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Fenﬂuramine can alter time perceptions and snap moods from one extreme to another order naltrexone overnight delivery treatment xeroderma pigmentosum. In humans fenﬂuramine has been found effective for diminishing panic at- tacks but has had mixed success when used to treat obsessive behavior best purchase for naltrexone treatment depression. Ex- perimental use against schizophrenia has been unsuccessful naltrexone 50 mg fast delivery medications in carry on luggage, with patients worsening under the drug regimen. A longer study (11 months) found the drug provided only limited help to autistic children, and a still longer study (27 months) found such long-term administration impractical due to unwanted effects and due to changes in the autistic children’s lives. A scientiﬁc review of such studies concluded that the drug’s potential nonethe- less merited further trials. Fenﬂuramine is a drug of many effects, but medically its primary use has been for weight loss. Studies consistently indicate the drug’s effectiveness for Fenﬂuramine 161 that purpose. Other unwanted actions can include headache, peevish feel- ings, dizziness, tiredness, nausea, vomiting, diarrhea, and frequent urination. Experience indicates that persons need to be weaned off the drug; cold turkey cessation can cause depression or even a medical emergency called “serotonin syndrome. Experimental animals have shown little interest in receiving fenﬂuramine doses, a classic sign of small addiction potential. Researchers discovered that fenﬂuramine could be administered in combi- nation with phentermine, an anorectic that works in a different way. Rat experiments showed that fen-phen reduces food intake far more than either drug can do alone, and experience conﬁrmed the same kind of multiplier effect in humans. Such impact allows persons to take lower doses than would be necessary with either drug alone, thereby minimizing any undesired actions of the drugs. Phentermine counteracts fenﬂuramine’s common sedative quality, allowing users to function more normally. Weight control is one of the most challenging conditions encountered by medical practitioners, and fen-phen became tremendously popular. One study found that almost 90% of 88 obesity patients taking fenﬂuramine or the closely related drug dexfenﬂuramine were also taking phentermine and that almost 33% of the 88 patients lacked obesity levels for which these or other anti- obesity drugs were an appropriate treatment. Suddenly, after many years of wide use without much report of alarming adverse effects, in 1997 accounts began associating fenﬂuramine with rapidly developing fatal heart valve disorders. Food and Drug Administra- tion asked the manufacturer to withdraw fenﬂuramine and dexfenﬂuramine from the market. Hot debate then erupted in medical circles about whether heart disease was caused by fenﬂuramine, phentermine, or the two drugs in combination. Studies purported to conﬁrm that the drugs alone or in combi- nation really did create heart valve afﬂiction. Highly knowledgeable and distin- guished medical authorities took differing stances on the question and raged at one another in scientiﬁc journals. An issue also arose of whether fen-phen caused fatal pulmonary hypertension (high pressure in blood circulation to lungs), with researchers reminding fellow scientists that fenﬂuramine works in ways similar to the anorectic drug aminorex, which had been linked to pulmonary hypertension in the 1960s and was thereafter withdrawn from the market. Particular concern was expressed about fenﬂuramine’s impact on pul- 162 Fenﬂuramine monary hypertension and edema among users living or traveling in high al- titudes. Phentermine is a monoamine oxidase inhibitor, and despite a lack of reports about acute adverse interaction with fenﬂuramine, some researchers noted that a more chronic interaction could cause the kind of heart and pul- monary damage that was appearing. Researchers began reporting organic brain damage from fenﬂuramine and dexfenﬂuramine in animal experiments. Investigators now noticed many instances of psychiatric disturbance among persons taking fenﬂuramine and noted that the disorders implied organic brain damage. The drug was also linked to human angina pectoris (a fright- ening sensation of pain and suffocation typically caused by insufﬁcient oxygen supply to the heart) and to a case of a gangrenous condition resulting in amputation of ﬁngers. As time passed, evidence appeared that the heart valve and pulmonary hypertension disorders could stabilize and even improve after patients stopped taking fen-phen. Scientiﬁc debate continues about fenﬂura- mine’s role in heart ailments and pulmonary hypertension. Despite the beating that fen-phen took from the news media and from many scientists, researchers remain curious about whether the drug combination still has a role in medicine. Even though fenﬂuramine can cause depression, in- terest arose in possible psychotherapeutic uses.
