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Synonyms of this drug are chlorozide best order naproxen arthritis degenerative neck, diaqua purchase 250 mg naproxen with amex arthritis sore feet, esidrix proven 250mg naproxen arthritis in neck from cracking, hydrodiuril discount naproxen severe arthritis in neck and back, hydrozide, hypothiazide, novohydrazide, urozide, and others. Diuretics scheme of making the aforementioned drugs using phenylacetaldehyde or its acetale as a carbonyl component, and using 2,4-disulfonamido-5-trifluoromethylaniline (21. Synonyms of this drug are sinesalin, docidrazine, tensionorm, aprinox, naturetin, and others. However, it is primarily used as an ingredient of a combination drugs intended for lower- ing pressure, in particular in minizide, which is a combination of prazozine and polythi- azide. These widely used drugs include hydroflumethiazid, trichlormethiazide, methylcyclothiazide, cyclothiazide, benzothiazide, diazoxide, and others, whose methods of synthesis and phar- macological action are practically identical to those listed above. Methylcyclothiazide: Methylcyclothiazide is 1,1-dioxide 3,4-dihydro-3-(chloromethyl)- 6-chloro-2H-1,2,4-benzothiadiazin-7-sulfonamide (21. Cyclothiazide: Cyclothiazide is 1,1-dioxide 3,4-dihydro-3-(5-norbornen-2-yl)-6-chloro- 2H-1,2,4-benzothiadiazin-7-sulfonamide (21. Benzothiazide: Benzothiazide is 1,1-dioxide 3,4-dihydro-3-benzylthiomethyl-6- chloro-2H-1,2,4-benzothiadiazin-7-sulfonamide (21. Chemically they are not thiazides; however, being sulfonamide derivatives and having, in a certain sense, structural similarities and a similar mechanism of action common among thiazides, with the exception being that they do not inhibit carbonic anhy- drase. The ability of metolazone, chlorothalidone, and indapamide to remove edematous liq- uid from the body is practically identical to that of thiazide diuretics. These drugs are used for relieving edema associated with hepatic, renal, and cardiac diseases, as well as for treating general hypertension either independently, or in combination with other drugs. The amino group is acylated by ethyl chloroformate, forming 5-chloro-N-ethoxycarbonyl-2-methylaniline (21. The product, upon subsequent reaction with chlorosulfonic acid and ammonia, is transformed in the usual manner into 4-sulfonamido-5-chloro-N-ethoxycarbonyl-2-methyl- aniline (21. The methyl group of this product is oxidized by potassium permanganate, giving 5-sulfonamido-4-chloro-N-ethoxycarbonyl anthranylic acid (21. Upon treating this with thionyl chloride it cycles into the corresponding anhydride (21. This reacts with o-toluidine, turning it into 2-amino-5-aminosulfonyl-4-chloro-o-toluolbenzamide (21. It is used for treating edema caused by cardiac insufficiency and adrenal irregularities, including nephrotic syndrome. The nitro group in the resulting compound is reduced by tin dichloride to 2 - carboxy-3-amino-4-chlorobenzophenone (21. Next, subsequent diazotation and reac- tion with sulfur dioxide in the presence of copper dichloride gives the corresponding sul- fonylchloride (21. Upon reaction with thionyl chloride, this compound undergoes cyclization into phtahlide (21. This is reacted with aqueous ammonia in the aforementioned manner, and it rearranges into chlorothalidone (21. Subsequent sulfochlorination and amination of this product gives 2-chloro-5-(3-oxo-1-isoindolinyl)-benzolsulfonamide (21. Diuretics oxidized by various oxidizers such as oxygen or hydrogen peroxide in alkaline or chromic acid in acetic acid into chlorothalidone (21. Reducing this with lithium aluminum hydride leads to forma- tion of 1-amino-2-methylendoline (21. It is intended for lowering arterial blood pressure and as an adjuvant drug for treating edema caused by cardiac insufficiency. In both oral and intravenous introduc- tion, they cause a rapid rise in excretion of sodium and chloride ions from the kidneys and an increase in secreted urine volume. An increase in potassium, hydrogen, magnesium, and calcium ions is observed simulta- neously with the increase of sodium and chloride ions being excreted. The most widely used loop diuretics are bumetanide (derivative of monosulfamoyl methanylamide), ethacrynic acid (a derivative of aryloxyacetic acid), and furosemide (derivative of monosulfamoylanthranylic acid), which have more diuretic efficacy than thi- azides. Bumetanide, ethacrynic acid, and furosemide are used in treating edema associated with severe and chronic cardiac