By N. Kaelin. Huntington University. 2019.
Caffeine is a traditional remedy for alcohol intoxication viagra 50mg, but in fact it does not speed alcohol’s elimination from the body viagra 75mg, although caffeine’s stimulant properties may help a drunken person function better 50 mg viagra. Estrogen replacement therapy appears to interfere with women’s ability to metabolize caffeine viagra 50 mg. Indeed viagra 25mg, green and black tea reduce development of cancer in mice viagra 100mg, an effect in which caffeine is believed to play a part 100mg viagra. In humans viagra 25 mg, however 100 mg viagra, caffeine is suspected of promoting premenopausal ovarian cancer and also cancer of the pancreas and bladder viagra 100 mg. Experiments examining caffeine’s inﬂuence on pregnancy yield conﬂicting results, which may indicate the question is particularly complex or may simply mean that caffeine is an “invalid variable” having no effect. A 1994 survey of 259 women in the Netherlands found that caffeine raised the likelihood of becoming pregnant, but when the same subject was examined in the 1980s among almost 2,000 women in Connecticut, caf- feine was found to suppress fertility. During the 1990s a study of farm couples in Canada found that caffeine had no effect on fertility but that coffee-drinking women and tea-drinking men had lower birthrates, suggesting involvement of something besides caffeine in the natural products’ effect. Rat experimen- Caffeine 77 tation shows that caffeine reduces female fertility, produces smaller than usual offspring, and may affect brain development. Research in Yugoslavia indicates that pregnant women who do not smoke cigarettes but do take more than 71 mg of caffeine daily have smaller infants. A British study found the opposite; slightly smaller infants came from cigarette-smoking women who used 1,000 mg or more of caffeine a week, but the effect was not seen in nonsmokers. Still other studies ﬁnd no connection between caffeine and either birthweight or prematurity. Caffeine affects vital signs in a human fetus even when the dose is so low as to have no inﬂuence on the pregnant woman. Question has arisen about whether caffeine promotes spontaneous abortion; a study published in 1994 found 140 mg to 280 mg a day to pose a signiﬁcant risk; a rigorous study published in 1999 was unable to ﬁnd such a hazard among moderate caffeine users; and a study published in 1993 saw caffeine as reducing the incidence of spontaneous abortion. Still another study found that women who drank decaffeinated coffee were even more likely to expe- rience a spontaneous abortion than women who drank caffeinated coffee. Testing caffeine on mice produced birth defects in limbs, and tests on chicken embryos produced heart deformities. Chicken embryos, however, are so sensitive to various chemicals that such results are not con- sidered a warning of human danger. Indeed, a substantial body of research indicates that caffeine causes no human birth defects. Evidence does exist that caffeine can increase the likelihood of birth defects caused by alcohol and tobacco. A statistical study showed that women who use more than 300 mg of caf- feine daily around the time of conception and who do not smoke are less likely to have infants with Down syndrome. Given all the uncertainties, pregnant women are advised to use caffeine “moderately”—no more than 200 mg to 300 mg daily (150 mg or less is con- sidered “minimal”). Caffeine increases milk production in nursing mothers and passes into the milk but appears unharmful to infants if the women are moderate users. On occasions when mothers use a lot of caffeine, however, their nursing infants may be fussier and have more trouble sleeping. This substance is the ﬁrst synthetic central nervous system depressant, created in the 1830s. After that creation, however, several decades passed be- fore chloral hydrate’s medical usage as a sleep inducer began. In the nineteenth century the drug was popular among middle-class women and middle-aged men for reducing anxiety. In former times chloral hydrate was routinely administered to produce an- esthesia, but such use is tricky; the difference between an effective dose and a poisonous one is so close that the drug has been replaced by other substances for human anesthesia, although chloral hydrate is still used for that purpose in animals. The substance has been largely superseded by barbiturates but still has medical applications as a sedative and to induce sleep. Chloral hydrate is also used to treat seizures caused by fever and is a secondary choice for con- trolling the seizures of status epilepticus (an emergency in which persons keep having epileptic seizures, one after another, with little or no letup). The famed “Mickey Finn” drug used by criminals to knock out victims was a combination of chloral hydrate and alcohol, but animal and human experiments have failed to demonstrate that the combi- nation worked as advertised. The same research, however, also showed that if the product was taken to induce sleep the night before, persons performed better the next day after the drug had worn off, presumably because they were better rested than usual. At normal 80 Chloral Hydrate doses gastrointestinal distress may occur, and persons suffering from stomach irritation are supposed to avoid the compound. A case report notes a delib- erate overdose that destroyed part of a patient’s stomach. In high quantities the compound interferes with heart rhythm and reduces blood pressure and breathing; seizures are possible. Experiments using chloral hydrate on rats and mice have injured the liver, and inhaling the drug’s vapor has caused lung damage in mice. The substance is suspected of causing kidney damage and colon cysts and of aggravating a disease called porphyria. Although the substance is a de- pressant, some persons are stimulated by the drug. In the 1800s a number of prominent persons became addicted to chloral hydrate: English poet and painter Dante Gabriel Rossetti, German literary ﬁgure Karl Ferdinand Gutzkow, and renowned German philosopher Friedrich Wilhelm Nietzsche. Such addiction grew uncommon in the twentieth century as the drug itself grew less common. As is so often the case with drug abuse, chloral hydrate addicts were typically polydrug abusers, often using alcohol, opium,ormorphine as well. Today chloral hydrate does not seem to be a popular recreational intoxicant, quite possibly because the kind of person who would enjoy chloral hydrate may instead be attracted to barbiturates, a type of drug that was unavailable in the nineteenth century. No dependence developed after experimenters gave chloral hydrate to mon- keys twice a day for six weeks, but tolerance and dependence can develop in humans. Chloral hydrate withdrawal