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Because the density of the gas is negligible compared to the density of tissue discount naltrexone 50 mg on-line medicine 968, the volume of the swim bladder required to reduce the density of the ﬁsh is smaller than that of the porous bone generic 50 mg naltrexone overnight delivery medications used to treat ptsd. For exam- ple 50 mg naltrexone otc medicine 7767, to achieve the density reduction calculated in the preceding example, the volume of the bladder is only about 4% of the total volume of the ﬁsh (see Exercise 7-6). The cuttleﬁsh alters its density by injecting or withdrawing ﬂuid from its porous bone. Fish with swim bladders alter their density by changing the amount of gas in the bladder. A molecule in the interior of the liquid is surrounded by an equal number of neighboring molecules in all directions. Therefore, the net resultant inter- molecular force on an interior molecule is zero. Because there are no molecules above the surface, a molecule here is pulled predominantly in one direction, toward the interior of the surface. This causes the surface of a liquid to con- tract and behave somewhat like a stretched membrane. This contracting ten- dency results in a surface tension that resists an increase in the free surface of the liquid. It can be shown (see reference [7-7]) that surface tension is a force acting tangential to the surface, normal to a line of unit length on the surface (Fig. At the same time, however, these molecules are also subject to the attractive cohesive force exerted by the liquid, which pulls the molecules in the opposite direction. If the adhesive force is greater than the cohesive force, the liquid wets the container wall, and the liquid surface near the wall is curved upward. If the adhesion is greater than the cohesion, a liquid in a narrow tube will rise to a speciﬁc height h (see Fig. Another consequence of surface tension is the tendency of liquid to assume a spherical shape. Such an uncontained liquid forms into a sphere that can be noted in the shape of raindrops. The pressure inside the spherical liquid drop is 92 Chapter 7 Fluids higher than the pressure outside. In other words, to create gas bubble of radius R in a liquid with surface tension T, the pressure of the gas injected into the liquid must be greater than the pressure of the surrounding liquid by P as given in Eq. As will be shown in the following sections, the eﬀects of surface tension are evident in many areas relevant to the life sciences. These spaces act as capillaries and in part govern the motion of water through the soil. When water enters soil, it penetrates the spaces between the small particles and adheres to them. If the water did not adhere to the particles, it would run rapidly through the soil until it reached solid rock. Because of adhesion and the resulting capillary action, a signiﬁcant fraction of the water that enters the soil is retained by it. For a plant to withdraw this water, the roots must apply a negative pressure, or suction, to the moist soil. For example, if the eﬀective capillary radius of the soil is 10−3 cm, the pressure required to withdraw the water is 1. Because capillary action is inversely proportional to the diameter of the capillary, ﬁnely grained soil will hold water more tightly than soil of similar material with larger grains (see Fig. When all the pores of the soil are ﬁlled with water, the surface mois- ture tension is at its lowest value. In other words, under these conditions the required suction pressure produced by the plant roots to withdraw the water from the soil is the lowest. As the soil loses moisture, the remaining water tends to be bound into the narrower capillaries. In addition, as the moisture content decreases, sec- tions of water become isolated and tend to form droplets. If, for example, the radius of a droplet decreases to 10−5 cm, the pressure required to draw the water out of the droplet is about 14.
