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By D. Aidan. William Penn College. 2018.

The introduction of the term ‘‘cosmeceutical’’ enables us to classify more precisely a product with an activity that is intended to treat or prevent a (mild) skin (abnormality) discount inderal 40mg mastercard. In order to avoid introducing new definition criteria purchase inderal 80mg without a prescription, we sug- gest that cosmeceuticals are only regarded as a subclass within the domain of a Definition 11 Table 1 Cosmeceuticals as a Subclass of Cosmetics (Europe and Japan) and as a Subclass of Drugs (U. In Europe and Japan, cosmeceuticals can be regarded as a subclass of cosmetics; however, in the United States cosmeceuticals can only be regarded as a subclass of drugs. Cosmeceuticals could be characterized as fol- lows: (1) The product has pharmaceutical activity and can be used on normal or near-normal skin. The definition of minor skin disorders or mild skin abnormalities is difficult and can be regarded as cosmetic indications. Even socioeconomic factors may have an impact on whether a skin disorder is regarded as a disease or as a cosmetic indication (8,9). Nevertheless, in most western countries there is no written consensus that skin abnormalities that are treated by over-the-counter drugs may be regarded as mild skin disorders or may be termed cosmetic indications (9,10). The procedure for registration of a cosmeceutical should not be as cumber- some as for drugs. The intended activity of the cosmeceutical for treatment of a minor skin disorder should be demonstrated by clinical studies within the frame- work of good clinical practice. Moreover, it should be shown that safety require- ments are optimal and that no side effects can be expected (11). The safety evalua- tion is mandatory for cosmetics in Europe, according to articles 2, 12, and 13. In the United States, this would mean that a subclass of drugs (cosmeceuti- cals) are registered in a similar manner as over-the-counter products (12). It would be beneficial if these countries could agree on the definitions of cosmetics and drugs and, in so doing, define cosmeceuticals as a subclass of cosmetics. This would prevent the current situation in which certain products are registered as drugs in the United States (sunscreens) and as cosmetics or cosmeceuticals in Europe and Japan. Evidence that cell shedding from plantar stratum corneum in vitro involves endogenous proteolysis of desmosomal protein desmogein. Aging skin was to be accepted as an inevitable, irreversible, and trivial conse- quence of getting old. These observations have coincided with several pertinent phenomena: (1) the incredible growth of scientific knowl- edge in recent years; (2) people in western populations living longer and spending increased leisure time exposed to sun in outdoor activities; and (3) the rampant cosmetic claims for products that will ‘‘turn back the clock’’ to youth overnight. One is the northern hemisphere, where life is rigid, cold scientific proof is difficult, and only the hardiest survive in the frozen tundras of pharmaceutical bureaucracy and governmental regulation. The southern hemisphere is friendly and warm and things that make you ‘‘feel’’ better are considered good, rather than inherently evil because they are not ‘‘natural’’ and may prevent us from looking our age. Advocacy of the term cosmeceutical, as an attempt to compromise and bridge the gap between cosmetic and pharmaceutical, greatly enlivened the de- bate. In fact, the debate has forced us to reevaluate what we truly believe, even made us iconoclasts, willing to listen to new ideas. It has taken place during an era of unprecedented discovery about the structure and functioning of the skin, and the discussion has begun to rise above the former shrill hysteria and is now on a higher plane of logic and scientific facts. On one hand, appearance of the facial skin makes this condition so obvious to the subject and observers, which in turn makes the use of cosmetic products so appealing. On the other hand, only a pharmaceutical product can truly and meaningfully effect change in the substantial pathology of the condition. The clear demonstration of the clinical efficacy of tretinoin, a pharmaceutically active retinoid topically ap- plied for a cosmetic condition, speaks to the utility of the term cosmeceutical. Cosmetic effect should be at least a partial result of structural or functional change, which can be reproducibly demonstrated by some reliable, accurate, and validated methodology—be it clini- cal or instrumental. Topical products presently predominate in the discussion, yet nontoxic, systemic substances such as vitamins and naturally occurring sub- stances should also be considered in the definition. Distinction between intrinsic aging of the skin and photoaging has been repeatedly emphasized, but in the context of this discussion it has little relevance; skin that is visible and cosmetically deteriorated is invariably sun exposed and usually highly sun damaged. In the vast majority of individuals, photoaging over- shadows intrinsic changes, especially in the skin of the face, neck, and dorsal forearms (1). The terms photoaging and photodamage have frequently been used inter- changeably, although we have previously preferred to define photoaging as a process and photodamage as a description of the clinical or histological condition at any point in time.

