By N. Snorre. Massachusetts College of Liberal Arts.
Most striae buy donepezil 5 mg line, which are hyperemic during pregnancy purchase generic donepezil, will diminish in appearance (often becoming small purchase cheap donepezil online, silvery lines). Condyloma acuminata Wart-like growths, condyloma acuminata, may proliferate rapidly during pregnancy. A common therapy in the nonpregnant patient is local application of a 20 percent solution of podophyllin in benzoin. Podophyllin is contraindicated in pregnancy because of the potential for maternal and fetal toxicity. Use of 5-fluorouracil is not recommended because it is an antineoplastic agent and there are no human studies of the topical administration of this agent during pregnancy. For small, isolated lesions, surgical excision, electrocoagulation, and cryotherapy gen- erally produce satisfactory results. Atopic/allergic dermatitis This condition is characterized by a pruritic rash and is secondary to a variety of incit- ing factors, such as stress, soap (especially with aroma additives), and irritants. Topical steroids are recommended during pregnancy and generally prove satisfactory. Erythema multiforme The etiology of erythema multiforme, another dermatitis, is virtually unknown. Papular dermatitis of pregnancy Papular dermatitis is very rare (< 1 percent) and is limited to pregnancy (Spangler et al. Recurrence in subsequent pregnancies is known and it is associated with an increased frequency of pregnancy loss. Papular dermatitis is characterized by small, ery- thematous papules that usually involve all of the skin. High-dose systemic steroids, such as prednisone, are used to treat this dermatitis. The rash usually starts on the abdomen and spreads to the extremities, with facial spar- ing (Alcalay et al. Treatment consists primarily of topical steroids, although oral prednisone may be required for severe cases. Herpes gestationis Another rare dermatologic disease of unknown etiology is herpes gestationis. Contrary to what might be implied from the name, herpes gestationis is not a viral infection but an autoimmune disease. Erythematous papules and large, tense bullae, usually on the abdomen and extremities characterize this disease. Some investigators have reported that an increased frequency of pregnancy loss is associated with this condition in some studies (Lawley et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Quinine overdoses are associated with an attempt to induce abortion over 90 percent of the time, but most other over- doses of the drug are also attempted suicide. Successful suicide during pregnancy occurs among one in every 88 000–400 000 live births (Table 14. Among 162 pregnant women who presented with an indication of poisoning, 86 percent were overdoses (78 percent suicide attempts and 8 percent induced abortion attempts (Czeizel et al. Maternal death associated with suicide gestures occurs in approx- imately 1 percent of gravid women and more than 95 percent of suicide gestures involve ingestion of a combination of drugs (Rayburn et al. In New York city, suicide was identified as the cause of 13 percent of maternal deaths (Dannenberg et al. Use of drug megadoses that are potentially lethal in pregnant women involves two patients: mother and fetus. Assessment of the pregnant woman who has potentially toxic (megadoses) amounts of drugs must begin with laboratory evaluation of the sub- stance(s) ingested (i. In Finland in the late 1990s, the pattern was similar with the top three substances used in suicide attempts being benzodiazepines, analgesics, and psychotropics (antipsychotics/antidepressants) (Table 14. The patient will usually recall approximately how much she took of which substances. If family members or signifi- cant others are present, they may be able to provide corroborative information, such as presence of medicine bottles, known prescriptions, etc. Toxicology screens with samples every hour or two (for serial evaluation) should be ordered as soon as possible to deter- mine exactly what substances are involved and whether or not levels are rising or falling, or toxic or approaching toxic. However, a generalized treatment plan may be under- taken before toxicology results are available. If the patient still has a gag reflex, orogastric lavage with normal saline should be begun. Following lavage, administer an activated charcoal slurry regimen (the nonspecific anti- dote regimen). Whole-bowel irrigation has been used successfully in some cases of drug overdose and has a clinically significant effect on lowering serum drug levels. Evaluation of the fetal heart rate should begin as soon as possible, especially in cases in which the fetus is viable.