symptoms include tremors, worry, sleeping difﬁculty, confusion, delirium, hallucinations, and convulsions. Actions of anti–blood clotting medicines may be tem- porarily boosted by chloral hydrate, but the amount of change and its medical signiﬁcance are disputed. The drug may reduce blood levels of the epilepsy medicine phenytoin, thereby impeding phenytoin’s therapeutic actions. In mice experimentation chloral hydrate had inconsistent impact on alcohol blood level (sometimes raising it, sometimes reducing it) but extended the time that intoxication lasted. In humans the combination produces changes in heart rate and blood pressure that might harm cardiac patients (the face and neck of one volunteer turned reddish purple from the combination). Alcohol and chloral hydrate are both depressants, and taking them together is like taking an extra dose of one or the other. Lab tests of chloral hydrate’s potential for causing cancer have pro- duced mixed results. The compound has increased the liver cancer rate in mice, but skepticism exists about human relevance of those mice results be- cause dosage was long term and so high as to be poisonous—circumstances not at all similar to an occasional normal therapeutic dose. Experimenters administered the substance to hundreds of rats every day for over two years Chloral Hydrate 81 without evidence developing that the drug causes cancer. Chloral hydrate passes from a pregnant woman into the fetus but is not considered a cause of birth defects. Infants born to such women are, however, more likely to have a condition called hyperbilirubinemia, which can lead to jaundice. Some investigators also believe that administering the drug to infants after birth causes hyperbilirubinemia. The compound passes into the milk of a nursing mother, enough to slightly sedate the infant. Chlordiazepoxide was the ﬁrst benzodiazepine tranquilizer and has been commonly used since 1960. It is considered one of the safer psychiatric drugs and has actions comparable to those of barbiturates and alcohol. This classic benzodiazepine is used mainly for calming anxiety and for treat- ing symptoms of alcohol withdrawal, including delirium tremens. Studies have found, however, that alcoholics receiving this drug to help them through withdrawal are about three times more likely to resume drinking than alco- holics who receive a placebo. The substance is also used to overcome convul- sions and to treat insomnia, migraine headache, gastric ulcers, and irritable bowel syndrome (persistent cramps and diarrhea). Actions from a dose of this drug take longer to appear than actions from a dose of lorazepam or diaze- pam, so those latter substances are sometimes preferred when faster results are needed. Researchers have used rats and mice to demonstrate partial cross-tolerance between pentobarbital, alcohol, and chlordiazepoxide, and that relationship may contribute to the latter’s therapeutic role in treating alcohol withdrawal. An argument has been made that when clinical signs of alcohol withdrawal can be treated as well with chlordiazepoxide as with lorazepam, the former is preferable because of cheaper cost. Chlordiazepoxide can be substituted for alprazolam to wean someone from that drug, although one study found chlor- diazepoxide to be about 86 times weaker than alprazolam (consistent with animal experiments, where large doses of chlordiazepoxide are needed to pro- duce dependence). Chlordiazepoxide can be used in place of most benzodi- azepines if someone who stops taking one of those drugs is troubled by Chlordiazepoxide 83 withdrawal. An experiment found chlordiazepoxide to be as effective as meth- adone in easing opiate withdrawal symptoms experienced by heroin addicts. Chlordiazepoxide is one of the longer-lasting benzodiazepines, which can have advantages—but it can also have disadvantages; for example, the drug is associated with higher chance of hip fractures in older persons, perhaps because it makes them unsteady longer and more likely to fall. Blood disorders can be an unusual unwanted effect, and a case is reported in which long-term use produced purpura, tiny purple spots in the skin caused by bleeding under the skin surface. Although the drug is used to re- lieve anxiety, studies conﬂict on whether it increases users’ hostility. The drug reduces aggression in animal experiments, and human aggression is certainly not a typical result of a dose; perhaps lowered anxiety among resentful per- sons also lowers inhibitions, allowing those angry individuals to engage in aggression they had been afraid to attempt. That outcome is more likely when a person using chlordiazepoxide has also been drinking alcohol, and alcohol deﬁnitely can lower inhibitions. Chlordiazepoxide can make people weary, degrade verbal communication ability, and raise or lower interest in sex. A case report indicates that the substance may worsen symptoms of Parkinson’s disease, possibly due to untoward reaction with the Parkinson’s drug levodopa. Another case report notes a diabetic whose blood sugar levels rose substantially while taking chlor- diazepoxide. An instance is known of continual hiccups starting soon after a person started taking the drug and stopping soon after the drug dosage stopped. Persons who receive chlordiazepoxide by injection should avoid hazardous activity (such as driving a car) for several hours; a test of the oral format showed that it lowered driving ability as well. A study of bronchitis patients found that the drug worsened their breathing, and in general the compound impairs respiration. Chlordiazepoxide is also suspected of worsening porphyria, a dis- ease involving body chemistry and that makes a person extremely sensitive to light. Sudden stoppage of chlordiazepoxide dosage can produce symptoms similar to those of alcohol or barbiturate withdrawal: tremors and cramps, vomiting, perspiring, and even convulsions. In mice chlordiazepoxide can increase potency of the anticancer drug ifosfamide, and in both mice and humans alcohol can boost chlordiazepoxide’s potency (though a rat experi- ment did not ﬁnd that effect). Cigarette smoking 84 Chlordiazepoxide reduces chlordiazepoxide actions, and morphine and meperidine each make oral dosage of chlordiazepoxide less effective. The drug is suspected of af- fecting blood clotting and is known to constrain the healing abilities of the anticoagulant medicine warfarin. Some studies suggest that using chlor- diazepoxide during pregnancy may cause human birth defects, but conﬁr- mation is elusive. For example, a study of 50,000 pregnancies published in 1975, including many women who used chlordiazepoxide, found no difference in outcome regardless of whether women used the drug. In contrast, a study of almost 20,000 pregnancies (published in 1974) compared