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By T. Gelford. Alcorn State University.

An increase in placental infarcts occurred in pregnant rats who received iproniazid dur- ing gestation (Poulson et al 30caps sleepwell overnight delivery. Decreased fertility was reported in the offspring of rats treated with nialamide (Tuchmann-Duplessis and Mercier-Parot discount 30caps sleepwell overnight delivery, 1963). No animal teratology studies have been published on the monoamine oxidase inhibitor, phenelzine. These agents are generally not used during pregnancy because of potential adverse maternal side effects, and are category C drugs. Failure to do so may result in hypertensive crisis (Yonkers and Cunningham, 1993). Importantly, monoamine oxidase inhibitors given with meperidine, or other similar agents, may cause hyperthermia (Yonkers and Cunningham, 1993). These drugs are continued only as long as the underlying cause of psychosis is present because 190 Psychotropic use during pregnancy of the tardive dyskinesia associated with these medications. Commonly used antipsychotics or neuroleptic agents, with the exception of clozapine (Box 10. These agents have numerous side effects including anticholinergic effects such as constipation, dryness, and orthostatic hypotension, and extrapyramidal side effects such as akathisia (Miller, 1996; Yonkers and Cunningham, 1993). Antipsychotics may cause transient neonatal side effects including withdrawal symp- toms and extrapyramidal dysfunction (hand posturing, tremors, and irritability) (Auerbach et al. Two major confounders make it problematic to evaluate possible associations of antipsychotics and congenital malformations. First, many of these agents are used for indications other than psychosis (hyperemesis, anxiety) where lower doses may be used (Yonkers and Cunningham, 1993). Second, the psychiatric disease itself may be associ- ated with an increased frequency of malformations (Elia et al. It has pharmacological properties similar to the piperazine phenothiazines, although it is not chemically related to them. Haloperidol is used as a major tranquilizer to treat psychosis, Tourette’s syndrome, mania, and severe hyperactivity. In a cohort study of 98 pregnant women who received haloperidol for hyperemesis gravi- darum (90 during early pregnancy), there were no obvious congenital anomalies or adverse fetal effects noted (van Waes and van de Velde, 1969). Among 56 infants whose mothers took haloperidol during the first trimester, the frequency of congenital anomalies was not increased (3, or 5. Two cases of newborns with limb reduction malformations after haloperidol exposure during the first trimester have been published (Dieulangard et al. The pertinence of animal studies to the clinical use of haloperidol in human pregnancy is unclear. No information on the use of this tricyclic antipsychotic during pregnancy in humans has been pub- lished. In mice and rats whose mothers were treated with loxapine during embryogene- sis, a low incidence of exencephaly and an increase in fetal loss was observed in only one mouse litter out of 20 studied (Mineshita et al. Phenothiazines Phenothiazines are related drugs with potent adrenergic-blocking action. Pharmacologic effects include central nervous system depression, prolonged effects of narcotic or hyp- notic drugs, and hypotensive, antiemetic and antispasmodic activity. Two well- described side effects – hypotension and extrapyramidal tract symptoms – of this drug need special attention. The frequency of congenital anomalies was not increased among 140 infants born to women exposed to this agent during the first trimester of pregnancy (Heinonen et al. In a cohort study of 264 pregnant women who took chlorpro- mazine for hyperemesis gravidarum in the first trimester, the frequency of congenital anomalies was not increased (Farkas and Farkas, 1971). One study reported an increase in the frequency of congenital anomalies in offspring exposed to chlorpromazine com- pared to controls (Rumeau-Rouquette et al.