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None of these receptors is truly tissue specific best 80mg inderal, and many organs contain both α and β adrenoceptors buy discount inderal 40 mg on-line, although usually one type predominates. Studies using radiolabeled agonists and antagonists have identified α receptors in both brain and peripheral tissues and have demonstrated that the binding properties are essentially the same in both of these locations. Early pharmacological and physio- logical studies supported the existence of two types of α receptor (α1, α2 ). Some tissues possess only α1 receptors, some possess only α2 receptors and some possess mixtures of both. The brain, for example, contains proportions of both α1 and α2 receptors with highly variable distributions in different brain regions. The primary amino acid sequences of both the α1 and α2 receptors have been determined. The sequences of these two α receptors are not more closely related to each other than either is to any of the three proteins that make up the β-adrenergic receptor family. Not surprisingly, the α adrenergic receptors share marked structural similarities with dopamine receptors (discussed in detail in section 4. Recent cloning and sequence analysis studies suggest that there are three subtypes of α1 receptors and three subtypes of α2 receptors. The three subtypes of the α1 receptor have been designated α1A, α1B, and α1D, and tend to be differentially distributed in the kidney, liver, and aorta, respectively. Cloning studies reveal that each arises from a dif- ferent chromosome and each contains a different number of amino acids: α1A [466 amino acids], α1B [515], α1D [560]. Similarly, there are three subtypes of α2 receptors, designated α2A, α2B, and α2C. As with the α1-receptor subtypes, each α2 receptor is encoded on a different chromosome and contains a varying number of amino acids: α2A [450 amino acids], α2B [450], α2C [461]. All three of the known subtypes of the α receptor are 2 linked to inhibition of adenylyl cyclase activity. As with other receptors linked to inhi- bition of adenylyl cyclase, these receptors have relatively short C-terminal tails. Numerous sites accessible to phosphorylation are located on the C-terminal portion of the protein, while sites for N-glycosylation are on the N-terminal extracellular segment. There are seven membrane-spanning helical regions composed of hydrophobic amino acid sequences, and at least two glutamine-linked glycosylation sites near the N-terminal. Three distinct and pharmacologically important β receptor subtypes exist: β1, β2, and β3. The genomic organization of the genes encoding the biosynthesis of these three receptor proteins is somewhat unusual. Introns differ from coding sequences in that frequently they can be exper- imentally altered without changing the gene function. Moreover, introns seem to accu- mulate mutations rapidly during evolution, leading to hypotheses that introns are composed mainly of “genetic junk”. The three β-adrenoreceptor subtypes have varying localizations and functional prop- erties. The brain contains both β1 and β2 receptors; the density of β1 receptors varies in different brain areas to a much greater extent than does that of β2 receptors. Likewise, there is a coexistence of β1 and β2 receptors in the heart, with both receptor subtypes being coupled to the electrophysiological effects of catecholamines upon the myocardium. In humans, the β3 receptor is linked to obesity, diabetes, and control of lipid metabolism. In the human receptor, this substituted amino acid at position 64 lies at the junction of the first transmembrane spanning domain and the first intracellular loop. A large number of studies suggest associations between the Trp64Arg β3 receptor variant and an increased capacity to gain weight, resistance to weight loss, increased blood pressure, and coronary heart disease. The β receptor is highly stereospecific, preferentially binding only to certain stereoisomers of drugs. Drugs acting on presynaptic receptors These classes afford a logical, mechanistic approach to adrenergic drugs and each class will be discussed individually. The analogous α-methyltyrosine inhibits tyrosine hydroxylase, but is not used as a drug. While useful as hypotensive and antidepressant drugs, their side effects can be serious.