women who took chlordiazepoxide to those who took assorted other antianxiety drugs or none at all in early pregnancy. In the chlordiazepoxide group birth defects were more than two times as frequent compared to the “other drugs” group and over four times as frequent compared to the “no drug” group. Some research- ers believe chlordiazepoxide may cause infant skull deformities if a pregnant woman uses the drug. Limbitrol is a combination product using chlordi- azepoxide to reduce anxiety and amitriptyline as a tricyclic antidepressant. An experiment with hamsters showed that the drug combination is more likely to produce birth defects than either drug alone. Amitriptyline is Pregnancy Category C and passes into a nursing mother’s milk supply. Primary medical uses are against some kinds of convulsions, par- ticularly in certain kinds of epilepsy, and against panic attacks. For persons suffering from panic attacks, measurements indicate the drug improves both quality of life and work productivity. The drug is also used as an antidepres- sant and to treat anxiety, catatonia, obsessive-compulsive disorder, the manic phase of manic-depressive behavior, and social phobia in general. A two-year follow-up study of persons receiving brief clonazepam treatment for social phobia found their improvement to be sustained after dosage stopped, and at the two-year mark they were doing better than a control group that had re- ceived a placebo. Clonazepam is sometimes preferred over alprazolam in treating anxiety because that condition seems less likely to reappear between doses of clonazepam than between doses of alprazolam. Clonazepam can be substituted for alprazolam in order to withdraw persons who have depen- dence with the latter drug. Clonazepam has been used to ﬁght tics and also to treat muscle control diseases such as akathisia and tardive dyskinesia. Although clonazepam is not a multiple sclerosis medicine, it is administered to relieve the afﬂiction’s symptoms. It is prescribed to relieve insomnia and to reduce a disorder in which sleeping persons thrash about. The substance has promoted cure of sleepwalking, including a docu- mented extreme case in which a sleeping person would drive a car and engage in violence involving knives.
In living organisms 50mg viagra, membranes comprise the largest surface 100mg viagra, covering all cells (the plasma membrane) and many cell organelles (the nucleus viagra 100mg, mitochondria 100 mg viagra, and so forth) viagra 75mg. Dissolved macromolecules such as proteins also account for an enormous surface area (e viagra 50 mg. Biological membranes also (i) serve as a scaffold that holds a large variety of enzymes in proper orientation viagra 50mg, (ii) provide and maintain a sequential order of enzymes that permits great efficiency in multistep reactions viagra 75 mg, and (iii) serve as the boundaries of cells and many tissue compartments 50 mg viagra. It is therefore apparent why the physical chemistry of surfaces and the structure and activity of surface-active agents are also of interest to the medicinal chemist viagra 25mg. Antimicrobial detergents and many disinfectants exert their activity by interacting with biological surfaces and are important examples of surface-active drug effects. We have already discussed the hydrogen-bonding interaction of water molecules that creates clusters. The water molecules at a gas–liquid interface, however, are exposed to unequal forces, and are attracted to the bulk water of the liquid phase because no attraction is exerted on them from the direction of the gas phase. Because the dissolution of a solid is the result of molecular interaction between a solvent and the solid (which, once dissolved, becomes a solute), polar compounds capable of forming hydrogen bonds are water soluble, whereas nonpolar compounds dissolve only in organic solvents as the result of van der Waals and hydrophobic bonds. The nonpolar alkyl chains are in the nonpolar phase; the polar carboxylate head groups are in the aqueous phase. Only in this way can amphiphilic detergents, through their hydrogen bonding with water and nonpolar interaction with a nonpolar (organic) phase or with air, maintain an orientation that ensures the lowest potential energy at an interface. A classic example of such behavior is given by soap, a mixture of alkali-metal salts of long-chain fatty acids. At a higher concentration, the molecules find it more energy efficient to “remove” their hydrophobic tails from the aqueous phase and let them interact with each other, thus forming a miniature “oil drop” or nonpolar phase, with the polar heads of the soap molecules in the bulk water. At a concentration that is characteris- tic for a given individual detergent, molecular aggregates, known as micelles, are formed. The concentration at which such micelles are formed is called the critical micellar concentration, and can be determined by measuring the light diffraction of the solution as a function of detergent concentration. When soap is dispersed in a nonpolar phase, inverted micelles are formed in which the nonpolar tails of the soap molecules interact with the bulk solvent while the hydrophilic heads interact with each other. This behavior of amphiphilic molecules explains how they can disperse nonpolar particles in water: the hydrocarbon tail of the amphiphile interacts with the particle, such as an oil droplet, dirt, or a lipoprotein membrane fragment, covers the particle, and then presents its hydrophilic head groups to the aqueous phase. This patient had a seven–year history of epilepsy, well controlled with the drug phenytoin at a dose of 300 mg/day. When asked why he had stopped taking his phenytoin he stated that he had not, but had been taking the same dose for years. She stated that he took his daily dose of phenytoin every morning at breakfast and that she had witnessed his doing so, every day for the past six years. Upon questioning, it was discovered that this individual purchased his phenytoin in bottles of 1,000 capsules, in order to save money. He routinely stored this phenytoin in the basement of his home—a relatively damp and cool location—for months at a time; one week earlier he had started to use the capsules from one of these old stored bottles. When thirty “old” capsules from this recently opened bottle of 1000 capsules were weighed, all had masses in excess of 295 mg. When thirty capsules from a recently pur- chased supply of “new” phenytoin were weighed, all had masses less than 280 mg. An examination of an old capsule revealed that the contents were hardened and slightly dis- coloured. Subsequent analyses revealed that the phenytoin within the old capsules had become excessively hydrated from the ambient humidity of their storage conditions. The resulting hardened