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Thus 30 caps sleepwell with visa, in the millennia extending from antiquity to the mid-nineteenth century buy discount sleepwell 30 caps on line, epilepsy remained a medical condition surrounded by mystique—permitting charla- tanism, superstition, and quackery to prosper. After an emetic and 2 purgatives, he was given an enema containing antimony, bitters, rock salt, mallow leaves, violets, beet root, chamomile flowers, fennel seed, linseed, cinnamon, cardamom seed, saffron and aloes. A sneezing powder of hellebore root and one of cowslip flowers were administered to strengthen the king’s brain. Soothing drinks of barley water, licorice and sweet almond were given, as well as extracts of mint, thistle leaves, rue, and angelica. For external treatment, a plaster of Burgundy pitch and pigeon dung was liberally applied to the king’s feet. After continued bleeding and purging, to which were added melon seed, manna, slippery elm, black cherry water, and dissolved pearls, the king’s condition did not improve and, as an emergency measure, 40 drops of human skull extract were given to allay convulsions. As the king’s condition grew increasingly worse, the grand finale of Raleigh’s antidote, pearl julep, and ammonia water were pushed into the dying king’s mouth. Fortunately, by the mid 1800s times began to change, and over the subsequent 150 years substantial progress was made. Although advances were obviously being made, much of this drug discovery relied on serendipity rather than rational drug design. The discovery of the benzodiazepines is a good example of the importance of serendipity. In the early 1950s, following the accidental discovery of phenothiazines as antipsy- chotic agents, interest in tricyclic molecules as potential therapeutic agents for neurolog- ical and psychiatric disorders became widespread. Accordingly, in 1954, Sternbach of Hoffmann–La Roche laboratories decided to reinvestigate the synthetic chemistry of a series of tricyclic benzheptoxdiazine compounds upon which he had worked more than twenty years earlier. By reacting an alkyl halide with a variety of secondary amines, he prepared forty analogs, all of which were inactive as muscle relaxants and sedatives. When additional chemical studies revealed that these compounds were really quinazoline- 3-oxides rather than benzheptoxdiazines, the project was summarily abandoned in 1955. Nearly two years later, a colleague at Hoffmann–La Roche discovered an untested crystalline sample while cleaning and tidying cluttered laboratory benches. Although many other compounds had been simply discarded, this compound, later called chlor- diazepoxide, was submitted for biological evaluation. Chlordiazepoxide (7-chloro- 2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide; Librium) demonstrated profound anti-anxiety properties. Additional chemical studies revealed that this single compound was a 1,4-benzodiazepine, unlike its forty quinazoline-3-oxide predecessors— the chance use of methylamine, a primary rather than a secondary amine, had resulted in a different synthetic pathway. Numerous analogs, including diazepam (Valium), were soon prepared and the anticonvulsant properties of this class of compounds were quickly discerned. The benzodiazepines soon emerged as one of the most important, and lucrative, classes of drug molecules. The discovery of benzodiazepines is a story of serendipity and certainly one that is difficult to predictably reproduce as part of a drug discovery program. Regrettably (or fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid, an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder, was also discovered by accident. In doing so, they gained immense practical experience with the handling and manipulation of this solvent.

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The frequency of heterogenous anomalies (chromosomal abnormalities purchase 30caps sleepwell fast delivery, hypospadias discount sleepwell 30caps, limb reduction defects, neoplasms) was statistically increased in more than 700 infants born to women who had used any vaginal spermicide within 10 months of conception (Jick et al. However, method- ological flaws in that study (Cordero and Layde, 1983), combined with simple data errors in classification of spermicidal exposures in the cases, cast doubt on the meaning of this study. It is now widely accepted that neither nonoxynols nor other spermicides are associated with an increased risk for chromosomal abnormalities and congenital anom- alies (Bracken, 1985). A case–control study of the use of topical contraceptives among mothers of infants with chromosomal abnormalities or limb reduction defects found no General hormonal therapy 91 difference in the frequency of spermicide use around the time of conception between the case and the normal control groups (Cordero and Layde, 1983). Women using clomiphene should be cautioned that pregnancy is to be excluded before each new course of the drug. Malformations were not increased in frequency among 1500 infants of women who had clomiphene preconceptionally (Barrat and Leger, 1979; Harlap, 1976; Kurachi et al. Multiple case–control studies of neural tube defects failed to find a signifi- cant association with artificial induction of ovulation and risk of a congenital anomaly (Cornel et al. In a well-designed, case–control study, the frequency of clomiphene usage was not increased among more than 500 women who delivered children with a neural tube defect compared with a sim- ilar number of normal controls (Mills et al. In summary, clomiphene is not asso- ciated with an increased risk of congenital anomalies. It is administered by intramuscular injection and is used to stimulate multiple ovarian follicular development in ovulation induction cycles. No epidemiologic studies have been reported regarding malformations in the offspring of women exposed to Pergonal or Metrodin before or during pregnancy. However, the risk does not appear to be high, although a very small risk cannot be excluded. Leuprolide acetate (Lupron) is an agent that is frequently used for these conditions. Although no epidemiological studies are published of infants born following Lupon therapy, 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.