The notion was initially formulated by John Langley buy naltrexone without prescription treatment interventions, a British physiologist who worked on the biological properties of atropine (2 buy generic naltrexone 50 mg line symptoms iron deficiency. However naltrexone 50mg for sale treatment yeast infection, the actual term receptor was first intro- duced in 1907 by Paul Ehrlich, the famous pioneer of chemotherapy and immunochem- istry. His concepts of receptor binding (corpora non agunt nisi fixata—“compounds do not act unless bound”), bioactivation, the therapeutic index, and drug resistance are still valid in principle, though they have undergone considerable expansion and refinement. True receptors, that is, those initiating a chain of physicochemical events leading to a pharmacological response, have a diverse molecular nature. Among the well-described receptors, several classes of receptor molecules may be distinguished: 1. Lipoproteins or glycoproteins are the macromolecules that most commonly form receptors. They are often firmly embedded in the plasma membrane or cell-organelle membrane as intrinsic proteins (see section 7. At times, this renders their isolation and subsequent functional reconstitution difficult, as their structure may be dependent upon the surrounding membrane. Isolation of such a receptor molecule may cause its structural collapse, even to the extent that specific binding properties are lost. Many drugs exert their effects by specifically affecting enzymes involved in vital biochemical reactions (see section 8. Cell membranes contain “protein icebergs floating in a sea of lipid,” and many drug molecules do interact with cell membranes. Lipids intimately envelop proteins and thus may profoundly influence their structure and function. When one starts to work with a new class of molecules or a new tissue, it is important to use an extensive set of criteria for receptor identification in both in vitro and in vivo studies. The receptor should be present in the tissues in quantities commensurate with established receptor concentrations (10–100 pmol/g). The binding of a drug to its receptor should be saturable, with a binding equilibrium constant in the nanomolar range. However, it must be borne in mind that saturability is not identical with specificity. Binding kinetics should be proportional to the rate of the in vivo response and should yield an equilibrium constant equal to the dissociation rate constant divided by the association rate constant. Wherever applicable, binding should be stereospecific; but the fulfilment of this cri- terion is not absolute proof that the site being investigated is a receptor. The receptor should be isolated from an organ or tissue relevant to the disease process under investigation. Hallucinogen binding to liver tissue, for example, is unlikely to indicate more than the presence of a metabolizing enzyme. It is desirable that the order of drug binding to a receptor preparation in a related series of drugs be the same as the order of their clinical or at least their in vivo activity. Failure to meet even one of these criteria jeopardizes the identification of the receptor. Even when all of the criteria are fulfilled, extreme caution in data interpretation is still mandatory. As discussed above, a macromolecule should be “worthy and capable of being targeted for drug design. A macromolecule that can be usefully attacked for purposes of drug design is termed a druggable target. As discussed earlier, covalent and noncovalent bonds are both based on electronic interactions but differ greatly in their stabilities, which are expressed in terms of bond dissociation energies. Although there is no direct correlation between drug–receptor binding energy and drug potency, the energy values provide an approximate estimate of the ease of formation, the ease of disruption, and the relative strengths of various intermolecular interaction types. It is generally not desirable to have a drug covalently linked to its receptor, since such an interaction would persist for a long period of time. Such prolonged interactions tend to lead to dif- ficulties with lengthy drug half-lives and potentially to toxicity problems. Accordingly, the only receptors to which covalent binding is desirable are those that belong to exoge- nous (or “non-self”) targets, including viruses, bacteria, parasites, or tumours (see sec- tions 9. In short, it is okay for a drug to covalently bind to a disease-causing bacterium, but it is not okay for a drug to covalently bind to a diseased liver.