mass of drug material was less soluble within the gastrointesti- nal tract and was thus less bioavailable for absorption. Many factors can influence the bioavailability of a drug molecule following oral absorption. Damp storage conditions of the drug can cause increased molecular hydra- tion with concomitant altered solubility. When a drug molecule is crystallized using dif- ferent solvents or different conditions, the resulting change in crystal morphology can influence bioavailability and thus alter biological results. The inter- action of the drug molecule’s pharmacophore with its complementary receptor during the pharmacodynamic phase of drug action is dependent upon a geometrically precise and accurate intermeshing of two molecular fragments. A rigorous control of molecu- lar geometry and shape is crucial to the drug design process. Knowledge of molecular geometry also plays an important role in understanding quantitative structure–activity relationships during drug optimization (see section 3. Conformational isomerism is the process whereby a single molecule undergoes transi- tions from one shape to another; the physical properties of the molecule have not changed, merely the shape. Conformational isomerism is demonstrated by compounds in which the free rotation of atoms around chemical bonds is not significantly hindered. Rotation around torsional angles permits many different conformers (shapes) of a molecule. The concept and biophysical reality of “preferred” drug conformations and their potential role in receptor binding are currently important issues among drug designers. For aliphatic compounds, the well-known Newman projection is used to show the relative position of the substituents on two atoms connected to each other (as in ethane derivatives). When the trimethylammonium-ion and acetoxy functional groups are as far removed as possible, we speak of a fully staggered conformation (erroneously and confusingly also called a trans conformation). Between these two extremes are an infinite number of conformers called gauche (or skew) conformers or rotamers (rotational isomers). The potential interaction energy of the trimethylammonium-ion and acetoxy groups is lowest in the staggered conformation and highest when the two groups are eclipsed. An exception to this exists when two functional groups show a favorable nonbonding interaction (e. Since the transition between rotamers occurs very rapidly, the existence of any one conformer can be discussed in statistical terms only. For example, in acyclic hydrocar- bon molecules, it has been assumed that long hydrocarbon chains exist in the staggered, fully extended, zigzag conformation. There is, however, a considerable probability of their also existing in skew conformations, effectively reducing the statistical length of the carbon chain. Such considerations become important if one wishes to calculate effective intergroup distances in drugs, which play a role in the geometric fit and bind- ing to receptors. Many publications have proposed receptor mapping techniques based on the distances between assumed key atoms (usually heteroatoms) or functional groups in drugs, determined by prolonged quantum-chemical calculations of “preferred” conformers. Similarly, the design of a number of drugs has been based on questionable assumptions about drug–receptor binding, all founded on conformational analysis. Such caveats, however, do not detract from the utility of conformational analysis of drugs, from the importance of calculating intergroup geometric distances, or from the potential value of these methods in drug design and molecular pharmacology. Flexible molecules that lack conformational constraints may assume a variety of dif- ferent conformations, thus increasing the likelihood of drug toxicity by enabling inter- actions with undesirable receptor sites. The drug designer may address these problems by using various methods to decrease the degrees of conformational freedom. For instance, within the hydrocarbon skeleton of a drug, an alkane moiety could be replaced by either an alkene or an alkyne; the increased barrier to rotation around double or triple bonds (as compared to single bonds) adds a considerable measure of conformational constraint. However, one of the most popular techniques for decreasing conformational freedom is to replace acyclic hydrocarbon fragments with cyclic fragments, such as cyclohexane rings or aromatic rings. The conformational analysis of cyclohexane and its derivatives has been well explored. The chair conformation is more stable than either the boat or twist form because it permits the maximum number of substituents to exist in a staggered conformation relative to their neighbors. The sub- stituents can assume two conformations relative to the plane of the ring (defined by carbon atoms 2, 3, 5, and 6): axial (a), in which they point up or down; and equatorial (e), in which they point in the direction of the ring’s circumference. As the cyclohexane ring keeps flipping back and forth between many chair forms, the substituents on the ring alter- nate between axial and equatorial conformations unless stabilized (see figure 1. Although cyclohexane is more conformationally rigid than an acyclic hydrocarbon, there are several ways to additionally stabilize or “freeze” the conformation of a cyclohexyl ring. By using a bulky substituent like the tert-butyl group, which always maintains an equatorial position. Polycyclic structures, such as decaline or the steroids, are rigid and maintain stable conformations. The chair conformation is more stable than the boat or twist because it permits a maximal number of substituents to exist in a staggered conformation relative to their neighbors. In substituted cyclohexanes, or their heterocyclic analogs, 1,2–diaxial or the equivalent diequatorial substituent pairs are considered to be trans, while the axial–equatorial pair is regarded as cis. The axial or equatorial nature of a substituent has a bearing on its reactivity, or abil- ity to interact with its environment. Equatorial substituents are more stable and less reactive than their axial counterparts. For example, equatorial carboxyl groups are stronger acids than axial ones because of the higher stability of the carboxylate ion, whereas equatorial esters are hydrolyzed more slowly than axial ones because they are less accessible to protons or hydroxyl ions during acid- or base-catalyzed hydrolysis. Even better than an acyclic saturated hydrocarbon such as cyclohexane is the use of aromatic rings, especially polyaromatic systems. Drugs in which the functional groups are appended to an aromatic ring have marked conformational rigidity. In the realm of neurologic drug design, the use of tricyclic structures containing aromatic rings is