Dose-related fetal growth retardation buy 60 mg alli with amex, cleft palate discount 60 mg alli with visa, genital anomalies order alli 60mg with visa, and behavioral alterations occur in the offspring of mice treated in pregnancy with prednisone or prednisolone in doses within or above the human therapeutic range (Ballard et al. Increased frequen- cies of cleft palate are also observed among the offspring of pregnant hamsters treated during pregnancy with prednisolone in doses 80–240 times that used in humans (Shah and Kilistoff, 1976). Corticosteroids in general In one study of 631 whose mothers used therapeutic corticosteroids during the first trimester, the risk of non-syndromic cleft palate was increased more than sixfold (Rodriguez-Pinilla and Martinez-Frias, 1998). However, given the prevalence of the use of these drugs and of cleft palate, the absolute risk is probably less than 1 percent in pregnancies exposed to corticosteroids in the first trimester (Shepard et al. Genital virilization is common in female infants, and both sexes manifest elec- trolyte imbalance and hypotension that can be life-threatening if not promptly treated by steroid hormone replacement. Currently, all known heterozygotes are treated with high-dose glucocorticoids until chorionic villus sampling occurs. If a female fetus is present, treatment is continued because virilization of affected females can be prevented. Medications used to treat congenital adrenal hyperplasia include prednisone, fludro- cortisone (see the section on Medications for Addison’s disease), and dexamethasone. If exposure to oral contraceptives during embryogenesis increases the risk of birth defects, the increase is small compared to the risk of malformations in the general pop- ulation (3. Congenital anomalies were not increased in frequency among more than 500 infants born to women who took oral contraceptives during the first trimester (Harlap and Eldor, 1980; Heinonen et al. A slight increase of congenital anomalies was associated with use of oral con- traceptives in the first trimester in several studies, but it is generally accepted that the risk is not real, or extremely small. No epidemiologic studies have been published regarding malformations in the off- spring of women who became pregnant with a Norplant system in place. Levonorgestrel is the progestin component in many oral contraceptive preparations. When the device is removed or expelled spontaneously, spontaneous abortion is reduced to approximately 20–30 percent, which is much closer to the rates of miscarriage in the general population (Alvior, 1973; Tatum et al. Spermicidal agents (nonoxynols) Spermicidal intravaginal sponges, foams, creams, and suppositories contain nonoxynols, surfactants that are extremely toxic to sperm. The risk of congenital anomalies was not increased in frequency among more than 1200 infants whose mothers used nonoxynol spermicides during embryogenesis (Heinonen et al. Similar results were found in large studies of the frequency of congenital anomalies among infants whose mothers used a multiagent spermicide that contained nonoxynol (Huggins et al. The frequency of heterogenous anomalies (chromosomal abnormalities, hypospadias, 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. 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.

It is applicable in the nervousness of depression because of its gentle stimulating influence discount 60mg alli fast delivery, and in these cases its influence is heightened by combining it with stimulants alli 60 mg generic. This result is effectually obtained from the valerianate of ammonium buy discount alli 60 mg line, which is the most active of the valerian compounds. In conditions where the nervousness is induced by hyperactivity—actual increased nerve force—or where there is organic disease, it is not the remedy. The agent exercises a good influence in combination with cimicifuga in the treatment of chorea. Its influence upon disordered motility, although not marked, is similar to that of cannabis indica, hyoscyamus and scutellaria. It has been used in stomach disorders and in diabetes, but its influence is not marked in these cases. A preparation of thirty drops of the tincture in four ounces of water, may be given in teaspoonful doses, to infants. Specific Symptomatology—Diarrhea with large watery discharges expelled with violence, spasmodic pains in the bowels, cramps, cramp colic, pain producing prostration, with cold skin, cold sweat and sunken eyes. Therapy—This remedy, in small doses frequently repeated, is specific in cholera infantum, cholera morbus, and in various forms of acute diarrhea. It is said to be found Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 449 beneficial in some forms of nervous headache and in cases of mental derangement. Physiological Action—Taken in moderate doses, Veratrum Viride reduces the pulse rate in a marked degree, which becomes extremely rapid and feeble on any exertion; this condition is followed by severe nausea and vomiting, together with muscular weakness. Taken in a poisonous dose these symptoms are increased in severity, the pulse becomes almost imperceptible, the skin cold and clammy together with vomiting, retching, hiccough, faintness, dizziness, blindness and unconsciousness. These symptoms indicate that the drug is a powerful spinal and cerebral depressant. Although veratrum is a powerful poison, it is so regular and uniform in its action, and so devoid of erratic and unaccountable or uncontrol-lable influences, that it can be given within the limits of its maximum dosage with safety. In overdoses it produces vomiting, usually before enough is absorbed to produce serious results. It is better given in small doses, repeated every half hour or hour, in acute cases, as its influence is exercised in a more uniform manner, is more permanent, is more easily controlled and is not so apt to disturb the stomach. A large dose produces Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 450 quick depression, although the effect is transient. If the dose be often repeated, the stomachic irritation quickly becomes so great as to interfere with all medication. It is not as easily adapted to infants and the feeble as aconite, and its manner of action is not as satisfactory. Veratrum, in its direct heart