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If the water did not adhere to the particles cheap sleepwell 30 caps overnight delivery, it would run rapidly through the soil until it reached solid rock generic sleepwell 30 caps on line. 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. Capillary action also depends on the strength of adhesion, which in turn depends on the material composition of the capillary surface. There is a limit to the pressure that roots can produce in order to withdraw water from the soil. A plant may thrive in loam and yet wilt in a clayey soil with twice the moisture content. Many of these insects are adapted to utilize the surface tension of water for locomotion. The surface tension of water makes it possible for some insects to stand on water and remain dry. As is shown in Exercise 7-11, a 70 kg person would have to stand on a platform about 10 km in perimeter to be supported solely by surface tension. Further, examination with an electron microscope reveals that the myofibril is composed of two types of threads, one made of myosin, which is about 160 A(˚ 1A˚ 10−8 cm) in diameter, and the other made of actin, which has a diameter of about 50 A. The threads are aligned in a regular pattern with spaces between threads so that the threads can slide past one another, as shown in Fig. The calcium ions in turn produce conformational changes that result in the sliding of the threads through each other, shortening the myosin-actin structure. Clearly, a force must act along the myosin-actin threads to produce such a contracting motion. It has been suggested by Gamow and Ycas [7-5] that this force may be due to surface tension, which is present not only in liquids but also in jellylike materials such as tissue cells. Here the movement is due to the attraction between the surfaces of the two types of thread. Let us now estimate the force per square centimeter of muscle tissue that could be generated by the surface tension proposed in this model. If the average diameter of the threads is D, the number of threads N per square centimeter of muscle is approximately 1 N (7.

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The Hershey – Chase experiment A very well known experiment with radioactive tracers was the Hershey– Chase experiment from 1952 sleepwell 30caps with visa. Alfred Hershey and Martha Chase used the isotopes P–32 (b-emitter with half-life 14 days) and S–35 (b-emitter with half-life 87 days) buy sleepwell 30 caps without prescription. Alfred Hershey (1908 – 1997) was the principal investiga- Numerous experiments within bio- tor, whereas Martha Chase (1927 – 2003) was the lab. Isotopes in radiation therapy In radiation therapy the purpose is to irradiate cancer cells to death and let the normal cells survive. Radium (Ra–226) was used from the beginning, both for teletherapy and as im- plants in brachytherapy. Attached to compounds (monoclonal antibodies) the isotope can be transported to the the cancer cells. Isotopes for diagnostic purposes Several isotopes emitting g-rays can, and have been used for diagnostic purposes. For example, I–131 will be accumulated in the thyroid and can via a gamma camera give information about sicknesses in the thyroid. We have pointed out before that the isotope most often used for medical information is Tc–99m. Thus, after the b-particle emission the newly formed technetium isotope is in a socalled “meta- stable” state. If we could isolate this metastable isotope it would be perfect for medical use, since the isotope would only emit a g-photon with no contamination from b-particles. Decay scheme for Mo-99 Mo–99 67 h The decay of Mo–99 results in a metastable nucleus – de- noted Tc–99m. By emitting a g- photon it ends up in Tc–99 which is radioactive with a Tc–99 halfife of 213 000 years. The compound is rinsed with physi- ological saline, and the Tc-99m that has been formed follows the water – it is like “milking”. The next step is to hook on this isotope to compounds that can bring it to particular places in the body that can be studied. More than 30 compounds based on Tc-99m have been made for imaging and functional studies of the brain, myocardium, thyroid, lungs, liver, gallbladder, kidneys, skeleton, blood and tumors. Tc-99m emits γ-radiation with an energy of 140 keV, which readily escapes the body and is easily measurable. From a physicists point of view it is probably the technique developed to observe the distribution of radioactivity that is the most interesting – whereas from a medical point of view it is the diagnostic power that is the most interesting. Ben Cassen and Hal Anger The technique with the radioactive isotopes in medical diagnostics started in the 1950s when Benedict Cassen invented the rectilinear scanner and in 1958 with the g-camera (or Anger camera). Blahd A picture of Hal Anger (1920 – 2005) and Benedict Cassen (1902 – 1972) at the International Confer- ence on Peaceful Uses of Atomic Energy in Geneva, Switzerland, in 1955. It can be mentioned that the “Society of Nuclear Medicine” every second year since 1994 give out a prize in honor of Benedict Cassen (The Benedict Cassen prize) for outstanding achievements in nuclear medicine. The illustration to the right demonstrate the technique introduced by Benedict Cassen. He assembled the frst auto- mated scanning system that was com- prised of a motor driven scintillation de- tector coupled to a relay printer. After the ini- tial studies, it was an extensive use of the scanning system for thyroid imaging during the early 1950s. Cassen’s devel- opment of the rectilinear scanner was a defning event in the evolution of clinical nuclear medicine. In 1956, Kuhl and his colleagues developed a photographic attachment for the Cassen scanner that improved its sensitivity and resolution.

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