extremely common in major antipsychotics (e. Although they are superb for achieving planarity and rigidity, polyaromatic systems may come accompanied with the risk of a side-effect—carcinogenicity. When contemplating the effect of drug conformation on drug–receptor interactions, one must not forget that the receptor macromolecule also undergoes changes in its molecular geometry, as postulated by the Koshland induced-fit hypothesis (see chapter 2). Owing to the enormously more complex nature of macromolecular structure, less is known about such changes. Many examples of conformational changes of enzymes during their reac- tions with substrates have been well studied and described in the literature, including those of carboxypeptidase, dihydrofolate reductase, and acetylcholinesterase (see section 7. At times, a large, bulky sub- stituent appended to a fragment within a drug molecule may physically impede the geometry of interaction between a drug and its receptor. Another classical measure of the molecular geometry of substituents is the Verloop steric parameter. This is calculated from bond angles and atomic dimensions—primarily the lengths of substituent groups and several measures of their width. Trivial as this may sound, the consideration of molecular “bulk” is an important and often neglected factor in making multiple quantitative correlations of structure and pharmacological activity. This means that there is a difference in action between stereoisomers of the same compound, with one isomer showing pharmacological activity while the other is more or less inactive. In 1860, Louis Pasteur was the first to demonstrate that molds and yeasts can differentiate between (+)- and (−)-tartarates, utilizing only one of the two isomers. Therefore, complementarity between an asymmetric drug and its asymmetric receptor is often a criterion of drug activity. The effects of highly active or highly specific drugs depend more upon such complementarity than do those of weakly active drugs. Occasionally, the stereoselectivity of a drug is based on a specific and preferential metabolism of one isomer over the other, or on a biotransformation that selectively removes one isomer. Since this hydroxylated metabolite is pharmacologically active, the stereochemical circumstances of the activation process are crucial, not only for the extent of the activation but also for the rate of elimination of the metabolite. The basic aspects of optical isomerism are discussed in various textbooks of organic chemistry. Optical isomers (enantiomers) may have different physiological activities from each other provided that their interaction with a receptor or some other effector structure involves the asymmetric carbon atom of the enantiomeric molecule and that the three different sub- stituents on this carbon atom interact with the receptor. The Easson–Stedman hypothesis assumes that a three-point interaction ensures stereospecificity, since only one of the enantiomers will fit; the other one is capable of a two-point attachment only, as shown in figure 1. However, it is reasonable to assume that receptor stereospecificity can also undergo a change when the receptor conformation is altered by a receptor–drug interaction. Qualitatively, dextrorphan is not an analgesic at all, but a very effective antitussive (cough suppressant), an action entirely different from analgesia. It should be emphasized that the mere sign (+ or −) of the optical rotation produced by an enantiomer is not biochemically decisive to the action of such a molecule. The absolute configuration of the compound in question must be considered; in modern organic chemistry the Cahn–Ingold–Prelog sequence rules are followed, and have increasingly replaced the ambiguous and obsolescent D and L designations for relative configuration. Stereoisomerism may also occur around double bonds, producing cis or trans orientations of the substituents on either face of the double bond. Even though enantiomeric drug pairs quite often show different potencies, they are seldom antagonists of each other, since the differences in their action are due to differ- ences in their binding properties; antagonists (see section 2. Diastereomeric drugs—those having two or more asymmetric centers—are usually active in only one configuration. Unlike enantiomers, which have identical physico- chemical properties, the absorption, distribution, receptor binding, metabolism, and every other aspect that influences the pharmacological activity of a drug are different for each diastereomer. Because of wide- spread misconceptions, the distomer of a racemate is often considered “inactive” and of no consequence to pharmacological activity, an idea reinforced by the fact that resolution (i. The distomer should therefore be viewed as an impurity constituting 50% of the total amount of a drug—an impurity that in the majority of cases is by no means “inert. However, there are instances in which the use of a racemate has advantages; sometimes it is more potent than either of the enantiomers used separately (e. However, now that we are in the 21st century, the need for optically active drugs capable of stere- ospecific interactions with drug receptors is a recognized prerequisite in drug design. These isomers are not mirror images and have very different physicochemical properties, as reflected in their phar- macological activity. Because the functional groups in these molecules are separated by different distances in the different isomers, they cannot as a rule bind to the same recep- tor. Therefore, geometric isomerism as such may be of interest to the medicinal chemist. In biological systems, there are a number of examples of the importance of cis/trans isomerization. Rod cells and cone cells are the two types of light-sensitive receptor cells in the human retina.