depression, resembles the coal-tar depressants, although much more regular and uniform in its action and perfectly controllable. It steadily slows the heart and circulation, the temperature declining correspondingly. Aconite influences the heat production and heat-radiation, stimulates all emunctories and the function of all the glandular organs and hastens the removal of inflammatory products. Effusion or suppuration are thus prevented, and if this agent is begun early, when the temperature has declined, there will be no local lesions remaining to contend with as the results of the inflammatory action. Veratrum will assist in the removal of morbific products, but not with the immediate influence upon the results of inflammatory actions that are apparent from the use of aconite. Veratrum should not be given when inflammation has resulted in marked structural change and the products of inflammation are plainly present. Specific Symptomatology—Veratrum is indicated in the onset of sthenic fever when the pulse is full, large and bounding, and the tissues are engorged, where there is fullness of the capillary circulation. It is especially serviceable when there seems to be obstruction of the venous capillary circulation. The face and skin are flushed, but usually of a full, dull, dark hue, and not always the bright-red flush with hot, dry skin which indicates aconite and gelsemium. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 451 The skin is usually soft and covered with warm perspiration. In these cases Veratrum reduces the arterial pressure and permits, or even assists, the more rapid removal of the venous obstruction. In administering veratrum, because of its direct action on the heart it is necessary, if given for a short time only, in full doses, that the patient remain in a recumbent position. In sthenic inflammations, especially such as results from infections—and this includes a long list—and exophthalmic goitre, it exercises a most delightful influence when given in small doses, frequently repeated, the patients should thus get the best results when in a recumbent position, but that position is not then obligatory. Therapy—The characteristic indications for veratrum are found in the onset of pneumonitis in strong men previously healthy and vigorous. In these cases, given in doses of a drop of the tincture every half hour, it will slow the pulse and slowly reduce the temperature after four or five hours. This effect can be continued for a few doses longer, and then the doses should be smaller or given farther apart. The pulse should be slowed, in a case with violent premonitory symptoms, down to the normal beat and held there for awhile, and if the symptoms do not quickly abate, the influence may be continued until a pulse of sixty or fifty-five, or even, in a strong man, fifty beats is reached, if the stomach be not yet irritated. In pleuritis, in bronchitis, in peritonitis, especially pelvic peritonitis from sepsis; in hepatitis and nephritis and cystitis always at the beginning of the acute stage before much structural change has occurred, it may be given, and will retard and often throw off the attack. It is of value in the earlier stages of meningitis and cerebritis, if given understandingly. If the violent heart action be controlled, the processes of disease and any tendency to convulsive action will be at once restrained. In continued fevers this agent, like other depressants of nerve force, is not always the best remedy to use. The reactionary power of the nerve centers is greatly lowered by disease, and if depressants are given they are apt to still further decrease the nerve force and minimize its restorative influence over the system. Advantage will sometimes follow its early use in a case of extremely high temperature with violent and noisy delirium, but it is not the remedy to persist in nor to continue when the prostrating influence of the fever is apparent. Diluted-one dram in a half-glass of water it is an excellent gargle in any inflamed throat. For external use in this disease a somewhat dilute non-alcoholic preparation is preferable, or the fluid extract, full strength or diluted one-half. If begun early in erysipelas, there are few conditions likely to arise that will contraindicate its use. The first investigators into the properties of veratrum pronounced it an excellent alterative. It has not been generally used as such, but those who have so used it have expressed the strongest confidence in it. Clark, writing on the subject in 1889, said: “As an alterative, especially as an antisyphilitic remedy, there is no better agent in the vegetable kingdom. Indeed, there is room for doubt whether the animal, vegetable or mineral kingdoms furnish a better remedy in purely syphilitic cases. If the patient has been already saturated with mercury, as is too often the case, doubtless the administration of some of the preparations of iodine will be a necessary, adjuvant. In the uncomplicated secondary forms of the disease it will be seldom that any other remedy will produce as satisfactory results as can be obtained with the veratrum alone. Of a reliable fluid extract four or five drops three times a day will be usually well borne by the stomach, and the sensitiveness of that organ is my sole guide in dosage. If four drops disturb the stomach use three for a few days, then increase to four, then perhaps to five. Its smallness of bulk, not disagreeable taste, and, above all, its satisfactory effects, constitute strong recommendations for its use. Its alterative and eliminative influence as well as its sedative power caused the older writers to say that veratrum would positively cure puerperal fever. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 453 Other observers have spoken most highly of its action in developing phthisis pulmonalis. Positive claims are made that, judiciously administered, it has aborted the disease. While I have spoken against its use in continued fevers, there are several writers who have given it in full doses at the onset of typhoid fever, while sthenia was yet present, and have had most salutary results. In the early stages of acute rheumatism, its indications are present sometimes quite conspicuously, and if given in emphatic doses, it will sometimes quickly terminate the disorder.