In 1905 he presented a very interesting piper to the New York Society on the influence of this agent in the treatment of Ellingwood’s American Materia Medica cheap donepezil 5 mg without prescription, Therapeutics and Pharmacognosy - Page 117 general bubonic inflammation cheap donepezil 10mg free shipping. He believes the remedy to be very valuable in leucorrhea order generic donepezil on line, and diseases where there is an excessive outpour of mucus. He gave it also when the abdomen seemed to be filled with nodules, when there was diarrhea or cholera infantum. He claimed that it will reduce the mammary glands if taken too long by females, and in males it will reduce the size of the testicles. It does not cause derangement of the stomach nor produce free action of the kidneys. When the glands are large or inflamed either in the acute or chronic form he believes that this remedy is superior to our other glandular remedies, even to phytolacca. With it he can determine whether an enlarged gland is simple, or whether a tumor is developing. He gives it in bubo, ostitis, and mastitis with excellent results; also when the glands of the skin are affected. It can be correctly adjusted to the uric acid diathesis, in dropsy, with debility and loss of appetite. Also in cases where there are inflamed and ulcerated cervical glands, enlargement of the parotid glands from retained excrementitious products, dropsy after scarlatina and measles, dropsy with debility from any cause, chronic rheumatism, skin diseases with enlarged cervical glands in scrofulous subjects, hectic fever with night sweats, enlargement of the mesenteric glands, also where there is an inflamed and swollen prostate gland, with discharge of prostatic fluid, urine thick, ropy, with bloody sediment, itching and pain in the urethra and bladder, strangury, chronic gonorrhea, chronic nephritis, urethritis with profuse and purulent discharge, obstinate and ill-conditioned ulcers, in latter stages of typhoid fever with deficient excretion, tumors of the mammae supposed to be cancerous, this agent is used. In acute rheumatism a warm infusion should be given till it produces perspiration, while hot fomentations of the same should be applied to the swollen and painful joints. In obstinate skin diseases in scrofulous subjects, the tincture from the fresh leaves should be applied to the diseased skin and taken internally. Specific Symptomatology—The specific influence of the agent is exerted upon the liver. It is a remedy for hepatic engorgement; jaundice more or less pronounced; pain over the region of the gall bladder; pain in the epigastrium; pain radiating from the navel over the abdomen; soreness in the region of the liver, extending to the umbilicus; enlargement of the liver, determined by percussion; nausea; occasional vomiting; constipation with dry feces; temperature slightly above normal; skin usually yellow. This latter indication—a distinctly yellow skin—has always been my immediate suggestion for chionanthus and I have rarely been disappointed. Therapy—It is a cholagogue cathartic in full doses, but its best influence is in acute congestion of the liver with imperfect discharge of bile, or catarrh of the common bile duct. The indications are acute jaundice evidenced by yellowness of the conjunctiva first, subsequently of the skin, with distress in the right hypochondrium, with cramp-like pains in the abdomen. It overcomes catarrh, liquefies the bile, prevents the formation of calculi, and promotes the discharge of those formed. It is a remedy for chronic forms of liver disease, but its influence is not so plainly apparent, being much slower in its operations. It is not indicated in jaundice from permanent occlusion of the duct, from impacted gall stones or foreign and malignant growths. Bilious headaches resulting from liver faults especially if irregular or periodical are cured by chionanthus. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 119 It will quickly overcome the jaundice of childhood and infancy, and especially sure in the jaundice of the pregnant term. It is an excellent remedy for malarial conditions with atonicity of the stomach and intestinal apparatus. It can be given during the chill and fever, and it assists greatly in the relief of both. The agent may be pushed to the maximum dose and given with full confidence when indicated, as it is absolutely certain in its action. Fearn claimed to have early made the discovery of the use of chionanthus in reducing the quantity of sugar in the urine. Patients with no appetite, losing flesh, listless, increasingly anemic with a little sugar in the urine were those to whom he first gave it, ten drops four times a day. Probably in those cases in which this remedy is beneficial in diabetes there is functional disease of the liver. Whether the remedy would be equally beneficial in cases in which no liver fault could be diagnosed, might be questionable, and yet Hauss, says that he has never treated a case of diabetes mellitus along the lines indicated that has not yielded to this treatment. If no febrile condition is present or if there is general atonicity, with nervous depression, he adds from one-half to one drop of nux vomica. He has the patient drink from one to two pints of hot water each morning, before breakfast, to which he adds a small teaspoonful of the sulphate of magnesium, or in preference one-half wine glass of French Lick Pluto water in a pint of hot water. This treatment, with proper dietary, he claims, has a rapid effect upon the glycosuria, immediately reducing the specific gravity of the urine. The agent is beneficial in chronic splenitis, pancreatic disease and disease of the other glandular organs; also in the incipient stages of nephritis. It influences the stomach in the process of digestion; it exerts a beneficial, stimulating effect upon the entire glandular apparatus. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 120 Prof.
