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Drugs used in the treatment of infections caused by Mycobacterium leprae (leprosy) 1 buy 60mg alli otc. Dapsone is a sulfone structurally related to sulfonamides; it competitively inhibits dihydrop- teroate synthase to prevent folic acid biosynthesis cheap 60mg alli otc. Treatment may require several years to life; dapsone is often used in combination with rifampin to delay the development of resistance order alli 60 mg with amex. Rifampin is also effective discount alli 60mg with amex, but it is often used in combination with dapsone to decrease the risk of resistance buy discount alli 60mg on-line. Clofazimine (Lamprene) is used with dapsone and rifampin for sulfone-resistant leprosy or in patients intolerant to sulfones; it may also be effective against atypical mycobacteria. Amphotericin B is an antibiotic that binds to ergosterol, a major component of fungal cell membranes. It is believed to form ‘‘amphotericin pores’’ that alter membrane stability and allow leakage of cellular contents. Amphotericin B binds to mammalian cholesterol with much lower affinity, but this action may explain some adverse effects. Therapeutic uses (1) Amphotericin B is used to treat most severe fungal infections, including those caused by Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Cocci- dioides immitis, Blastomyces dermatitidis, Aspergillus spp. Adverse effects (1) The adverse effects of amphotericin B are significant; this agent causes chills and fever in 50% of patients and impaired renal function in 80%. Itraconazole, ketoconazole, miconazole, fluconazole, clotrimazole, voriconazole, and others a. General properties (1) These agents are imidazoles or triazoles that inhibit the cytochrome P-450–mediated sterol demethylation of lanosterol to ergosterol in fungal membranes. The affinity of the mammalian P-450–dependent enzyme is significantly lower; however, these agents can inhibit cortisone and testosterone synthesis. Itraconazole (Sporonox), ketoconazole (Nizoral) (1) Itraconazole has replaced ketaconazole for treatment of all mycoses except when cost is a factor. Ketoconazole is used topically for dermatophyte infections and mucocutaneous candidiasis and as a shampoo for seborrheic dermatitis. Miconazole (Monistat) (1) Miconazole is available for topical application, which is associated with a high inci- dence of burning and itching. This agent can be used for tinea pedis, ringworm, and cu- taneous and vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex), econazole (Spectazole), oxiconazole (Oxistat), sulconazole (Exelderm), sertaconazole (Ertaczo), butoconazole (Gynazole-1), terconazole (terazol-3) (1) These agents are available for topical application and are useful for many dermatophyte infections. Voriconazole (Vfend) (1) Voriconazole is approved for primary treatment of acute invasive aspergillosis and sal- vage therapy for rare but serious fungal infections caused by the pathogens Scedospo- rium apiospermum and Fusarium spp. Nystatin is a polyene antibiotic that is similar in structure and mechanism of action to amphotericin B. Nystatin is used only for Candida infections of the skin, mucous membranes, and intestinal tract. Griseofulvin binds to microtubules and prevents spindle formation and mitosis in fungi. Flucytosine is actively transported into fungal cells and is converted to 5-fluorouracil and subsequently to 5-fluorodeoxyuridylic acid, which inhibits thymidylate synthetase and thus pyrimidine and nucleic acid synthesis. Human cells lack the ability to convert large amounts of flucytosine to the uracil form. Resistance develops rapidly and limits its use; flucytosine is rarely used as a single drug, but it is often used in combination with other antifungal agents. Flucytosine is relatively nontoxic; the major adverse effects of this agent are depression of bone marrow function at high doses and hair loss. Tolnaftate (Aftate, Tinactin), naftifine (Naftin), terbinefine (Lamisil), butenafine (Lotrimin), cyclopirox (Loprox). It is used for sal- vage therapy in patients with severe aspergillosis who failed therapy with amphotericin B. Malaria (1) In the primary state of infection, sporozoites are injected into the host by the female mosquito (or a contaminated needle).