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Com- parison of substrate recognition between Oct1 and Oct2 was performed using a þ gene expression system best 60mg alli. There was no difference in the transport activities of cimetidine buy alli 60mg low price, ranitidine buy cheap alli 60 mg on-line, and famotidine by Oct1, while Oct2 efficiently transports cimetidine rather than ranitidine and famotidine (120). Oct3 is ubiquitously expressed in normal tissue with low level, and, among them, gonads (testes and ovaries), placenta, and uterus exhibited relatively high expression (119). Oat1 is predom- inantly expressed in the kidney, where it is localized in basolateral membrane of the proximal tubules (130). The kidney expression is markedly higher in female rats than in male rats with similar hepatic expression (136,137), whereas the hepatic expression exhibits gender difference in mice, high in female and almost absent in male (138), although a controversial result was also obtained (139). Functional analyses of Oat2 elucidated that it exhibits substrate specificity similar to Oat1 (141), and accepts nonsteroidal anti-inflammatory drugs, such as salicylate, ketoprofen, and indomethacin as substrate (141–143). Oat2 has been suggested to be involved in the uptake of indomethacin and ketoprofen by rat hepatocytes (142,143). Rat Oat3 is expressed in the kidney, liver, eye, and brain (144), while its human counterpart is detected predominantly in the kidney (145,146). In rat brain, Oat3 is expressed in brain capillaries and choroid plexus, where it is localized on the abluminal and brush border membranes of the brain capillaries and choroid plexus epithelial cells, respectively, and accounts for the uptake of hydrophilic organic anions (81,147–150). In addition, it accepts some cationic compounds, cimetidine, ranitidine, and famoti- dine (144,150), which have been known as bisubstrate and recognized by both organic anion and cation transporters (153). Using rat kidney slices, it has been suggested that Oat3 is responsible for the uptake of amphipathic organic anions, such as pravastatin, and steroid conjugated with sulfate (24,53,151). Since the transport characteristics seem to be consistent with the previous observation using brush border membrane vesicles, it has been considered to be expressed on the brush border membrane of the kidney. Octn2 is hereditarily deficient in a mouse strain, jvs mice, which exhibits the similar symptoms of systemic carnitine deficiency (165). Valinyl esterification of the antiviral agent acyclovir showed a three- to fivefold increase in bioavailability (174–176). This uptake does not depend on Na and H , but on Cl (190), and increasing extracellular concentration of chloride reduced the uptake of benzyl- penicillin (190). The substrates include faropenem, foscarnet, and mevalonate, as well as benzylpenicillin (190). In contrast to the kidney, the expression is localized to the sinusoidal membrane of the liver (190). When the direction of the – concentration gradient of Cl is taken into consideration, the transport direction mediated by NaPi-1 is efflux from inside the cells to the blood and urine in the liver and kidney, respectively. P-gp P-gp was originally found as overexpressed protein on the plasma membrane of multidrug-resistant tumor cells, and confers multidrug resistance by actively extruding anticancer drugs to the outside (191,192). In normal tissue, P-gp is 164 Kusuhara and Sugiyama expressed in the clearance organs (liver and kidney), the site of absorption (small and large intestine), and tissue barriers (brain capillary endothelial cells), where it is localized to the luminal side, i. In the small intestine and brain capillaries, Mdr1a is the predominant isoform, while both isoforms are expressed in the liver and kidney (200). P-gp expression exhibits regional difference; it increases from the duodenum to the colon, both in rodent (201–203) and human (204–206). This expression pattern is associated with functional activity, namely, lowest activity in the duodenum and highest in the ileum (202) and colon (203). The substrate specificity of P-gp is quite broad, and a number of com- pounds have been identified as P-gp substrates, generally overall positive charge or neutral compounds (193–199,207). The tissue distribution and membrane localization suggest that P-gp limits oral absorption and penetration into the brain and mediates biliary and urinary excretion of drugs. This has been sup- ported by an in vivo finding using Mdr1a(–/–) and Mdr1a/1b(–/–) mice. The biliary excretion clearance and intestinal excretion clearance of tri-n-butylme- thylammonium, azidoprocainamide methoiodide and vecuronium was decreased in Mdr1a(–/–) mice, and the renal clearance of tri-n-butylmethylammonium and azidoprocainamide methoiodide was also decreased in Mdr1a(–/–)(208). For digoxin, the amount