according to their different constitution and the other ailments attending it. These should, however, be always used in the higher and dynamizations (potencies), unless a psora, slumbering in the body of the patient, has been developed by means of a strongly affecting, irritating or weakening treatment by Allopathic physicians. In such a case frequently secondary gonorrhoeas remain, which can only be cured by an anti- psoric treatment. It is not necessary to use any external application, except in the most inveterate and difficult cases, when the larger figwarts may be moistened. But if the patient was at the same time affected with another chronic ailment, as is usual after the violent treatment of figwarts by Allopathic physicians, then we often find developed psora** complicated with sycosis, when the psora, as is often the case, was latent before in the patient. At times, when a badly treated case of venereal chancre disease had preceded, both these miasmata are conjoined in a threefold complication with syphilis. Then it is necessary first to come to the assistance of the most afflicted part, the psora, with the specific anti-psoric remedies given below, and then to make use of the remedies for sycosis, before the proper dose of the best preparation of mercury, as will be described below, is given against the syphilis; the same alternating treatment may be continued, until a complete cure is effected. Only, each one of these three kinds of medicine must be given the proper time to complete its action. The second chronic miasma, which is more widely spread than the figwart-disease, and which for three and a half [now four] centuries has been the source of many other chronic ailments, is the miasm of the venereal disease proper, the chancre-disease (syphilis). This disease only causes difficulties in its cure, if it is entangled (complicated) with a psora that has been already far developed - with sycosis it is complicated but rarely, but then usually at the same time with psora. When syphilis is still alone and attended with its associated local symptom, the chancre, or at least if this has been removed by external applications, it is still associated with the other local symptom, which in a similar manner acts vicariously for the internal disorder, the bubo. The chancre appears, after an impure coition, usually between the seventh and fourteenth days, rarely sooner or later, mostly on the member infected with the miasma, first as a little pustule, which changes into an impure ulcer with raised borders and stinging pains, which if not cured remains standing on the same place during manÕs lifetime, only increasing with the years, while the secondary symptoms of the venereal disease, syphilis, cannot break out as long as it exists. In order to help in such a case, the Allopathic physician destroys this chancre, by means of corroding, cauterizing and desiccating substances, wrongly conceiving it to be a sore arising merely from without through a local infection, thus holding it to be a merely local ulcer, such also it is declared to be in their writings. They falsely suppose, that when it appears, no internal venereal disease is as yet to be thought of, so that when locally exterminating the chancre, they suppose that they remove all the venereal disease from the patient at once, if only he will not permit this ulcer to remain too long in its place, so that the absorbent vessels do not get time to transfer the poison into the internal organism, and so cause by delay a general infection of the system with syphilis. They evidently do not know, that the venereal infection of the whole body commenced with the very moment of the impure coition, and was already completed before the appearance of the chancre. The Allopathic doctor destroys in his blindness, through local applications, the vicarious external symptom (the chancre ulcer), which kind nature intended for the alleviation of the internal extensive venereal general disease; and so he inexorably compels the organism to replace the destroyed first substitute of the internal venereal malady (the chancre) by a far more painful substitute, the bubo, which hastens onward to suppuration; and when the Allopath, as is usually the case, also drives out this bubo through his injurious treatment, then nature finds itself compelled to develop the internal malady through far more troublesome secondary ailments, through the outbreak of the whole chronic syphilis, and nature accomplishes this, though slowly, (frequently not before several months have elapsed), but with unfailing certainty. He relates that Petit cut off a part of the labia of a woman, who had thereon for a few days a venereal chancre; the wound healed, but syphilis, nevertheless, broke out. The disease is not cured except when through the effect of the internal remedy alone, the chancre is cured; but it is fully extinguished, as soon as through the action of the internally operating medicine alone (without the addition of any external remedy) the chancre is completely cured, without leaving any trace of its former presence. But whenever anyone is so imprudent, as to destroy this vicarious local symptom, the organism is ready to cause the internal syphilis to break out into the venereal disease, since the general venereal disease dwells in the