insufficiency, cirrhosis of the liver, nephrotic syndrome, and renal diseases. They are also used to treat chronic hypertension both independently as well as in combination with other antihypertensive drugs. The efficacy and safety of bumetanide and ethacrynic acid in chronic hypertension has not been proven. In the first stage of synthesis, it undergoes sul- fonylchlorination by chlorosulfonic acid, forming 4-chloro-3-chlorosulfonylbenzoic acid (21. Reacting this with ammonia gives 5-aminosulfonyl-4-chloro-3-nitroben- zoic acid (21. Reduction of the nitro group in this product by hydrogen using a palladium on carbon catalyst gives 3-amino-5-aminosul- fonyl-5-phenoxybenzoic acid (21. Finally, reacting this with butyl alcohol in the pres- ence of sulfuric acid gives the desired bumetanide (21. Diuretics Ethacrynic acid: Ethacrynic acid—[2,3-dichloro-4-(2-methylenbutyryl)phenoxy]acetic acid (21. This is acylated with buty- royl chloride, forming 4-butyroyl-2,3-dichlorophenoxyacetic acid (21. It is used for edema syndrome of various origins, edema of the lungs and brain, chronic renal insufficiency, some forms of hypertonic crises, and poisoning by barbiturates and other compounds excreted mainly with urine. In general, when used as independent agents, drugs of this class are not powerful diuretics 21. They are primarily used in combination with other diuretics for increasing diuresis and for preventing development of hypokalemia. Because of completely different structures and the presence of specifically unique characteristics, properties of drugs of this series (spironolactone, triamterene, and amiloride) will be examined individually. Spironolactone: Spironolactone is the 7-acetate of the γ-lactone of 17-hydroxy-7-mercapto- 3-oxo-17-α-pregn-4-ene-21-carboxylic acid (21. Spironolactone is synthesized industri- ally in two different ways from androstenolone—3β-hydroxy-5-androsten-17-one. According to the first method, androstenolone undergoes ethynylation by acetylene in a Normant reaction condition using sodium amide in liquid ammonia, which forms 17 α-ethynyl-3β-,17β-dihydroxy-5-androstene (21. Subsequent reaction of this with methylmagnesiumbromide and then with carbon dioxide gives the corresponding propenal acid (21. Reduction of the triple bond in this product with hydrogen using a palladium on calcium carbonate catalyst forms the corresponding acrylic acid derivative (21. The double bond is reduced by hydrogen, in this case using a palla- dium on carbon catalyst. Diuretics rhodium chloride, which forms 17β-hydroxy-17α-(3-hydroxypropyl)-4-androsten-3-one (21. It is a competitive antagonist of aldosterone, and its action is most effective when the level of circulated aldosterone in the organism is high. Aldosterone lowers excretion of sodium ions from the body, thus increasing their reabsorption and increasing secretion of potassium ions in renal tubules. Being a competitive antagonist of aldosterone, spironlactone blocks aldosterone receptors, thus increasing excretion of sodium, chloride, and corresponding equivalents of water with urine, thus retaining the amount of potassium ions in the organism.
Beta-adrenergic receptor agonists Ritodrine and terbutaline are beta-agonist drugs order naproxen 500 mg with mastercard rheumatoid arthritis definition wikipedia, structurally related to epinephrine order naproxen 500mg on line arthritis diet citrus, and are used as tocolytics order 250mg naproxen fast delivery arthritis pain relief walgreens. This type of tocolytic binds to beta-adrenergic receptors on the outer myometrial cell membrane and acti- vates adenylate cyclase buy naproxen in united states online arthritis in dogs toes. Another pathway is the phosphorylation of myosin light chain kinase which inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain. Maternal metabolic abnormalities (gluconeogenesis, hypokalemia, and hyper- glycemia), as well as cardiopulmonary complications (tachycardia, hypotension, arrhyth- mias, myocardial ischemia, pulmonary edema) are associated with beta-agonist tocolyt- ics (Box 15. Every beta-agonist is associated with pulmonary edema and occurs among as many as 5 percent of gravidas who took any of these drugs (Boyle, 1995; McCombs, 1995). Maternal tocolytic therapy has been associated with neonatal hypoglycemia and tachycardia. Several fetal and neonatal cardiovascular adverse effects are associated with beta-sympathomimetic therapy (Katz and Seeds, 1989) (Box 15. Decreases in the systolic/diastolic