Moreover cheap 50mg naltrexone with visa treatment uti infection, radiotherapy may present a significant risk to the fetus (Petrek effective 50 mg naltrexone medicine 5852, 1994) discount naltrexone 50 mg without prescription treatment hemorrhoids. These guidelines are consistent with the recommendations made in 2005 (Pentheroudakis and Pavlidis, 2006). Chemotherapy is frequently recommended for either adjunctive therapy or treatment in advanced cases. Women with axillary lymph node metastases appear to be the best candidates for adjunctive chemotherapy (Barnavon and Wallack, 1990). As detailed pre- viously in this chapter, chemotherapy with currently available antineoplastic agents car- ries an increased risk of congenital anomalies with first-trimester exposure, and fetal growth retardation is the major risk in the latter two-thirds of pregnancy, although long- term effects are unknown. Special considerations 143 The efficacy of breast carcinoma treatment during pregnancy appears to be enhanced little, if at all, by therapeutic abortion and prophylactic oophorectomy (Donegan, 1986). Therapeutic abortion might be a consideration if radiotherapy is deemed neces- sary or if chemotherapy is necessary during the first trimester. However, with proper shielding and focused radiotherapy above the maternal diaphram, it may be possible to minimize the adverse effects of radiation on the fetus (Pentheroudakis and Pavlidis, 2006). Leukemia Acute leukemia is extremely rare during pregnancy, occurring in approximately one in 100 000 pregnancies. However, it is among the most common neoplasms in young women (Caliguri and Mayer, 1989; Catanzarite and Ferguson, 1984; Koren et al. Review of 72 cases of leukemia during pregnancy (13 separate reports), 64 (89 percent) women had acute leukemia and eight (11 percent) had chronic or other forms of leukemia (Caliguri and Mayer, 1989). The survival rate was approximately 75 percent in one report of 45 pregnant women with acute leukemia (Reynoso et al. Antineoplastic drugs most commonly used to treat chronic leukemia include antimetabolites (methotrexate, thioguanine, mercaptopurine, and cytarabine), anthracy- cline antibiotics (daunorubicin and doxorubicin), and plant alkaloids (vincristine). Therefore, all antineoplastics have a very high potential for production of birth defects during embryogenesis because this period is character- ized by the highest rate of cell division (hyperplasia) in a human’s life. The prognosis for survival in the untreated woman is extremely poor, with life expectancy of less than 3 months (Catanzarite and Ferguson, 1984; Hou and Song, Table 7. Therefore, chemotherapy should be initiated immediately (even during the first trimester) once the diagnosis of acute leukemia is made. Among a series of 58 infants born to pregnant women who had either acute myelo- cytic or lymphoblastic leukemia, there were 31 (53 percent) premature births (including five stillbirths), and 23 (43 percent) full-term infants (two of whom were of low birth weight) (Caliguri and Mayer, 1989). No studies have been published of congenital anomalies among the infants born to women with leukemia during pregnancy. No con- genital anomalies have been reported among the 13 fetuses exposed to chemotherapy for leukemia during the first trimester (Caliguri and Mayer, 1989). Lymphomas and Hodgkin’s disease An estimated 40 percent of malignant lymphomas are of the Hodgkin’s variety and are the most commonly encountered lymphoma among pregnant women, and occur among approximately one in 6000 pregnancies. As with breast carcinoma, pregnancy does not seem to affect the prognosis for Hodgkin’s disease (Lishner et al. Both leukemias and lymphomas are known to metastasize to the placenta, but the empirical risk is unknown. Treatment of Hodgkin’s lymphoma, like that of most other malignancies, depends on the stage of the disease and the gestational age at which the disease is diagnosed. Staging is of paramount importance, and pregnancy may interfere with the types of diagnostic studies that can be performed. Most diagnostic radiographic procedures not involving the abdomen or fetus can be accomplished, if necessary, with minimal risk to the con- ceptus. Staging laparotomy lymphomas is somewhat controversial and difficult, if not impossi- ble, to accomplish in the latter half of pregnancy because the large uterus obstructs the operating field (Bloss and Miller, 1995). For early stages of lymphomas in the first half of pregnancy, several options are avail- able. Obviously, therapeutic abortion is one consideration, although it is not always nec- essary. Modified radiotherapy can be utilized if done at a significant distance from the shielded pelvis, i. If chemotherapy is deemed necessary, it is best to wait until after the first trimester.