body from the first moment of infection. For in the spot, into which at the impure coition the syphilitic miasma had been first rubbed in and had been caught, it is, in the same moment, no more local: the whole living body has already received (perceived) its presence, the miasma has already become the property of the whole organism. All wiping off and washing off, however speedy, and with whatever fluid this be done (and as we have seen, even the exsection of the part affected), is too late - is in vain. There is not to be perceived, indeed, any morbid transmutation in that spot during the first days, but the specific venereal transformation takes place in the internal of the body irresistibly, from the first moment of infection until syphilis has developed itself throughout the whole body, and only then (not before), nature, loaded down by the internal malady, brings forth the local symptom peculiar to this malady, the chancre, usually in the place first infected; and this symptom is intended by nature to soothe the internal completed malady. Therefore also, the cure of the venereal disease is effected most easily and in the most convincing manner, so long as the chancre (the bubo) has not yet been driven, out by local applications, so long as the chancre (the bubo) still remains unchanged, as a vicarious symptom of the internal syphilis. In this state, and especially when it is not yet complicated with psora, it may be asserted from manifold experience and with good reason, that there is on earth no chronic miasma, no chronic disease springing from a miasma, which is more curable and more easily curable than this. In a few days after taking such a dose of mercury, the chancre (without any external application) becomes a clean sore with a little mild pus, and heals of itself - as a convincing proof, that the venereal malady is also fully extinguished within; and it does not leave behind the least scar, or the least spot, showing any other color than the other healthy skin. But the chancre, which is not treated with external application, would never heal, if the internal syphilis had not been already annihilated and extinguished by the dose of mercury; for so long as it exists in its place, it is the natural and unmistakable proof of even the least remainder of an existing syphilis. I have, indeed in the second edition of the first part of Materia Medica Pura (Dresden, 1822), described the preparation of the pure semi-oxide of mercury, and I still consider this to be one of the most excellent anti-syphilitic medicines; but it is difficult to prepare it in sufficient purity. In order, therefore, to reach this wished for goal in a still simpler manner, free from all detours, and yet just as perfectly (for in the preparation of medicines we cannot proceed in too simple a manner), it is best to proceed in the way given below, so that one grain of quite pure running quick-silver is triturated three times, with 100 grains of sugar of milk each time, up to the millionth attenuation, in three hours, and one grain of this third trituration is dissolved, and then potentized through twenty-seven diluting phials up to (x) the decillionth degree, as is taught at the end of this volume, with respect to the dynamization of the other dry medicines. I formerly used the billionth dynamization (ii) of this preparation in I, 2 or 3 fine pellets moistened with this dilution, as a dose, and this was done successfully for such cures; although the preparation of the higher potencies (iv, vi, viii), and finally the decillionth potency (x), show some advantages, in their quick, penetrating and yet mild action for this purpose; but in cases where a second or third dose (however seldom needed) should be found necessary, a lower potency may then be taken. But just as incontrovertibly does it follow that every disappearance of the chancre (or the bubo) owing to a mere local destruction, since it was no real cure founded on the extirpation of the internal venereal disease through the internally given appropriate mercury medicine, leaves to us the certainty that the syphilis remains behind; and every one who supposes himself healed by any such merely local, pretended cure, is to be, considered as much venereally diseased as he was before the destruction of the chancre. The second state in which, as mentioned above, syphilis may have to be treated, is the rare case when an otherwise healthy person, affected with no other chronic disease (and thus without any developed psora), has experienced this injudicious driving away of the chancre through local applications, effected by an ordinary physician in a short time and without attacking the organism overmuch with internal and external remedies. Even in such a case, - as we have not as yet to combat any complication with psora - all outbreaks of the secondary venereal disease may be avoided, and the man may be freed from every trace of the venereal miasma through the before-mentioned simple internal cure effected by a like dose of the above mentioned mercurial medicine - although the certainty of his cure can no more be so manifestly proved as if the chancre had still been in existence during this internal cure, and as if it had become a mild ulcer simply through this internal remedy, and had been thus manifestly cured of itself.