ratios of the umbilical artery have been reported in patients using either terbutaline or ritodrine (Brar et al. By 1979, ritodrine was available as a tocolytic agent in 23 foreign countries (Barden, et al. Ritodrine hydrochloride is a beta-adrenergic agonist with beta2-receptor effects that relax smooth muscle in the arterioles, bronchi, and uterus. Although ritodrine use is in widespread use for the inhibition of preterm labor (Leveno et al. No long-term benefi- cial effect of tocolytic therapy (decreased perinatal mortality or severe neonatal respira- tory disorders) was found in meta-analysis of 890 pregnancies in which ritodrine or another beta-mimetic tocolytic agent was used to prevent premature delivery (King et al. Downregulation of beta2-adrenergic receptors following the use of these drugs may explain their poor efficacy because uterine-relaxant effects are short lived (Berg et al. For this indication, a dose of 1–3 mg is usually given over a 2-min period (Smith, 1991). It is possible that a weak effect was pres- ent and the signal could not be separated from background noise. Maternal effects Acute maternal pulmonary edema, in addition to hypokalemia and hyperglycemia, has been reported among women given ritodrine. Steroids administered concomitantly to accelerate fetal lung maturity seem to increase the risk for this maternal complication Tocolytics 283 (see Box 15. Severe maternal cardiovascular complications occurred among nearly 5 percent of women treated with terbutaline (Katz et al. Beta-mimetics also alter glucose tolerance and have been associated with ketoacidosis among women with poorly controlled insulin-dependent diabetes. Fetal effects Fetal tachycardia and arrhythmias are associated with beta-mimetic therapy, including ritodrine (Barden et al. Protracted ritodrine therapy has been associated with increased septal thickness in exposed neonates (Nuchpuckdee et al. However, these do not appear to be frequent complications of ritodrine, or beta-mimetic, therapy in general. Beta-sympathomimetic tocolytic therapy, including ritodrine, was associated with a 2. In another investiga- tion, no association of ritodrine with intraventricular–periventricular hemorrhage was found (Box 15. Beta-mimetics are generally not used during the period of organogenesis, with the exception of terbutaline for asthma. An increased frequency of cardiovascular anomalies in chick embryos exposed to ritodrine and terbutaline was found in one study, and it was concluded that teratogenic effects were secondary to stimulation of beta-2-adrenergic receptors (Lenselink et al. Interestingly, according to its manufacturer, it should not be used for tocolysis. Terbutaline has also been utilized in the management of symptomatic placenta previa in pregnancies remote from term (Besinger et al. Neonatal myocardial dysfunction and necrosis have been associated with terbutaline tocolytic therapy (Fletcher et al. Neonatal hypoglycemia and fetal tachycardia were associated with terbutaline tocolytic therapy late in pregnancy (Peterson et al. Neonatal behavior was transiently altered among the infants of pregnant women who received terbutaline tocolysis (Thayer and Hupp, 1997). One review of car- diopulmonary effects of low-dose continuous terbutaline infusion in 8709 women found 47 women (0. In another review of 1000 women given a combination of intravenous terbutaline and mag- nesium sulfate, the side effects of protracted therapy were negligible (Kosasa et al. Magnesium sulfate has no proven efficacy in delaying delivery beyond 24–48 h (Cotton et al. Maternal effects Hypermagnesemia (cutaneous flushing, nausea, vomiting, respiratory depression, intracar- diac conduction delays) is the major maternal adverse effect of magnesium sulfate therapy. Protracted ther- apy (many days) with magnesium sulfate for preterm labor increases calcium loss and may decrease bone mineralization (Smith et al. Bleeding time during pregnancy may be prolonged with magnesium sulfate therapy, but this is not clinically significant (Fuentes et al. Unlike ritodrine, magnesium sulfate is not associated with a ‘peripheral vascular steal’ syndrome and does not decrease placental perfusion (Dowell and Forsberg, 1995). Fetal effects Magnesium sulfate crosses the placenta and, in extremely large doses, may cause neona- tal cardiorespiratory depression and transient loss of beat-to-beat variability (Hallak et al. Osseous lesions (metaphyses, costochondral junctions, skull) have been