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Transepidermal water loss and water content in the stratum corneum in infantile seborrhoeic dermatitis. Correction of essential fatty acid deﬁciency in man by the cutaneous application of sunﬂower-seed oil. The repair of impaired epidermal barrier function in rats by the cutaneous application of linoleic acid. Selective recovery of deranged Moisturizers 91 water-holding properties by stratum corneum lipids. Dietary supplementation with ethyl ester concentrates of ﬁsh oil (n-3) and borage oil (n-6) polyunsaturated fatty acids induces epidermal generation of local putative anti-inﬂammatory metabolites. Anti-inﬂammatory effects of eicosapentaenoic acid on experimental skin inﬂammation models. Highly puriﬁed omega- 3-polyunsaturated fatty acids for topical treatment of psoriasis. Effect of di- etary supplementation with n-3 fatty acids on clinical manifestations of psoriasis. A randomized, double blind, placebo-controlled study to evaluate the effect of ﬁsh oil and topical corticosteroid therapy in psoriasis. Dietary supple- mentation with very long-chain n-3 fatty acids in patients with atopic dermatitis. Atopic eczema unresponsive to evening primrose oil (linoleic and α- linolenic acids). Atopic eczema unresponsive to evening primrose oil (linoleic and α-linolenic acids). Double-blind, multicentre analysis of the efﬁcacy of borage oil in patients with atopic eczema. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Stratum corneum lipid morphology and transepidermal water loss in normal skin and surfactant-induced scaly skin. Topical stratum corneum lipids accelerate barrier repair after tape stripping, solvent treatment and some but not all types of detergent treatment. A method for the study of the effect of barrier creams and protective gloves on the percutaneous absorption of solvents. Skin protection against ionized cobalt and sodium lauryl sul- phate with barrier creams. The inﬂuence of two barrier creams on the percutaneous absorption of m-xylene in man. Commercially available barrier creams versus urea- and glycerol-containing oil-in-water emul- sions. Opposing effects of glycerol on the protective function of the horny layer against irritants and on the penetration of hexyl nicotinate. Decreased level Moisturizers 93 of ceramides in stratum corneum of atopic dermatitis: An etiologic factor in atopic dry skin? Decreased stratum corneum ceramides in atopic individuals—a pathobiochemical factor in xerosis? Lipid composition of outer stratum corneum and nails in atopic and control subjects. Studies of the barrier in ‘‘dry’’ and clinically normal skin of patients with atopic dermatitis. Quantiﬁcation of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyosis. The effect of 4 barrier creams on the absorption of water, benzene, and formaldehyde into excised human skin. Effect of long-term use of moisturizers on skin hydration, barrier function and susceptibility to irritants. Efﬁcacies of a barrier cream and an afterwork emollient against cutting ﬂuid dermatitis in metalworkers: a prospective study. Regula- tion of epidermal sphingolipid synthesis by permeability barrier function. Transepidermal water loss: the signal for recovery of barrier structure and function. Transepidermal water loss and absorption of hydro- cortisone in widespread dermatitis. In vivo relationship be- 94 Loden´ tween percutaneous absorption and transepidermal water loss according to ana- tomic site in man. Basal transepidermal water loss, skin thickness, skin blood ﬂow and skin colour in relation to sodium-lauryl-sulphate-induced irritation in normal skin. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Cano- derm). The effect of two urea-containing creams on dry, eczematous skin in atopic patients. Assessment of efﬁcacy and side-effects by non-invasive techniques and a clinical scoring scheme. The effect of several lotions on the progression of dam- age and healing after repeated insult with sodium lauryl sulfate. Differences between a urea-con- taining emulsion and its placebo in affecting skin susceptibility to surfactant- induced irritation. The efﬁcacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and deter- gents. Methodology to measure the transient effect of occlusion on skin penetration and stratum corneum hydration in vivo. A silicone membrane sandwich method to measure drug transport through isolated human stratum corneum having a ﬁxed water content. The diffusion of water across the stratum corneum as a function of its water content. Hydration of human stratum corneum studied in vivo by optothermal infrared spectrometry, electrical capacitance measurement, and evaporimetry. A multicenter comparison of different test methods for the assessment of the efﬁcacy of skin care products with 368 human volunteers. The inﬂuence of urea on the penetration kinetics of topically applied corticosteroids. The inﬂuence of urea on the penetration kinetics of vitamin-A-acid into human skin. Effect of fatty acids and urea on the penetra- tion of ketoprofen through rat skin. The effect of urea and lactic acid on the percutaneous absorption of hydrocortisone. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. Lipid content and lipid type as determinants of the epidermal permeability barrier. Effect of mineral oil and linoleic-acid-containing emulsions on the skin vapour loss of sodium-lauryl- sulphate-induced irritant skin reactions. The efﬁcacy of different moisturiz- ers on barrier recovery in hairless mice evaluated by non-invasive bioengineering methods. Relationship between skin permeabil- ity and corneocyte size according to anatomic site, age, and sex in man. The European Commission has been wiser and its 1976 deﬁnition of cosmetics was modiﬁed in 1993 to acknowledge the fact that everything put on the skin or hair may have a physio- logical effect (1). It puts the responsibility on the industry to ascertain product safety and efﬁcacy (claims justiﬁcation) (2). Natural extracts, whether from animal, botanical, or mineral origin, have been used as ‘‘active ingredients’’ of drugs or cosmetics for as long as human history can go. Oils, butter, honey, beeswax, lead, and lemon juice were common ingredients of the beauty recipes from ancient Egypt. Many botanical extracts are used today in traditional medicine and large pharmaceutical companies are rediscovering them. The major differences between the drug and the cosmetic approach rely on the intent (i. In the drug industry, you need to know the chemical structure of the active ingredient within the extract, very often to synthesize it, to purify it, sometimes to discover that isolation and puriﬁcation leads to a loss in the biologi- 97 98 Khaiat cal activity, or to realize that, despite all the skills of organic chemists, nature is not easy to reproduce. There are plant pow- ders for hair coloring (Henne), scrubs (apricot kernel, corn), or masks (oat ﬂour); plant extracts (‘‘as is’’ or puriﬁed); and biotechnology extracts obtained through fermentation, cloning, soilless culture (aquaculture, artiﬁcial media, etc. Therefore, it is usually only one part of the plant that is used: fruit, bark, root, bud, ﬂower, leaves, etc. Depending on the future use of the extract, various extraction processes can be used. As mentioned, it is industry’s responsibility to ensure the absence of toxic substances that could lead to unwanted side effects. The drug approval process allows side effects to be present provided the beneﬁts outweight the dis- advantages, while the cosmetics consumer has the choice of using a product that may have side effects or using another that has none, the product with side effects would not be acceptable. Total Extracts Total extracts are most common in the cosmetics industry, rarely, if ever, used in drugs.