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Leuprolide acetate (Lupron) is an agent that is frequently used for these conditions trusted viagra 25 mg. Although no epidemiological studies are published of infants born following Lupon therapy generic viagra 25mg fast delivery, it is 92 Endocrine disorders, contraception, and hormone therapy during pregnancy unlikely that the risk of congenital anomalies is high following exposure to this drug during pregnancy (Friedman and Polifka, 2006). Typically, administration is begun in the luteal phase of the cycle, when a patient may be in the early stage of a pregnancy. No epidemiologic studies are published on the risk malformations in the offspring of women treated with this drug during pregnancy. Congenital anomalies were not increased in frequency among infants born to women given ethinyl estradiol during embryogenesis or at any time during pregnancy (Heinonen et al. Results from two other studies of ethinyl estradiol use during pregnancy showed that it was not associated with an increased risk of congenital anomalies (Kullander and Kallen, 1976; Spira et al. Congenital anomalies were not increased in frequency in teratology studies of three species of nonhuman primates given large doses of ethinyl estradiol during pregnancy (Hendrickx et al. An increased frequency of intrauterine deaths was observed at doses that were also mater- nally lethal in one monkey species studied. Miscarriages occurred more frequently among monkeys given approximately 100 times the amount of ethinyl estradiol included in oral contraceptive dose regimens (Prahalada and Hendrickx, 1983). In rodent teratol- ogy studies, no increase in the frequency of congenital anomalies after embryonic treat- ment was found, but early intrauterine deaths were increased in frequency at the high- est doses (Chemnitius et al. Among 614 infants born to women who used estrogenic compounds during gestation, an increase in certain congenital anomalies was found – cardiovascular, eye and ear defects, and Down’s syndrome (Heinonen et al. However, this association was reevaluated in another report, and the link between estrogens and cardiac malformations was not borne out (Wiseman and Dodds- Smith, 1984). The malignancy was diagnosed among females 7–30 years old, with a median age of 19 years. Nonmalignant abnormalities, especially adenosis, are common among the daughters of pregnant women who were treated with diethylstilbestrol. Gross structural abnormal- ities of the cervix or vagina are identified in about one quarter and abnormalities of the vaginal epithelium in one-third to one-half of women whose mothers took diethylstilbe- strol during gestation (Bibbo, 1979; Herbst et al. T-shaped uterus, constricting bands of the uterine cavity, uterine hypoplasia or paraovarian cysts also occur with increased frequency among females exposed in utero (Kaufman et al. Preterm delivery, spontaneous abortions, and ectopic pregnancy occurred with increased frequency in females whose mothers took diethylstilbestrol during gestation (Barnes et al. Progesterone is the only natural progestin and is not well absorbed by the oral route unless given in micronized form. Synthetic progestins structurally related to proges- terone are more commonly used. Low-dose progestins are used for contraception with an estrogen, and are used in the therapy of menstrual disorders at higher doses. In the 1960s and 1970s much higher doses of progesterones were used for oral contraception (Schardein, 1985), and are currently used to treat threatened abortion. In a review, female pseudohermaphroditism, including various degrees of clitoral hypertrophy with or without labioscrotal fusion, was reported in several-hundred children born to women treated with progesterone analogs in high doses during early pregnancy (Schardein, 1980, 1985). Fewer than 100 cases of male pseudohermaphroditism have been reported, and the anomaly is usually isolated hypospadias (Aarskog, 1979; Mau, 1981; Schardein, 1985). Exposure to progestational agents during embryogenesis, therefore, seems not to increase substantially the risk for nongenital congenital anomalies in infants born to treated women. Among more than 100 94 Endocrine disorders, contraception, and hormone therapy during pregnancy infants born to women who took norethindrone during the first trimester, congenital anomalies were not increased in frequency, or in more than 100 infants whose mothers took this drug after the first trimester (Heinonen et al. Two case–control stud- ies of 365 infants with congenital anomalies yielded similar results (Kullander and Kallen, 1976; Spira et al. Several cases were reported in which use of norethin- drone during pregnancy, at doses that were much greater than those used in contempo- rary practice, was associated with masculinization of the external female genitalia (cli- toral hypertrophy with or without labioscrotal fusion), but internal genitalia and subse- quent pubertal development were normal (Schardein, 1980, 1985). The genital anom- alies observed include various degrees of masculinization (Wilkins et al. Clitoral hypertrophy may occur in exposures any time after the 8th embryonic week, but labio- scrotal fusion is limited to exposure during the 8th to 13th embryonic weeks. The risk for pseudohermaphroditism among female infants born to women who took norethin- drone during pregnancy is probably less than 1 percent (Bongiovanni and McPadden, 1960; Ishizuka et al. No increased risk of fetal sexual malformation was reported in a meta-analysis of published reports of women exposed to sex hormones after conception (Ramin-Wilms et al. Masculinized external female genitalia were observed in several species of experimental animals, including nonhuman primates, following maternal treatment with high doses of norethindrone during pregnancy (Hendrickx et al. Nongenital malformations were not increased in frequency among three species of nonhuman primates given up to 100 times the oral contraceptive dose of norethindrone during pregnancy in combination with ethinyl estradiol (Hendrickx et al. Contemporary low-dose therapy with norethindrone is not a risk factor for genital mal- formations, and probably poses no increased risk for congenital anomalies in general. Congenital anomalies were not increased in frequency among more than 150 infants born to women who took norethynodrel during the first trimester, or among more than 150 women who took the drug after the first trimester (Heinonen et al. Virilization of female fetuses has not been reported in the human; however, female rat fetuses born to mothers that received several-hundred times the human contraceptive dose had masculinized external genitalia (Kawashima et al.

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