Dopamine activates peripheral b1-adrenoceptors to increase heart rate and contractility discount 60 mg alli amex. Dopamine activates prejunctional and postjunctional dopamine D1-receptors in the renal purchase alli 60 mg amex, coronary cheap alli 60mg mastercard, and splanchnic vessels to reduce arterial resistance and increase blood flow buy alli 60 mg with amex. At low doses trusted 60 mg alli, dopamine has a positive inotropic effect and increases systolic pressure, with little effect on diastolic pressure or mean blood pressure. At higher doses, dopamine activates a-receptors and causes vasoconstriction, with a reflex decrease in heart rate. Dobutamine (1) Dobutamine is a synthetic catecholamine that is related to dopamine. Terbutaline (Brethine, Bricanyl), albuterol (Proventil, Ventolin), metaproterenol (Alupent), pirbuterol (Maxair), levalbuterol (Xopenex), bitolterol (Tornalate), salmeterol (Serevent), and formoterol (Foradil) (1) These drugs are more selective b2-receptor agonists that relax bronchial smooth mus- cle with fewer cardiac effects and longer duration of action than epinephrine. Isoproterenol (Isuprel) (1) Isoproterenol activates b-receptors with little activity on a-receptors. Phenylephrine, methoxamine (Vasoxyl), and metaraminol (Aramine) (1) These drugs produce effects primarily by direct a1-receptor stimulation that results in va- soconstriction, increased total peripheral resistance, and increased systolic and diastolic pressure. Metaraminol also has indirect activity; it is taken up and released at sympathetic nerve endings, where it acts as a false neurotransmitter. Xylometazoline (Otrivin) and oxymetazoline (Afrin) (1) These drugs have selective action at a-receptors. Clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin), and guanfacine (Tenex) (1) These antihypertensive agents directly or indirectly activate prejunctional and, prob- ably, postjunctional a2-receptors in the vasomotor center of the medulla to reduce sym- pathetic tone. At higher, nontherapeutic doses, it activates peripheral a-receptors to cause vasoconstriction. Ephedrine and mephenteramine (1) These drugs act indirectly to release norepinephrine from nerve terminals and have some direct action on adrenoceptors. Amphetamine, dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), phendime- trazine (Preludin), modafinil (Provigil), methylphenidate (Ritalin), and hydroxyamphet- amine (Paredrine) (see Chapter 5) (1) These drugs produce effects similar to those of ephedrine, with indirect and some direct activity. Phenylephrine, methoxamine, norepinephrine, and other direct-acting a-receptor sympa- thomimetic drugs are used for short-term hypotensive emergencies when there is inad- equate perfusion of the heart and brain such as during severe hemorrhage. Ephedrine and midodrine (Pro-Amatine), prodrug that are hydrolyzed to the a1-adrenoceptor agonist desglymidodrine, to treat chronic orthostatic hypotension. The use of sympathomimetic agents in most forms of shock is controversial and should be avoided. Fenoldopam (Corlopam) is a selective dopamine D1-receptor agonist used to treat severe hypertension. Epinephrine is commonly used in combination with local anesthetics (1:200,000) during infiltration block to reduce blood flow. Epinephrine is used during spinal anesthesia to maintain blood pressure, as is phenyleph- rine, and topically to reduce superficial bleeding. Phenylephrine and other short- and longer acting a-adrenoceptor agonists, including oxy- metazoline, xylometazoline, tetrahydrozoline (Tyzine), ephedrine, and pseudoephedrine, are used for symptomatic relief of hay fever and rhinitis of the common cold. Long-term use may result in ischemia and rebound hyperemia, with development of chronic rhinitis and congestion. Metaproterenol, terbutaline, albuterol, bitolterol, and other b2-adrenoceptor agonists are pre- ferred for treating asthma. Phenylephrine facilitates examination of the retina because of its mydriatic effect. Hydroxyamphetamine and phenylephrine are used for the diagnosis of Horner syndrome. Dexmedetomidine (Precedex), a novel selective a2-adrenoceptor agonist that acts centrally, is used intravenously as a sedative in patients hospitalized in intensive care settings. Other uses include ritodrine and terbutaline to suppress premature labor by relaxing the uterus, although the efficacy of these drugs is controversial. The adverse effects of sympathomimetic drugs are generally extensions of their pharmacologic activity. Overdose with epinephrine or norepinephrine or other pressor agents may result in severe hypertension, with possible cerebral hemorrhage, pulmonary edema, and car- diac arrhythmia. Increased car- diac workload may result in angina or myocardial infarction in patients with coronary insufficiency. Phenylephrine should not be used to treat closed-angle glaucoma before iridectomy as it may cause increased intraocular pressure. Sudden discontinuation of an a2-adrenoceptor agonist may cause withdrawal symptoms that include headache, tachycardia, and a rebound rise in blood pressure. Tricyclic antidepressants block catecholamine reuptake and may potentiate the effects of norepinephrine and epinephrine.