reported among infants born to women treated with magnesium sulfate for more than a week prior to delivery (Malaeb et al. Indomethacin is effi- Tocolytics 285 cacious as a tocolytic for short periods of time (Niebyl et al. Maternal effects Indomethacin resulted in few maternal side effects when used as a tocolytic. Potential adverse effects include: interstitial nephritis, acute renal failure, peptic ulcer disease, decrease in platelets, prolonged bleeding time (Clive and Stoff, 1984; Lunt et al. Among 83 women who received indomethacin during pregnancy, no adverse mater- nal or fetal effects were noted, except for oligohydramnios, which resolved sponta- neously (Sibony et al. Fetal effects In a review of 28 studies including 1621 infants exposed to indomethacin for tocolysis, the risk for adverse neonatal outcomes was not increased (Loe et al. However, there were only three randomized clinical trials included and one of them did find an increased risk for adverse neonatal outcomes associated with indomethacin tocolysis. Sulindac was as effective as indomethacin, but with fewer adverse fetal effects in a randomized prospective study of 36 women in preterm labor (Carlan et al. No epidemiological studies of sulindac during pregnancy have been published, but it is probably associated with potential adverse effects similar to indomethacin. Owing to smooth muscle relaxation, there may be maternal hypotension and subsequent decreased uteroplacental perfusion, although in human studies there has been no evidence that nifedipine compromises the fetus (Ray and Dyson, 1995). In a preliminary study of nifedipine versus ritodrine, it was suggested that nifedipine was associated with fewer maternal and fetal side effects (van Dijk et al. A recent case report of severe hypotension and fetal death associated with nifedipine, tocolysis- ascribed causality (van Veen et al. No epidemiologic studies on the safety of this agent during pregnancy have been published.
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A body at temperature T1 in an environment at temperature T2 will both 4 emit and absorb radiation buy naproxen 250mg overnight delivery arthritis detox diet. The rate of energy emitted per unit area is eσT purchase naproxen with visa arthritis in neck horse, 1 4 and the rate of energy absorbed per unit is eσT purchase naproxen 250 mg with visa arthritis and fatigue. If a body at a temperature T1 is placed in an environment at a lower tem- perature T2 cheap naproxen american express arthritis knee surgery recovery, the net loss of energy from the body is 4 4 Hr eσ T − T (9. Diﬀusion is the main mechanism for the delivery of oxygen and nutrients into cells and for the elimination of waste products from cells. On a large scale, diﬀusive motion is relatively slow (it may take hours for the colored solution in our example to diﬀuse over a distance of a few centimeters), but on the small scale of tissue cells, diﬀusive motion is fast enough to provide for the life function of cells. Although a detailed treatment of diﬀusion is beyond our scope, some of the features of diﬀusive motion can be deduced from simple kinetic theory. Consider a molecule in a liquid or a gas which is moving away from the starting point 0. The molecule has a thermal velocity v and travels on the average a distance L before colliding with another molecule (see Fig. As a result of the collision, the direction of motion of the molecule is changed randomly. On the average, however, after a certain number of collisions the molecule will be found a distance S from the starting point. A statistical anal- ysis of this type of motion shows that after N collisions the distance of the molecule from the starting point is, on the average, S L N (9. A frequently used illustration of the random walk examines the position of a drunkard walking away from a lamppost. If the length of each step is 1 m, after taking 100 steps he will be only 10 m away from the lamppost although he has walked a total of 100 m. After 10,000 steps, having walked 10 km, he will be still only 100 m (on the average) from his starting point. Let us now calculate the length of time required for a molecule to diﬀuse a distance S from the starting point. Therefore, the mean free path of a diﬀusing molecule is short, about 10−8 cm (this is approximately the distance between atoms in a liquid). Gases are less densely packed than liquids; consequently, in gases the mean free path is longer and the diﬀusion time shorter. In