excreted into the intestine fell markedly, while that into the bile and urine was unchanged in Mdr1a(–/–) mice (209), but fell to half the normal value in the Mdr1a/1b(–/–) (210). Following oral administration, the plasma concentration of ivermectin (200), paclitaxel (211), and fexofenadine (212) was greater in Mdr1a(–/–) mice. In situ intestinal perfusion study elucidated that the outflow concentrations of quinidine, ritonavir, cyclosporin A, dauno- mycin, loperamide, and verapamil (for some time points) was decreased in Mdr1a/1b(–/–) mice, indicating that the intestinal absorption of these drugs is limited by P-gp. In addition, the brain uptake of many P-gp substrates increased by inhibiting P-gp activity or in Mdr1a(–/–) and Mdr1a/1b(–/–), but not Mdr1b(–/–), (195,198–200). Respiratory depression, an opioid central nervous system effect, produced by loperamide was induced by the simultaneous administration of quinidine to healthy volunteers (217). Cyclosporin A sig- 11 nificantly increased the brain concentration of C-verapamil (218). The concentration of etoposide in the cerebrospinal fluid in the Mdr1a/1b/Mrp1(–/–) mice was 10-fold greater than that in Mdr1a/1b(–/–) mice, while there was no significant difference in the plasma concentration (224). The efflux transport of E217bG from the brain was significantly delayed in Mrp1(–/–) mice (225), while there was no significant change in the elimination of E217bG from the cere- brospinal fluid (226). It turned out that the biliary excretion of amphipathic organic anions, such as glutathione conjugates, glucuronides, and relatively lipophilic nonconjugated organic anions, is mediated by primary active transport, and deficient in the mutant strains (228,230–232). In the small intestine, the Mrp2 expression is higher in the duodenum than that in the jejunum in rodent (234,238) and higher or similar to that in the ileum in human (204,206). Functional analysis was performed in vitro using Ussing chamber and everted sac (240). Furthermore, hepatic expression of Mrp3 was subjected to induction by bile duct ligation and the treatments of a-naphthylisothiocyanate, phenobarbital, or bilirubin in rats (249), while that of Mrp3 was unchanged by bile duct ligation in mice (245). Using Mrp3(–/–) mice, it was shown that Mrp3 is involved in the sinusoidal efflux of glucuronide conjugates of morphine, acetoa- minophen, and 4-methylumbelliferone in the liver (256–258). The membrane localization of Mrp4 is tissue dependent: sinusoidal membrane in the hepatocytes (261), brush border membrane of the renal tubules (262,263), luminal membrane of the brain capillaries (262), and basolateral membrane of the choroid epithelial cells (262). In addition, the concen- tration of topotecan in the cerebrospinal fluid was markedly increased in Mrp4(–/–) mice (262). In the kidney, the renal clearance of furosemide with regard to the plasma concentration was decreased, and the kidney concentrations of hydro- chlorothiazide, adefovir, and tenofovir were significantly increased in Mrp4(–/–) mice (267,268). Digoxin-Quinidine and Digoxin-Quinine Digoxin undergoes both biliary and urinary excretion in human (291). The drug- drug interactions between digoxin and quinidine or quinine (a stereoisomer of quinidine) are very well known (291). The degree of inhibition by quinidine and quinine of the biliary and urinary excretion of digoxin are different; quinine reduced the biliary excretion clearance of digoxin to 65% of the control value, while quinidine reduced both the biliary and renal clearance to 42% and 60%, respectively (Fig. In proportion to the reduction in total body clearance, coadministration of quinine and quinidine increases the plasma concentration of digoxin by 1. In addition to these agents, verapamil also has an inhibitory effect, but specifically on the biliary excretion (292), has only a slight inhibition of renal excretion (293). No inhibitory effect of quinine and quinidine was obtained in isolated human hepatocytes at a concentration of 50 mM (294), whereas stereoselective inhibition of quinine and quinidine has been observed in isolated rat hepatocytes (295). Quinine inhibits uptake into isolated hepatocytes at the concentration of 50 mM, while the effect of quinidine was minimal (at most a 20% reduction) Figure 7 Change in the biliary and renal clearance of digoxin caused by quinidine or quinine treatment. After a steady state concentration of quinine or quinidine was achieved by multiple oral administrations, the plasma concentration and biliary and urinary excretion of digoxin after oral administration were measured in healthy volunteers. On the basis of the animal (209,210) and clinical (216) observations, P-gp has been suggested to be the candidate transporter for the biliary and urinary excretion of digoxin. The role of P-gp in this drug-drug interaction has been examined using the Mdr1a(–/–) mice (297). Coadministration of quinidine caused a 73% increase in the plasma concentration of digoxin in normal mice, whereas it had little effect (20% increase) in the Mdr1a(–/–) mice at the same plasma concentration of quinidine (Fig. The drug-drug interaction between digoxin and quinidine has been also suggested in the intestinal absorption of digoxin in rats (298). These results indicate that digoxin undergoes active efflux in the small intestine (298). Indeed, the intestinal secretion of digoxin was significantly reduced in Mdr1a(–/–) and Mdr1a/1b(–/–) mice (209,210). Therefore, the interaction of quinidine and digoxin involving intestinal absorp- tion may be due to the inhibition of P-gp function. Fexofenadine-Itraconazole/Verapamil/Ritonavir Fexofenadine is mainly excreted into the bile and urine without metabolism. On the basis of in vivo study using Mdr1a and Mdr1a/1b(–/–) mice, it has been shown that P-gp limits intestinal absorption and brain penetration of fexofenadine, but makes only a limited contribution to the biliary and urinary excretion (212,302). Fur- thermore, inhibition of P-gp in the intestine allowed detection of saturable uptake of fexofenadine and inhibition by Oatp inhibitor in rats (88).

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Because the length of the step is proportional to the length of the leg order alli 60mg with visa, we have 1 1 vmax ∝ ∝ × 1 T This shows that the maximum speed of running is independent of the leg size purchase alli 60 mg with mastercard, which is in accordance with observation: A fox cheap alli 60 mg free shipping, for example, can run at about the same speed as a horse. However, as the speed of running (that is the number of steps in a given inter- val) increases, the elbows naturally assume a bent position. This in turn increases the nat- ural frequency of the arm, bringing it into closer synchrony with the increased frequency of steps. Here we will use the physical pendulum as a model for the swinging leg to compute this same quantity. This model is, of course, not strictly correct because in running the legs swing not only at the hips but also at the knees. We will now outline a method for calculating the energy expended in swinging the legs. During each step of the run, the leg is accelerated to a maximum angular velocity ωmax. In our pendulum model, this maximum angular velocity is reached as the foot swings past the vertical position 0 (see Fig. The rotational kinetic energy at this point is the energy provided by the leg muscles in each step of the run. From the rate of running, we can compute the period of oscillation T for the leg modeled as a pendulum. The angular velocity (see Appendix A) is then vmax ωmax where is the length of the leg. In computing the period T, we must note that the number of steps per second each leg executes is one half of the total num- ber of steps per second. In Exercise 4-8, it is shown that, based on the phys- ical pendulum model for running, the amount of work done during each step is 1. In Chapter 3, using different considerations, the amount of work done during each step was obtained as mv2. Considering that both approaches are approximate, the agreement is certainly acceptable. In calculating the energy requirements of walking and running, we assumed that the kinetic energy imparted to the leg is fully (frictionally) dis- sipated as the motion of the limb is halted within each step cycle. In fact, a significant part of the kinetic energy imparted to the limbs during each step cycle is stored as potential energy and is converted to kinetic energy during the following part of the gait cycle, as in the motion of an oscillating pendulum 56 Chapter 4 Angular Motion or a vibrating spring. The assumption of full energy dissipation at each step results in an overestimate of the energy requirements for walking and run- ning. This energy overestimate is balanced by the underestimate due to the neglecting of movement of the center of mass up and down during walking and running as is discussed in following Sections 4. More detailed and accurate descriptions can be found in various technical journals. However, the basic approach in the various methods of anal- ysis is similar in that the highly complex interactive musculoskeletal system involved in walking and/or running is represented by a simplified structure that is amenable to mathematical analysis. In our treatment of walking and running we considered only the pendulum- like motion of the legs. A way to model the center of mass motion in walking is to consider the motion of the center of mass during the course of a step. Consider the start of the step when both feet are on the ground with one foot ahead of the other. At this point the center of mass is between the two feet and is at its lowest position (see Fig. The center of mass is at its highest point when the swinging foot is in