If it is to be used only as food it will come within the deﬁnition of food and none other buy 10 mg donepezil visa. If it contains nutritive ingredients but is sold for drug use only discount 5mg donepezil, as clearly shown by the labeling and advertising buy cheap donepezil 10 mg on line, it will come within the deﬁnition of drug, but not that of food. If it is sold to be used both as a food and for the prevention or treatment of disease it would satisfy both deﬁnitions and be subject to the substantive requirements for both. The manufacturer of the article, through his representations in con- nection with its sale, can determine the use to which the article is to be put. For example, the manufacturer of a laxative which is a medicated candy or chewing gum can bring his product within the deﬁnition of drug and escape that of food by representing the article fairly and unequivocally as a drug product (15). This principle remains the touchstone for product classiﬁcation under the 1938 Act. The 1906 Act limited the drug deﬁnition to products intended to prevent or treat disease. Accordingly, from the initial bill to the ﬁnal law, the drug deﬁnition was ex- panded to include articles ‘‘intended to affect the structure or any function of the body of man or other animals’’ (16). Because the representations made for the product would determine the proper classiﬁcation of the product, and thus classi- ﬁcation was within the sole control of the seller, Congress concluded that the product should be subject to whatever statutory requirements are established for whatever product classiﬁcations applied, based upon those representations: It has not been considered necessary to specify that the deﬁnitions of food, drug, and cosmetic shall not be construed, other than to the extent expressly provided, as mutually exclusive. The present law does not have such a clause relating to the deﬁnitions of food and drug and there has never been a court decision to the effect that these deﬁnitions are mutually exclu- sive, despite the fact that repeated actions have been brought, for example, against ﬁlthy foods bearing unwarranted therapeutic claims, alleging these products to be adulterated as food because of their ﬁlth, and misbranded as drugs because of their false and fraudulent therapeutic claims (17). Thus, dual and even triple classiﬁcation of a product as a food, drug, and cosmetic was contemplated by Congress under the 1938 Act. Fourth, Congress realized that there must be one exception to the general rule of nonexclusive deﬁnitions. Accordingly, Congress explicitly excluded food from the structure/function prong of the drug deﬁnition, but not from the disease prong. In the Senate debate on the legislation in April 1935, the exclusion of food from the structure/function prong of the drug deﬁnition was expanded, without discussion, to include cosmetics (18). That bill was not passed by the House of Representatives, however, and no subsequent legislation retained the cosmetic exclusion. Accordingly, any cosmetic represented to affect the structure or func- tion of the human body is classiﬁed as a drug as well as a cosmetic and must meet the statutory requirements for both categories of products. Fifth, Congress also included in the 1938 Act, as it had in the 1906 Act, a third prong of the drug deﬁnition to include articles recognized in speciﬁed pharmacopeias. This was intended, however, to include pharmacopeial articles only when they are in fact represented for disease or structure/function purposes (19). Accordingly, this prong of the deﬁnition may be excluded from further consideration in this chapter. Parts of the drug deﬁnition not pertinent here have been revised since 1938, but the central core of the deﬁnition has not been altered. In short, it is only the very rare cosmetic product that could justify this level of investment. It is therefore essential that cosmetic products be formulated and labeled in such a way as to avoid the drug deﬁnition. Second, the agency published pamphlets and other educational materials with examples of product classiﬁcation. Third, it brought court action to contest the legality of cosmetic products with labeling that contained what the agency concluded to be drug claims. From this body of literature and precedent has emerged, over six decades, a number of well-developed examples: A suntan product is a cosmetic but a sunscreen product is a drug. An antibacterial deodorant soap is a cosmetic but an antibacterial anti-infec- tive soap is a drug. Products that are represented only to change the structure or function of the hair or nails are regarded as cosmetics and not drugs. Products that are repre- sented to affect the hair or nails systemically, on the other hand, are regarded as drugs. Cosmetic products represented as ‘‘hypoallergenic,’’ and thus with reduced allergic potential, remain classiﬁed as cosmetics and not as drugs (23). Only if these products are represented to treat speciﬁc reactions or diseases would they be classiﬁed as drugs. Inclusion of an active ingredient in a cosmetic does not automatically clas- sify it as a drug, unless the active ingredient is so closely identiﬁed with therapeu- tic properties that the mere use of the term would connote a drug claim. In many instances, however, ingredients can be used in both cos- metic and drug products. Legal Distinction in the United States Between a Cosmetic and a Drug 229 In many instances, the context of a word or phrase must be considered before a determination can be made about proper classiﬁcation of the product as a drug or cosmetic. A product represented as a treatment for disease is a drug, but a product represented as a beauty treatment is a cosmetic. A product repre- sented to kill germs that cause infection is a drug but a product tht is represented to kill germs that cause odor is a cosmetic.