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Physicians have observed that halazepam can reduce stress and depression and can improve epilepsy purchase inderal 80 mg free shipping. An experiment found that halazepam did not increase belligerence buy generic inderal 40mg on-line, unlike some benzodiazepine class drugs. Canine studies show that in the body the drug converts into nordiazepam and oxa- zepam, which are also metabolites of diazepam. With stronger dosages elderly persons sometimes experience difficulty in manual dexterity and other muscle control; during an experiment several elderly individuals fell. In an experiment some alcoholics had difficulty distinguish- ing halazepam from placebo, an outcome suggesting that the drug has low potential for abuse (as abusers of alcohol and other drugs should be particu- larly susceptible). Nonetheless, a person’s body can develop physical depen- dence with halazepam, which is a traditional sign of addictive potential. One group of researchers found withdrawal symptoms to be so mild, however, that a placebo could control them. The heartburn medicine cimetidine is suspected of inter- fering with halazepam’s effects. No cancer developed in rats and mice at daily dosage levels 5 to 50 times the maximum human dose. Experiments with rats and rabbits have produced no evidence that the drug causes birth defects. For most of the twentieth century drug addiction and heroin were synonymous in the United States; all substance abuse was assumed to lead to heroin. Only in the 1980s did heroin become displaced as the devil drug, supplanted in public fear and disapproval by cocaine. Being a Schedule I substance, heroin has no officially approved medical use in the United States. Heroin is produced from morphine, and body chemistry converts a heroin dose back into morphine. One study of pain relief found heroin comparable to hydromorphone, a standard med- ication administered to fight severe pain. Physicians have judged heroin to be a safe anesthetic for use during childbirth, with no apparent ill effect on mother or child. The drug is also used to treat porphyria, a body chemistry disorder making people sensitive to light and occasionally making them vio- lent. Heroin users of both genders have reported increased sexual activity upon starting the compound, with decline in that activity as usage continues. That sequence would be consistent with the drug at first reducing psycholog- ical anxiety, an effect gradually evolving into indifference about the world. Extrapolating from severity of withdrawal symptoms, any particular size heroin dose taken by intravenous injection is five times stronger than one taken by inhaling heated vapor (“chasing the dragon”). Other measurements show a dose to be four times more potent when taken intravenously instead of by inhaling powder. Sometimes intravenous injection of heroin produces a rush of feeling lik- ened to a total body sexual orgasm. Heroin may allow some nonmedical users to experience euphoria, but more typically an intoxicating dose increases psy- Heroin 193 chic distance between the user and the world, making reality seem unimpor- tant. People using lesser doses of heroin in that way may function more productively, or they may experience trouble because they feel confident enough to get into situations they would otherwise avoid. Researchers find, however, that injectors of a heroin variety called “black tar” have an increased risk for botulism infection at the injection site, no matter how hygienic their equipment and technique. Injectors of any type heroin are more prone to all sorts of infections, and some researchers suspect that heroin impairs the immune system. Inhaling heated heroin vapor can rapidly pro- duce enough brain damage to cripple a person, although case reports indicate that partial recovery is possible. Inhaling either the vapor or powder can also cause breathing trouble, and injection can cause swift fluid buildup in the lungs. A study found reduced bone density in chronic male heroin users, making broken bones more likely, and researchers suspected the problem re- sulted from lower testosterone levels caused by heroin (a heroin action that is also known to reduce male sex drive). Apparently the bone density and testosterone problems can correct themselves if heroin use stops. Although stroke is an uncommonly reported outcome of heroin use, autopsy examina- tions of 100 heroin addict brains indicate that 5% to 10% of injectors suffer small strokes that may not cause the person to seek medical treatment but that may thereafter affect the person’s behavior.