a gas at 1 atm pressure, the mean free path is on the order of 10−5—the exact value depends on the speciﬁc gas. Consider a cylinder containing a nonuniform distribu- tion of diﬀusing molecules or other small particles (see Fig. Although this solution for the diﬀusion problem is not exact, it does illustrate the nature of the diﬀusion process. The net ﬂux from one region to another depends on the diﬀerence in the density of the diﬀusing particles in the two regions. The ﬂux increases with thermal velocity v and decreases with the distance between the two regions. In our previous illustration of diﬀusion through a ﬂuid, where L 10−8 cm and v 104 cm/sec, the diﬀusion coeﬃcient calculated from Eq. By comparison, the measured diﬀusion coeﬃcient of salt (NaCl) in water, for example, is 1. Thus, our simple calculation gives a reasonable esti- mate for the diﬀusion coeﬃcient. The diﬀusion coeﬃcients for biologically important molecules are in the range from 10−7 to 10−6 cm2/sec. Oxygen, nutrients, and waste products must pass through these membranes to maintain the life functions. In the simplest model, the biologi- cal membrane can be regarded as porous, with the size and the density of the pores governing the diﬀusion through the membrane. If the diﬀusing molecule is smaller than the size of the pores, the only eﬀect of the membrane is to reduce the eﬀective diﬀusion area and thus decrease the diﬀusion rate. If the diﬀusing molecule is larger than the size of the pores, the ﬂow of molecules through the membranemaybebarred. The permeability depends, of course, on the type of membrane as well as on the diﬀusing molecule. Permeability may be nearly zero (if the molecules cannot pass through the membrane) or as high as 10−4 cm/sec. Many membranes, for example, are permeable to water but do not pass molecules dissolved in water. As a result water can enter the cell, but the components of the cell cannot pass out of the cell. In the type of diﬀusive motion we have discussed so far, the movement of the molecules is due to their thermal kinetic energy. Some materials, however, are transported through membranes with the aid of electric ﬁelds that are gen- erated by charge diﬀerences across the membrane. We have shown that over distances larger than a few millimeters diﬀusion is a slow process. Therefore, large living organisms must use circulating sys- tems to transport oxygen nutrients and waste products to and from the cells. The evolution of the respiratory system in animals is a direct consequence of the inadequacy of diﬀusive transportation over long distances. At rest, an average 70-kg adult requires about 70 Cal of energy per hour, which implies a consumption of 14. It has been determined that in a person only about 2% of oxygen consumed at rest is obtained by diﬀusion through the skin. The lungs can be thought of as an elastic bag suspended in the chest cav- ity (see Fig. When the diaphragm descends, the volume of the lungs increases, causing a reduction in gas pressure inside the lungs. The trachea branches into smaller and smaller tubes, which ﬁnally terminate at tiny cavities called alveoli. Itis here that gas is exchanged by diﬀusion between the blood and the air in the lungs. The lungs of an adult contain about 300 million alveoli with diameters ranging between 0. The total alveolar area of the lungs is about 100 m2, which is about 50 times larger than the total surface area of the skin. In fact, the full 1 volume of the lungs is about 6 liter, and at rest only about liter is exchanged 2 during each breath. The oxygen requirement, of course, rises with increased physical activity, which results in both faster and deeper breathing.
Although scientists have long believed that codeine’s therapeutic effects come from morphine buy on line naproxen arthritis earth clinic, as the twenty-ﬁrst century began buy generic naproxen 250mg line arthritis in my dogs back legs, one group of researchers reported that persons whose bodies cannot properly convert codeine into morphine can nonetheless experience medical beneﬁt from codeine itself buy line naproxen arthritis in neck from car accident. The substance is considered one of the best cough medicines naproxen 250mg line arthritis medication generic, although re- search in the 1990s indicated the drug has little ability to control coughs from colds. One study of the drug’s ability to ease pain after tonsillectomy found its effective- ness comparable to morphine, but another tonsillectomy study