The differences in bacterial colonization and host response point to mechanisms that may account for the increased prevalence and severity of periodontitis observed in African Americans discount 5mg donepezil amex. The early colonization by periodontal pathogens and the associated elevated immune response may either offer protection to the host or the immune response may be 21 insufficient or possibly contributory to the disease process manifesting in attachment loss and bone loss (Albandar et al 10mg donepezil for sale. Despite focused research in this area order 5 mg donepezil mastercard, the relationship between specific IgG antibody and protection against periodontal pathogens remains obscure. Some studies found high antibody levels against periodontal pathogens to be associated with disease stability and other studies detect no apparent antibody effect on disease activity (Kinane et al. From this group of children, in which a number were overweight/pre-diabetic or healthy, it can be concluded that gender and race may represent increased risk for elevated immune responses to the periodontal pathogens. A potential for improving periodontal risk assessment especially in the mixed dentition when traditional clinical examination may be difficult due to eruption patterns, would be to also assess the IgG responses to known periodontopathogens. Knowledge of the patient’s pathogenic exposure may alter the maintenance/intervention strategies for these at risk groups. Prevention and reduction of the inflammatory burden caused by periodontitis may have a profound effect on not only prognosis of periodontal disease but other systemic inflammatory diseases. As this paper reports, the immune/inflammatory burden starts at a very early age and the long term affects on overall periodontal and systemic health remains to be seen. The objective of the present study was to examine the nature of the immune response to periodontal pathogens and help to identify other risk factors in a cohort of children. It was observed that even in this young cohort there are variations in immune responses to periodontal pathogens with respect to race and gender. The information gained from this exploratory study may help to identify persons with disease/disease risk earlier and enable us to implement preventive measures for these patients. Longitudinal studies combining clinical and immune responses are necessary to unravel the complexities of periodontal disease acquisition, initiation and progression. Further research is needed to fully comprehend the immune response in periodontitis and its contribution to systemic inflammation, especially in patients with other inflammatory disease processes. This observational study revealed a surprisingly high number of 9-11- year-old children exhibiting IgG responses to known periodontopathogens. Significantly higher proportions of IgG immune responses were noted for girls and African Americans. This analysis shows that the immune-inflammatory burden may start very early with potential long term local and/or systemic consequences. Future studies are necessary to ascertain the impact of low grade chronic immune responses to periodontal pathogens and how these responses influence periodontal, as well as systemic health in children. Juvenile periodontitis – localization of bone loss in relation to age, sex and teeth. Microbiological diagnostics in periodontics: biological significance and clinical validity. Whincup P, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Hawkey C, Atherton J. There has been an alarming increase in the prevalence of obesity in the United States and across the world. The chronic systemic inflammatory and immune effects induced by obesity have been linked with many of these morbidities. Malnutrition and reduction in antioxidant intake have also been observed to affect inflammatory and immune pathways. These two conditions may also increase the host’s susceptibility to periodontal disease through its impact on inflammatory and immune parameters. The aim of this review is to provide a detailed update on both obesity and nutrition, examining the evidence and biological plausibility regarding the impact of nutrition and obesity on periodontal disease. Among the emerging factors that affect periodontal disease, obesity