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Roundworms are round like earthworms even though they may be as thin as hairs (threadworms cheap inderal 80mg with mastercard, filaria) or micro- scopically small (like Trichinella) cheap 80mg inderal overnight delivery. They have a way to attach themselves sometimes with the head (scolex) like tapeworms, sometimes with a special sucker like flukes. Worms Flatworms Roundworms Tapeworms Flukes Threadworms Pinworms Hookworms Worm parasites go through stages of development that can look very, very different from the adult. The favorite organ for Dirofilaria (dog heartworm) is the heart (even human heart). My tests show Dirofilaria can live in other organs, too, if they are sufficiently polluted with solvents, metals and other toxins. If you are a meat eater, you could eat such a cyst if it happens to be lodged in the meat you are eating! The little larva is swallowed and tries to attach itself to your intestine with its head. They come out of their metacercarial cyst as a small adult and quickly attach themselves to the intestine with a sucker. Four common flukes are: human intestinal fluke, human liver fluke, sheep liver fluke, pancreatic fluke of cattle. Has cilia, can swim vigorously and must find intermediate snail host in one to two hours or may be too exhausted to in- vade. Those are "mother" redia, and each one bears "daughter" redia for up to 8 months, all still inside the snail, and living on the fluids in the lymphatic spaces. If the snail is feeding on a plant, cercaria can latch onto plant with sucker mouth and start to encyst (form a "cocoon") within minutes. But as you eat the plant it is stuck to, the least pressure will break it, leaving the cyst in the mouth. The "almost unbreakable" inner cyst wall protects it from chewing, and the keratin-like coat prevents digestion by stomach juices. However when it reaches the duodenum, contact with intestinal juices dissolves away the cyst-wall and frees it. It then fastens itself to the intestinal lining and begins to develop into an adult. Note that the adult is the only stage that “normally” lives in the human (and then only in the intestine). Fasciolopsis depends on a snail, called a secondary host, for part of its life cycle. If propyl alcohol is the solvent, the intestinal fluke is invited to use another organ as a secondary host—this organ will become cancerous. If xylene (or toluene) are the solvents, I typically see any of four flukes using the brain as a secondary host. I call the diseases caused by fluke stages in inappropriate locations Fluke Disease; it is discussed in more detail later (page 249). Pollutants can invade your body via the air you breath, the foods and beverages you eat, and the products you put on your skin. The one who did not assumes the cream is not harmful to them…that they are like a bank vault, impreg- nable to that product. A better assumption is that the face cream is somewhat toxic, as evidenced by the rash that can develop, and they escaped the rash only because they had a stronger im- mune system. The immune system is like money, paid out of the bank vault, for every toxic invasion. Most other solvents dissolve fats and are life threatening, because fats form the membrane wall around each of our cells, especially our nerve cells. Metal Pollution Biochemists know that a mineral in raw element form always inhibits the enzyme using that mineral. Inorganic copper, like you would get from a copper bottomed kettle or copper plumbing, is 3 carcinogenic. We put metal jewelry on our skin, eat bread baked in metal pans, and drink water from metal plumbing. Mercury amalgam fillings, despite the assurances of the American Dental Association, are not safe. And sometimes the mercury is polluted with thallium, even more toxic than mercury!