line with the stationary foot. As the swinging foot passes the stationary foot, it becomes the forward foot and the step is completed with the two feet once again on the ground with the right foot now in the rear. In the sequence of the step described in the figure, the center of mass is alternately behind and then in front of the point of the single-foot contact with the ground as the free leg swings forward. That is, when the rear left foot starts swinging forward, it is of course off the ground, and the center of mass is behind the supporting right foot. During this part of the step the center of mass is swinging toward the stationary right foot and its kinetic energy is converted to potential energy (as in the upward swing of a pendulum; the supporting foot being the fulcrum). After the left foot passes the stationary right foot, the center of mass shifts forward of the right foot and accelerates as the potential energy is converted to kinetic energy (downward swing of the pendulum). With a step-length of 90 cm and the center of mass (with feet together) 1 m above the ground, the center of mass is raised 11 cm during each swinging Section 4. This is an upper limit because in this simplified treatment it is assumed that the legs remain straight throughout the step. Because the body in the process of walking is not a perfect pendulum, only part of this potential energy is converted back into kinetic energy. To reduce the energy expenditure, the body seeks adjustments to minimize the up-and-down movement of the center of mass (see Section 4. During walking, at one point in the step cycle, both feet are in contact with the ground. During a walking step the center of mass trajectory is similar to that of an inverted swinging pendulum with the fulcrum at the point where the two feet pass one another (Fig. Running can be compared to a person on a pogo stick as if bouncing from one leg to another. As shown in the figure, the energy consumed per distance traveled increases at both lower and higher walking speeds. Past this speed most people will spontaneously break into a run consuming less energy. Considering the approximate nature of the calculations and the difference in the methods, the agreement between the two numbers is again remarkably good. Measurements have shown that for most humans, as well animals such as dogs, horses and rats, the energy expended at a given walking speed increases directly with the weight of the load Chapter 4 Exercises 59 being carried. Specifically, carrying a load that is 50% of the body weight increases the energy consumption by 50%. For most people this added energy expenditure is the same whether they carry the load on their backs or on their heads. Recent studies have been focused on the extraordinary load carrying abil- ities of women in certain areas of East Africa who can walk with relative ease carrying large loads balanced on their heads. Quantitative measurements have shown that women from the Luo and Kikuyu tribes can carry loads up to about 20% of their body weight without any measurable increase in their energy con- sumption. Past this weight, the energy consumption increases in proportion to the weight carried minus the 20%. That is, carrying a load 50% of the body weight increases their energy consumption by 30% (50%–20%). What specific aspect of the movement or training that brings about these enhanced load carrying abilities is not yet understood. Explain why a runner is subject to a torque if she rounds a curve main- taining a vertical position. In the act of walking, the arms swing back and forth through an angle of 45◦ each second. Consider the carnival ride in which the riders stand against the wall inside a large cylinder. As the cylinder rotates, the floor of the cylinder drops and the passengers are pressed against the wall by the centrifugal force. Assuming that the coefficient of friction between a rider and the cylinder wall is 0. If a person stands on a rotating pedestal with his arms loose, the arms will rise toward a horizontal position. Assume that the length of the arm is 90 cm and the center of mass is at mid-length. Calculate the maximum velocity and acceleration of the foot of a runner who does a 100-m dash in 10 sec. Assume that the length of a step is 1 m and that the length of the leg is 90 cm and the center of mass is at mid-length. What is the most effortless walking speed for a person with 90-cm-long legs if the length of each step is 90 cm? Using the physical pendulum model for running described in the text, derive an expression for the amount of work done during each step. Compute the length of time for an erect human body without compen- sating movements to hit the floor once it looses its balance. Assume that the falling body behaves as a physical pendulum pivoted at the floor with the period given by Eq.

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