and nutritional intake have recently been identified as modifiable factors which could alter the course of periodontal disease progression (Genco et al. Presently the pathogenesis of periodontitis is based on the concept that there is an interaction of the plaque bacteria and the host at the gingival crevice leading to the destruction of the periodontal supporting tissues (Offenbacher, 1996). The innate defense is the first line directed against these pathogenic bacteria and comprises neutrophils that phagocytose the bacteria and limit the inflammation to the marginal gingiva (gingivitis). In certain susceptible individuals, this bacterial biofilm can evade the host defense mechanisms and gain access to the underlying periodontium. These inflammatory cytokines are released from 30 monocytes and macrophages, which can lead to further inflammation and tissue destruction This tissue destruction is evidenced clinically as periodontitis where gingival inflammation is accompanied by loss of collagen fiber attachment to the root cementum and migration of the junctional epithelium apically. If the pathological process is allowed to continue or there is robust host response, then resorption of supporting alveolar bone may occur (Armitage, 1995). The host response is integral to the clinical presentation of periodontitis and other diseases have been postulated to upregulate this inflammatory response.
Pharmacogenetic associa- tion between the formation of 4-hydroxymephenytoin and a new metabolite of S-mephenytoin in man buy generic donepezil 5mg online. Limitation to the use of the urinary S/R- mephenytoin ratio in pharmacogenetic studies buy donepezil with paypal. A methodological investigation on the estimation of the S-mephenytoin hydroxylation phenotype using the urinary S/R ratio discount donepezil american express. S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin. Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping Southeastern Oriental subjects. Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4 -hydroxylation. Identification of human liver cyto- chrome P450 isoforms mediating omeprazole metabolism. Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4 -hydroxylation0 recruited from an Oriental population. The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Phenocopies of poor metabolizers of omeprazole caused by liver disease and drug treatment. Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4 -hydroxylation recruited from0 an Indonesian population. Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man. The pharmaco-kinetics and activation of proguanil in man: consequences of variability in drug metabolism. Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark. Evidence for the polymorphic oxida- tion of debrisoquine and proguanil in a New Zealand Maori population. Evidence for the polymorphic oxidation of debrisoquine and proguanil in a Khmer (Cambodian) population. Chloro-guanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians. Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism. Proguanil metabolism in relation to S-mephenytoin oxidation in a Turkish population. Relation between chlor- oguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans. Inherited amplification of an active gene in the cytochrome P450 2D-locus as a cause of ultrarapid metabolism of debrisoquine. Metoprolol and debrisoquin metabolism in Nigerians: lack of evidence for polymorphic oxidation. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Molecular basis for rational mega- prescribing in ultrarapid hydroxylators of debrisoquine. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Oxidation phenotype—a major deter- minant of metoprololol metabolism and response. Metoprolol metabolism and debrisoquine oxidation polymorphism—population and family studies. Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations. Differential stereoselective of metoprolol in extensive and poor debrisoquin metabolisers. Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two East Asian pop- ulations. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 db 1 activity. Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype: inability of dextromethorphan metabolic ratio to dis- criminate reliably heterozygous and homozygous extensive metabolizers.