Opposing effects of glycerol on the protective function of the horny layer against irritants and on the penetration of hexyl nicotinate 50mg viagra. Decreased level Moisturizers 93 of ceramides in stratum corneum of atopic dermatitis: An etiologic factor in atopic dry skin? Decreased stratum corneum ceramides in atopic individuals—a pathobiochemical factor in xerosis? Lipid composition of outer stratum corneum and nails in atopic and control subjects 50 mg viagra. Studies of the barrier in ‘‘dry’’ and clinically normal skin of patients with atopic dermatitis 100mg viagra. Quantiﬁcation of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyosis 100 mg viagra. The effect of 4 barrier creams on the absorption of water 25 mg viagra, benzene viagra 50mg, and formaldehyde into excised human skin 25mg viagra. Effect of long-term use of moisturizers on skin hydration viagra 75 mg, barrier function and susceptibility to irritants viagra 75mg. Efﬁcacies of a barrier cream and an afterwork emollient against cutting ﬂuid dermatitis in metalworkers: a prospective study viagra 100 mg. Regula- tion of epidermal sphingolipid synthesis by permeability barrier function. Transepidermal water loss: the signal for recovery of barrier structure and function. Transepidermal water loss and absorption of hydro- cortisone in widespread dermatitis. In vivo relationship be- 94 Loden´ tween percutaneous absorption and transepidermal water loss according to ana- tomic site in man. Basal transepidermal water loss, skin thickness, skin blood ﬂow and skin colour in relation to sodium-lauryl-sulphate-induced irritation in normal skin. Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Cano- derm). The effect of two urea-containing creams on dry, eczematous skin in atopic patients. Assessment of efﬁcacy and side-effects by non-invasive techniques and a clinical scoring scheme. The effect of several lotions on the progression of dam- age and healing after repeated insult with sodium lauryl sulfate. Differences between a urea-con- taining emulsion and its placebo in affecting skin susceptibility to surfactant- induced irritation. The efﬁcacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and deter- gents. Methodology to measure the transient effect of occlusion on skin penetration and stratum corneum hydration in vivo. A silicone membrane sandwich method to measure drug transport through isolated human stratum corneum having a ﬁxed water content. The diffusion of water across the stratum corneum as a function of its water content. Hydration of human stratum corneum studied in vivo by optothermal infrared spectrometry, electrical capacitance measurement, and evaporimetry. A multicenter comparison of different test methods for the assessment of the efﬁcacy of skin care products with 368 human volunteers. The inﬂuence of urea on the penetration kinetics of topically applied corticosteroids. The inﬂuence of urea on the penetration kinetics of vitamin-A-acid into human skin. Effect of fatty acids and urea on the penetra- tion of ketoprofen through rat skin. The effect of urea and lactic acid on the percutaneous absorption of hydrocortisone. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. Lipid content and lipid type as determinants of the epidermal permeability barrier. Effect of mineral oil and linoleic-acid-containing emulsions on the skin vapour loss of sodium-lauryl- sulphate-induced irritant skin reactions. The efﬁcacy of different moisturiz- ers on barrier recovery in hairless mice evaluated by non-invasive bioengineering methods. Relationship between skin permeabil- ity and corneocyte size according to anatomic site, age, and sex in man. The European Commission has been wiser and its 1976 deﬁnition of cosmetics was modiﬁed in 1993 to acknowledge the fact that everything put on the skin or hair may have a physio- logical effect (1). It puts the responsibility on the industry to ascertain product safety and efﬁcacy (claims justiﬁcation) (2). Natural extracts, whether from animal, botanical, or mineral origin, have been used as ‘‘active ingredients’’ of drugs or cosmetics for as long as human history can go. Oils, butter, honey, beeswax, lead, and lemon juice were common ingredients of the beauty recipes from ancient Egypt. Many botanical extracts are used today in traditional medicine and large pharmaceutical companies are rediscovering them. The major differences between the drug and the cosmetic approach rely on the intent (i. In the drug industry, you need to know the chemical structure of the active ingredient within the extract, very often to synthesize it, to purify it, sometimes to discover that isolation and puriﬁcation leads to a loss in the biologi- 97 98 Khaiat cal activity, or to realize that, despite all the skills of organic chemists, nature is not easy to reproduce. There are plant pow- ders for hair coloring (Henne), scrubs (apricot kernel, corn), or masks (oat ﬂour); plant extracts (‘‘as is’’ or puriﬁed); and biotechnology extracts obtained through fermentation, cloning, soilless culture (aquaculture, artiﬁcial media, etc. Therefore, it is usually only one part of the plant that is used: fruit, bark, root, bud, ﬂower, leaves, etc. Depending on the future use of the extract, various extraction processes can be used. As mentioned, it is industry’s responsibility to ensure the absence of toxic substances that could lead to unwanted side effects. The drug approval process allows side effects to be present provided the beneﬁts outweight the dis- advantages, while the cosmetics consumer has the choice of using a product that may have side effects or using another that has none, the product with side effects would not be acceptable. Total Extracts Total extracts are most common in the cosmetics industry, rarely, if ever, used in drugs. Their activity is often empirical and their active ingredients are not al- ways identiﬁed, but their beneﬁts are, very often, without possible doubt. Their mode of preparation can be found in traditional pharmacopeas (China, India, Africa, Europe, America), or from observing shamans or traditional practitioners. Very often, plants are blended in order to better control or synergize their effects, but sometimes also to preserve the secret of the active ingredient. These processes allow for better controls: stability, preservation, manufac- turing reproducibility. The content of the extract is very much a function of the type of solvent, the temperature, the plant:solvent ratio, the time of contact, the part of the plant used and its species. Sometimes it is also dependent of the plant culture conditions and the season of harvest. In the drug industry, especially, the extract must be concentrated and the active material isolated by