found codeine no more effective than acetaminophen (Tylenol and similar products). Re- search examining pain from a wide variety of causes, ranging from cancer to backache, found no more discomfort relief from a combination dose of codeine Codeine 101 and acetaminophen than from combining hydrocodone and ibuprofen. Such ﬁndings probably indicate simply that various kinds of pain relievers work adequately for various discomforts, with codeine often being as good as the other drugs. Some regular codeine users take it to reduce anxiety, and some simply ﬁnd the substance’s effects pleasant. A clinical test of codeine found no antide- pressant action, but people who use codeine for a long time tend to be de- pressed and may be taking that drug to medicate themselves for depression— so if they have access to antidepressants they may have less interest in co- deine. Codeine cough syrups may include stimulants and other ingredients that persons ﬁnd pleasant, increasing the syrups’ appeal. Codeine can promote sleepiness, abdominal cramps, constipa- tion, urinary retention, nausea, and breathing impairment. A case report tells of a massive dose followed by several days of hallucinations and paranoia in a person already prone to psychiatric problems. After taking a dose, people should avoid operating dangerous machinery until they know the drug is not hindering their ability to do so. When 70 professional army drivers in Finland were tested in a driving simulator after taking 50 mg of codeine, they ran off the roadway more frequently than when they were under the inﬂuence of alcohol. Elderly persons who take codeine have an increased likelihood of hip fracture, presumably because the substance makes them woozy and more likely to fall. Codeine has been known to cause pancreatitis, particularly if the victim’s gallbladder has been surgically removed, but this effect is considered unusual. Medical personnel refrain from administering the drug through in- travenous injection because that route can lower blood pressure and blood oxygen to fatal levels. In two studies researchers found that people taking codeine felt few sen- sations from the drug and had normal performance on assorted tests of phys- ical and mental functioning. Those ﬁndings, however, may be related to dosages given by experimenters; higher dosages might well produce different results. Codeine abuse can be troublesome enough that persons need treatment to break the addiction. Nonetheless, prevalence of codeine addiction was disputed in 1989 by two authorities who carefully examined past reports of addiction: Little scientiﬁc research had been done on the topic, and most had involved persons already addicted to morphine. As morphine addicts will use codeine as a stopgap to hold off a withdrawal syndrome when their main drug is unavailable, their responses to codeine are not necessarily representative of a general popula- tion’s reactions. In addition, codeine cough syrups may contain a substantial percentage of alcohol, so heavy use of such a product can involve a further confounding factor of alcoholism. The 1989 authorities concluded that veriﬁ- able accounts of people being addicted primarily to codeine (rather than mainly to some other drug, with codeine on the side) were unusual. Dependence with codeine can develop; withdrawal symptoms are like those of morphine withdrawal, but milder. A study of rheumatism patients receiv- ing codeine found that quite a few needed higher doses to control pain as 102 Codeine months went by, but the increase was caused by decline of their physical condition rather than development of tolerance. The same study noted that almost no patients abused the drug, and of those few who did, all abused other substances as well. That ﬁnding is consistent with many observations of other drugs having abuse potential; only a small minority of users misuse them, and this minority is prone to problems with more than one substance. People having a bad relationship with codeine tend to have bad relationships with alcohol, marijuana, and (less commonly) her- oin. Background checks of deceased Los Angeles– area codeine abusers revealed almost 66% had attempted suicide, had a prior overdose on some drug, had been hospitalized for psychiatric problems, had been in physical ﬁghts, and had an alcohol problem (87% had an alcohol- related arrest record). Sometimes people develop an abusive relation- ship with a drug that is supplied to them through legitimate medical