However cheap 5mg donepezil amex, because the Sicilian Gambit is not a true classiﬁcation system generic 5mg donepezil with visa, it does not offer much help to the average clinicianinlearn- ing aboutorcommunicating aboutantiarrhythmic drugs donepezil 5mg. Es- pecially for the nonexpert, the Vaughan-Williams system, with all its limitations, remains the most useful meansofcategorizing an- tiarrhythmic drugs;it is the system that will be used throughoutthis book. Yet, because of their varied effects on the sodium channel and the potassium channel, drugs assigned to Class I can behave very differently from oneanother. The major clinical features, electrophysiologic properties, and adverse effects of Class I antiarrhythmic drugs are summarizedinthe accompanying tables. Unfortunately, they are also moderately effective in causing both major varieties of side effects—end-organ toxicity and proarrhythmias. Quinidine Quinidine is the D-isomer of the antimalarial quinine, a drug that was noted to be effective in the treatmentofpalpitationsaslong 55 56 Chapter 3 Figure 3. Quinidine itself was recognized as an effective antiarrhythmic agent in the early twentieth century. Clinical pharmacology Quinidine isadministered orally as one of three salts (quinidinesul- fate, quinidine gluconate, or quinidine polygalacturonate). All three forms of the drug have beenmade available because some patients tolerate one salt better than another. Approximately 80–90% of the sulfate preparationis absorbed after oral administration,and peak plasma concentrations are reachedwithin 2 hours. The gluconate and polygalacturonate preparations are absorbedmore slowly and less completely than the sulfate formulation. Quinidine is 80–90% protein bound in the circulation and has a large volumeofdistribu- tion. The concentration of the drug is 4–10 times higher in the heart, liver, and kidneys thanit is in the circulation. Its elimination half-life is 5–8 hours but may be prolongedinpatients with congestive heart failure or in the elderly. Electrophysiologic effects Quinidine blocks the sodium channel and slows the rate of depo- larization of the actionpotential. Its effects on the potassium channels result in prolongation of the actionpotential and, therefore, of the refractory period. Like all drugs that prolong refractoriness, quinidine cancause early afterdepolar- izations(and thus torsades de pointes) in susceptible individuals. Hemodynamic effects Quinidine blocks the α-adrenergic receptors, which can lead to pe- ripheral vasodilation and reﬂex sinustachycardia. The effects tend to be minimal when the drug is given orally but can be profound with intravenousadministration. Therapeutic uses Quinidine is moderately effective in treating both atrial and ven- tricular tachyarrhythmias. Approximately 50% of patients treated with quinidine for atrial ﬁbrillation remain in sinus rhythm af- ter 1 year. Thus, quinidine has Class I antiarrhythmic drugs 59 beenused to treat virtually all varieties of reentrantsupraventricular tachyarrhythmias. Quinidine is effective in suppressing premature ventricular com- plexes and nonsustained ventricular tachycardias, butbecause of the proarrhythmic potential of quinidine(and most other antiarrhyth- mic agents), these arrhythmias shouldnot be treated excepttosup- press signiﬁcantsymptoms. For the same reason,quinidine should not be used to treat sustained ventricular tachycardia without the protection of an implantable deﬁbrillator. Adverse effects and interactions Symptomatic side effects occur in 30–50% of patients taking quini- dine, and the drug must be discontinuedin20–30% of patients be- cause of toxicity. Ingeneral, if diarrhea occurs, the drug should be discontinued,because the diarrhea is usually not adequately con- trolledwith medication and the resultant electrolyte imbalances may exacerbate the very arrhythmias that are being treated. Quinidine can also cause dizziness, headache, or cinchonism (tinnitus, visual blurring,and hearing disturbances). Rashes are fairly common,and signiﬁcanthypersensitivity reactionssuchashemolytic anemiaand thrombocytopenia can also occur. Any drug that prolongs the duration of the actionpotential canproduce torsades de pointes in susceptible individuals, and any drug that alters conduction veloc- ity or refractoriness can exacerbate reentrant arrhythmias. Quini- dinethus can (and does) cause ventricular arrhythmias by either of these mechanisms. Quinidine-induced syncope was recognized decades ago, but it was only relatively recently that this clinical syn- drome was shown to be caused by ventricular tachyarrhythmias. Quinidine-induced ventricular arrhythmias often occur early, usu- ally within 3–5 days after the drug isbegun,but can be seen at anytime. Although the incidenceofquinidine-inducedproarrhyth- mia is difﬁcult to quantify, a meta-analysisofrandomized trials using quinidine to treat atrial ﬁbrillation indicated a total mortality of 2.