But it seems unwise to abandon the practice of recording race when we have barely begun to understand the architecture of the human genome and its implications for new strategies for the identiﬁcation of gene variants that protect against discount 60mg alli otc, or confer susceptibility to purchase alli 60mg without prescription, common diseases and modify the effects of drugs quality 60 mg alli. Although past studies have shown that genomic diversity and allele frequency patterns vary by population purchase 60 mg alli visa, those based solely on self-reported ancestry often do not reﬂect genetic ancestry and exclude individuals who are of mixed ancestry buy 60mg alli amex. Universal Free E-Book Store Gene Patents and Personalized Medicine 663 Genomic information is now increasingly replacing self-reported race in medical- and population-related research. With the availability of markers in population genetics that are informative of ancestry and reveal genetic clues, the concept of race is no longer useful in the context of this research. Gene Patents and Personalized Medicine Gene patents for therapeutics have often been subject of litigation but there is sur- prisingly little publicity. In contrast, genetic diagnostics have been highly contro- versial but rarely litigated until now. Problems do occur when patents are exclusively licensed to a single provider and no alternative is available. Courts have been chang- ing the thresholds for what can be patented, and how strongly patents can be enforced. Technologies for sequencing, genotyping and gene expression proﬁling promise to guide clinical decisions in managing common chronic diseases and infectious diseases, and will become an integral part of personalized medicine. A study found that patent claims, if strictly enforced, might block the use of multi-gene tests or full-genome sequence data (Chandrasekharan and Cook-Deegan 2009). With availability of new technologies that reduce the costs of complete genomic sequenc- ing to prices that are comparable to current genetic tests, policy makers and courts are unlikely to allow intellectual property to obstruct such technological advance, but prudent policy will depend on careful analysis and foresight. Since that time, Myriad has been a forerunner in the ﬁeld of personalized medicine through the use of effective commercialization strategies which have been emulated by other commercial biotechnology companies. Myriad’s strategies include patent acquisition and active enforcement, direct-to-consumer advertising, diversiﬁcation, and trade secrets. These business models have raised substantial ethical controversy and criticism, often related to the company’s focus on market dominance and the potential conﬂict between private sector proﬁtability and the promotion of public health. However, these strategies have enabled Myriad to survive the economic challenges that have affected the biotechnology sector and to become ﬁnancially successful in the ﬁeld of personalized medicine. A critical assessment of the legal, economic and ethical aspects of Myriad’s practices over this period allows the identiﬁcation of the company’s more effective business models (So and Joly 2013). The authors also discuss the consequences of implementing economically viable models without ﬁrst carrying out broader reﬂection on the socio-cultural, ethical and political contexts in which they would apply. Evaluating online direct-to-consumer marketing of genetic tests: informed choices or buyers beware? Keeping pace with the times – the genetic information nondiscrimination act of 2008. Impact of direct-to-consumer predictive genomic testing on risk perception and worry among patients receiving routine care in a preventive health clinic. Commercial opportunities and ethical pitfalls in personalized medicine: a Myriad of reasons to revisit the Myriad Genetics Saga. Universal Free E-Book Store Chapter 22 Regulatory Aspects of Personalized Medicine Introduction The regulatory agencies have not laid down any speciﬁc guidelines for the personalized medicines. Most of the discussion relevant to this topic is covered under the over- lapping components of personalized medicine: pharmacogenetics, pharmacoge- nomics, molecular diagnostics, and companion diagnostics. Accuracy, sensitivity and reproducibility are required for any diagnostic procedure that is to be used for predictive drug testing. Only after conﬁrmation of the identity of the polymorphism, should the company be allowed to proceed to the next step of analy- sis, which involves proteomics or analysis of protein expression of the genotype variant. Pharmacogenomic testing may be used in clinical trials of a drug, in reeval- uation of a failed drug candidate or for evaluation of patient responsiveness to a marketed drug. The quality of such testing is not yet adequately covered by the regulatory agencies. Regulatory agencies will need to apply new approaches towards the review and approval of molecular diagnostic tests that use new tech- nologies as well as drugs that work in concert with companion diagnostics, often using complex multianalyte test formats. The information revealed by pharmacoge- nomic testing during drug development and that based on study of marketed drugs might reveal potential hazards that need to be included in the labeling, which cur- rently includes only known hazards. Labeling should disclose not only risk infor- mation on the extrapolation of in vitro pharmacogenomic testing and in vivo drug responsiveness but also the recommended dose based on stratiﬁed patient groups according to genotype/phenotype proﬁles. New regulatory challenges will surface with the development of drugs targeted at special populations. Current guidelines of the European Medicines Evaluation Agency do not speciﬁcally mention pharmacogenetics but they recommend the value of a “population approach” to clinical trials to screen for drug interactions.