channels. Swedish researchers compared the use of codeine in that country to the use of propoxyphene, an opioid related to methadone. Those investigators found that doctors in two of Sweden’s largest cities typically tended to prescribe codeine to middle-aged females and that in one of those cities codeine was used the most in poor areas of town and was often associated with taking benzodiazepines frequently (in experiments the benzodiazepine diazepam lengthened the time that a codeine dose lasted, while codeine interfered with diazepam—suggesting that a codeine user would have to take more diazepam to get benzodiazepine sensations, consistent with the Swedish ﬁndings of in- creased benzodiazepine consumption among codeine users). Those kinds of codeine usage characteristics were not found for propoxyphene in the Swedish research even though both drugs would have opiate-type effects; the differ- ence in usage suggests that physicians’ customs may have been promoting codeine abuse. In drug abuse treatment programs codeine has been used successfully to shift addicts from other opiates—so successfully that one group of researchers suggests that codeine maintenance programs might be an alternative to meth- adone maintenance, particularly because codeine produces fewer unwanted effects than methadone. The antidepressants ﬂuoxetine (Prozac) and paroxetine interfere with the body’s transformation of codeine into morphine; therefore, persons taking those antidepressants are considered less likely to develop co- deine abuse (because they would experience fewer effects from codeine). Al- though codeine is weaker than morphine, similarities between the two drugs mean that interactions occurring with morphine can be expected to occur with codeine. Laboratory tests ﬁnd no evidence that the drug causes cell muta- tions that might lead to cancer. Experimenters gave codeine to rats and mice for two years and looked for evidence of cancer caused by the drug but found Codeine 103 none. Although no direct observations have noted codeine causing cancer in rats or mice, computer analysis of data from some experiments indicates that the drug may cause cancer in rodents. The human body produces very small amounts of codeine naturally, and researchers suspect this naturally occurring codeine may deter development of lung cancer; but those natural processes do not mean that doses of the drug would help prevent cancer. Co- deine reduced fetal weight in mice and hamsters in one experiment but did not increase the normal rate of defects in mice, nor was a statistically signif- icant change in malformation rate observed in hamsters. Investigators running another mice experiment, however, concluded that codeine does cause as- sorted malformations. Researchers seeking evidence about various human birth defects examined medical records of 100 to 199 women who used a cough remedy containing codeine and found that none of the offspring had any of the congenital abnormalities being investigated. Suspicion exists that codeine may cause cleft palate and cleft lip in humans, but birth defects are considered unlikely if the drug is used during pregnancy. A pregnant woman who takes codeine can produce an infant who is dependent on that drug and who undergoes a withdrawal syndrome upon birth. Codeine passes into the milk of nursing mothers, but researchers ﬁnd its level and that of its metabolite morphine to be acceptable if the woman is using codeine moderately. Nonetheless, nursing mothers are advised to avoid codeine because mechanisms that break down codeine in the body are incom- pletely formed in newborns, causing them to react more strongly to the drug than older children or adults. Volunteers report major changes in body perception, such as feeling porous or having an empty chest or absent hands. Hal- lucinations may seem real; typically they are visual, but sometimes sounds and smells are perceived as well. Users have reported that faces of individuals around them look different, taking on a masklike or caricature quality. Perception of space can also change; a room’s size may appear to grow, with walls getting further away or becoming curved, or motionless objects may appear to keep coming closer. Typically conscious- ness becomes fuzzy, with persons reporting they feel partially asleep. A researcher who engaged in self- experimentation, once a more common procedure in science but now uncom- mon, reported that his mood ﬂipped back and forth between happiness and anxiety.