In addition to its radical-scavenging potential cheap 5mg donepezil fast delivery, urate was proposed to stabilize reduced vitamin C in serum buy donepezil 5mg. This stabilizing effect appears to be due to inhibition of iron-catalyzed oxidation of ascorbate order 5 mg donepezil with mastercard, which largely results from the formation of a stable, noncatalytic urate–iron complex (30). Unlike radical- scavenging reactions, this protective effect provided by iron chelation is not asso- ciated with depletion of urate. Direct free-radical attack upon urate generates allantoin, which has therefore been proposed as a marker molecule for free-radi- cal reactions in vivo (31). Prevalence in Skin Only little data are available on urate levels in cutane- ous tissues. Thus, as found for other antioxidants, the highest cutaneous urate levels are present in epidermal tissue. Lipid-Soluble Antioxidants Vitamin E Antioxidant Properties Vitamin E is the major lipophilic antioxidant in plasma, membranes, and tissues (33). The term ‘‘vitamin E’’ collectively refers to the eight naturally occurring molecules (four tocopherols and four tocotrie- nols), which exhibit vitamin E activity. Tocotrienols differ from tocopherols in that they have an isoprenoid instead of a phytyl side chain (see Fig. In humans, α– tocopherol is the most abundant vitamin E homologue, followed by γ–tocopherol. Vitamin E is among the early recognized biological antioxidants, and its redox and free-radical chemistry are well documented (33). The major antioxidant role of vitamin E is generally considered to be the arrest of chain propagation by scavenging lipid peroxyl radicals. The initial oxidation product of tocopherol is the metastable tocopheroxyl radical (Fig. Thus, one molecule of tocopherol is able to scav- enge two peroxyl radical molecules. Since the physiological molar ratio of to- copherols to polyunsaturated phospholipids, ﬁrst-line targets of oxidative attack, is less than about 1:1000 in most biological membranes, regeneration of tocoph- erol is essential for its high antioxidant efﬁcacy in vivo. As mentioned above, several hydrophilic coantioxidants, such as ascorbate and glutathione, can regen- erate vitamin E from the tocopheroxyl radical and thus enhance the antioxidant capacity of vitamin E (14). Furthermore, there is some in vitro evidence that ubiquinol-10 protects α– tocopherol from photo-oxidation by recycling mechanisms (37). In vitro, unphys- iologically high concentrations of α–tocopherol were reported to induce prooxi- dative effects leading to acceleration of lipid peroxidation (38,39). In human skin in vivo, however, such adverse health effects have not been reported. Prevalence in Skin As demonstrated in other body tissues, α-tocopherol is the predominant vitamin E homologue in murine and human skin (Table 3) (5,6,18). In addition, γ–tocopherol is present in murine and human epidermis, dermis, and stratum corneum. The α–tocopherol/γ–tocopherol molar ratio in the human dermis and epidermis is approx. Notably, a vitamin E gradient has recently been demonstrated in human upper arm stratum corneum. The highest α–tocopherol levels were found in the lower stratum corneum, whereas the low- est levels were present in the upper layers. The α–tocopherol/γ–tocopherol ratio Antioxidant Defense Systems in Skin 153 154 Thiele et al. The α–tocopherol levels in human dermis and epidermis were sever- alfold higher than in corresponding layers of hairless mouse skin (17,18). Consis- tently, human stratum corneum contains almost tenfold higher α–tocopherol lev- els than measured in murine stratum corneum (5,6). As observed for hydrophilic antioxidants, higher vitamin E levels were found in murine and human epidermis, as compared with dermal levels. It remains to be clariﬁed whether the uptake and transport of α–tocopherol in the epidermis is an unspeciﬁc and passive process or, as described for human hepatocytes (33), is regulated by a mechanism involving a speciﬁc binding enzyme (α–tocopherol transfer protein). Ubiquinols/Ubiquinones (‘‘Coenzyme Q’’) Antioxidant Properties The terms ‘‘coenzyme Q,’’ as well as ‘‘ubiqui- none,’’ are commonly used for the redox couple ubiquinol/ubiquinone (see Fig. In nature, ubiquinone homologues containing 1 to 12 isoprene units occur; the predominant form of ubiquinone in humans is ubiquinone-10 (contains 10 isoprene units), and in mice ubiquinone-9. In liver cells, about 40 to 50% of the total cellular ubiquinone is located in the mitochondria, 25 to 30% in the nucleus, 15 to 20% in the endoplasmic reticulum, and only 5 to 10% in the cytosol (40). In vitro, the reduced forms of ubiquinones, the ubiquinols, are by two to three orders of magnitude more potent antioxidants (41).