selective precipitation, chromatography, electrophore- sis, etc. Solvents have to be carefully chosen, not only for their extraction proper- ties, but also for their compatibility with the ﬁnal formulation and their harm- lessness. Selective Extracts Special extraction processes or the use of speciﬁc solvents will lead to the obten- tion of a speciﬁc class of molecules. The fragrance industry has for centuries obtained essential oils or ﬂoral water by water vapor extraction or ‘‘enﬂeurage’’—a process by which the plant ﬂowers are put in contact with solid fats and terpens and sesquiterpens migrate into the oil phase. The use of vegetable oils as solvent allows for the extraction of oil-soluble vitamins or lipids. Puriﬁcation Extract puriﬁcation to separate speciﬁc molecules from others are done following classic physicochemical processes—cryoprecipitation, column chromatography, electrophoresis, use of selective solvents and salts, etc. Biotechnology Extracts Biotechnology can be used to obtain, purify, or transform extracts. One can ﬁnd different enzymes to be used for very speciﬁc reactions in certain conditions. They could become an alternative to chemical reactions as they provide stereospeciﬁcity or eliminate the risk of solvent residues. Today, protein hydrolysates obtained by enzymatic 100 Khaiat reaction are free of the chlorine residues formed when acid hydrolysis is used. In addition, the use of exo-, endo-, or amino-acid-speciﬁc proteases allows for a better control of the end result. Enzymes will allow for better yields by transforming or releasing speciﬁc molecules (use of pectinases, β-glucosidase, β-glucanase, lipases, transferases, esterases, etc. Amino acids, polyols, esters of fatty acids, polyol organic acids, more stable liposoluble vitamin esters with slow release properties, and new molecules (5) can be obtained. Usage Extracts or puriﬁed botanical molecules can be incorporated directly into solu- tions, emulsions, or vectors or can be used to form a vector (liposomes, phyto- somes, phytospheres) (6). They can be topically applied, ingested, or injected, depending on the intended use and provided absence of toxicity has been shown. For example, lilium bulb oil extract use for sunburns has been reported since ancient Greece, while the water extract has been shown to be toxic. Natural ingredients have been shown to have a broad spectrum of activity, including hallucinogenic mushrooms and cardiotonic belladona. Scientiﬁc research conducted on plant extracts described in traditional pharmacopeas (7,8) has led to a broader range of potential applications. Furthermore, research conducted during the last 10 years on skin biology allows us to better understand the biological mechanisms involved in dehydra- tion, aging, etc. This, in turn, leads to the search for extracts with speciﬁc activi- ties for targeted applications. Antioxidants Free radicals have been shown to play a major role in sun damage as well as in aging or in pollution (tobacco, stress). Free radical actions can be blocked by the following Vegetable oils rich in tocopherols and tocotrienols. Wheat germ oil and palm oil are particularly rich in tocopherols and α-, β-, γ-tocotrienols. Carotenoids, such as β-carotene, found in plants or in part of plants ex- posed to the sun. However, under extreme conditions (high salinity, low pH, high sunlight, lack of nitrogen or phosphorus), they protect themselves by multiplying their β-carotene concentration by 10. The ponds become red, and the β-carotene concentration can reach 14% of their dry weight. As ﬁrst shown by Kligman (10), the action of retinoids and carotenoids (11) on sun damage has led to numerous works. Ascorbic acid, which can be found in Rosa canina (dog rose) fruits, actini- dia (kiwi fruits), or Malphigia punicifolia (West Indian cherry) is an antioxidant that is also used for many of its other properties. It is active in the synthesis of carnitin, a molecule intervening in the transfer of lipids inside the mitochondria. Ascorbic acid thus plays a role in im- proving cell resistance due to a better use of lipids. Ascorbic acid is an anti-inﬂammatory agent that degrades and eliminates histamine. Flavonoids, rich extracts from Gingko, Fagopyrum (buckwheat), Eucalyp- tus sambucus (European elder), or Sophora japonica are used for their antioxidant and anti-free-radical properties (13). Rosmarinus (rosemary) extracts, rich in carnosic acid, are very potent anti- oxidants, used to protect food. They favor the exchanges between the inner and the outer compartment of the cells or between cells. Some of these have excep- tional healing properties that make them of particular value in sun or antiage products: camelia (tea), argania, medicago (alfalfa), spinacia (spinach), Butyro- spermomum (shea butter), Cucurbitaceae, Pongamia (hongay or pongamia oil). Phytosterols slow down the aging process by favoring fatty acid desatura- tion, which in turn maintains membrane ﬂuidity and catalytic activity. One can also ﬁnd plant waxes (sugar cane, Camauba, Ceroxylon, Jojoba, rose) which are used to protect lips, hands, or face from dehydration. Certain plants (yeast, wheat, apple, potatoes, rice bran, Agaricus, Morus alba, or white mulberry) are rich in ceramides and glycosylceramides. These may be used for their action on skin or hair to provide hydration or reconstitute epider- mal barrier function. Other plants are rich in oils containing very long-chain fatty acids (C22, 24, 26) like Pentaclethra or ewala oil used in Africa as a massage oil, or Lim- nanthes alba or shambrilla oil. Fat Storage and Slimming We are currently using botanical extracts with very speciﬁc actions that act at various levels of adipocyte metabolism. Phytosterols from plant oils are being investigated for their potential action Botanical Extracts 103 on fat storage or degradation, on adipocyte differentation or multiplica- tion. Antiage Ascorbic acid is a key element in collagen synthesis (also in ‘‘botanical colla- gen’’). They improve microcirculation leading to a better irrigation of the tissues and thus to nutrition, hydration, hormone transport, etc. Protection of elastic ﬁbers (collagens, elastin) is promoted by extracts hav- ing free-radical scavenging properties, activating the synthesis of these proteins or inhibiting the enzymes responsible for their degradation: streptomyces, black currant, Centella asiatica (rich in asiatic acid), Rudbeckia purpurea, Coleus, Areca,... Apigenin, extracted from Chamomile and its derivatives, and rutin from Fagopyrum have anti-inﬂammatory properties (by inhibiting histamine release), but they are also β-glucuronidase inhibitors. Other extracts rich in polyphenols—tanins—also have antihy- aluronidase activity (16–18).
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