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By attempting to classify drugsaccording to their major membrane effects purchase inderal 40 mg overnight delivery, the Vaughan-Williamsschemefacilitates thinking aboutan- tiarrhythmic drugs in terms of their electrophysiologic properties discount inderal 40mg with amex. The prototypical electrophysiologic effects of the various classes of drugs are depictedinFigure 2. Criticsofthis classification systempointout that antiarrhythmic drugs oftencause mixed effects on the cardiaccell and that antiar- rhythmic drugs in the sameVaughan-Williams group can, clinically speaking, behave quite differently from oneanother. The most im- portant confounding variable relates to how antiarrhythmic drugs affectsodium and potassium channels. The binding characteristics of the sodium-blocking drugs, for in- stance, are complex. Although all Class I drugsbind to the sodium channel, they do not bind tonically (i. Actual blockade of the sodium channel (and thus slowing of depolarization)occurs only ifadrug isbound to the sodium channel at the time the channel first opens. How- ever, many Class I drugsbind to the sodium channel only after it has alreadyopened (i. The solid lines represent the baselineactionpotential; dotted lines represent the changes that result when various classes of an- tiarrhythmic drugs are given. There- fore, the effect of a Class I drug on the sodium channel dependson its binding kinetics—the rate at which that drug bindstoand un- binds from the sodium channel (or alternatively, its effect depends on how“sticky” the drug isonce itbindstothechannel; Figure 2. Panels (a) through (e) illustrate the effectoflidocaine, a drug with rapid kinetics. Panels (f) through(j) illustrate the effectofflecainide, a drug with slow kinetics. Panels (f) through (h) show reactions identical to those in panels (a) through(c). At faster heart rates, drugssuchaslidocaine have less timetounbind and can behave more like flecainide. Drugs with rapid binding kinetics therefore produce rel- atively little reductioninconduction velocity. Ingeneral, the slower the binding kineticsofasodium-blocking drug, the more effect the drug has onconduction velocity. To further complicate the issue, the effect of Class I drugson the sodium channel is partially situational. All Class I drugs, for instance, display use dependence: at faster heart rates, the sodium-channel block increases. Use dependence issimply a result of binding kinetics, which reflects that at faster heart rates, there is less time for the drug to unbind from the sodium channel before the next actionpotential begins; thus, at faster heart rates, the drugs have a more profound effectonconduction velocity than they have at slower heart rates. In addition, ischemia, hyperkalemia, and acidosis can slow the binding kinetics of Class I drugsand thus increase the effectofthedrugson the sodium channel. The Vaughan-Williams classification system accounts for the bind- ing kinetics of the sodium-blocking drugs. Although no classification systemislikely to neatly charac- terize the nuances of sodium binding for every drug, the Vaughan- Williams system offers reasonably accurate generalizations about sodium-binding properties of antiarrhythmic drugs. The Vaughan-Williamsscheme is more challengedwhen one be- ginstoconsider the effectofantiarrhythmic drugson the potassium channel. As a result, application of the Vaughan-Williams system becomes very difficult in some cases. Ultimately, the classification of some drugsappears to be a matter of consensus rather than a matter of science. Although the Vaughan-Williamsschemethusappears incapable of offering definitive classification for all possible mixtures of sodium- and potassium-channel blockade, it nonetheless suggests a frame- work for characterizing evendifficult-to-classify drugs. The frame- work becomes apparent when onethinks of the general interplay of sodium-blocking and potassium-blocking properties as represent- ing a continuum of possible effects instead of a categorical series of discrete effects (Figure 2. The advantageofthinking about drug effects along a continuum is that hard-to-classify drugs, suchasmori- cizineand amiodarone, can be positioned at appropriate points along the continuum instead of being arbitrarily assigned to a specificclass. The Vaughan-Williams classification system, thoughad- mittedly imperfect, helpstolocate drugs along the continuum,and therefore helpstoelucidate the electrophysiologic properties even of drugs that are difficult to formally classify. As ithappens, the Vaughan-Williamsscheme also allowsoneto make other clinically relevant generalizations aboutantiarrhythmic drugs. What emergedwas a new approach to the classification of antiarrhythmic drugs; the inventors imaginatively named the approach the Sicilian Gambit.

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