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By U. Sanford. Houston Baptist University.

They can potentially be further improved order genuine augmentin online, in terms of effcacy and selectivity for the target 625mg augmentin with amex, or achieving optimal pharmacokinetic and pharmacodynamic properties [3] cheap 375 mg augmentin otc. As we described for natural conotoxins, the post-translational modifcation of peptides is an effcient strategy for regulating peptide localization, function and turnover, and infuences physicochemical properties, solubility, stability, aggregation, propensity to be degraded by protease activity, and specifcity of peptides [273]. In a similar way, pharmaceutical companies modify drug leads as a strategy to improve their properties. Some examples of chemical modifcations to improve peptide properties and their value as therapeutics are discussed below. For instance, Met is sensitive to oxi- dation [274], Asn is susceptible to deamination, and Asp is prone to isomerisation [275]. Trypsin and chymotrypsin in the human gastrointestinal tract have the potential to decrease the bioavailability of peptide-based therapeutics by causing proteolysis. Peptide bonds following Lys or Arg are cleaved by trypsin [276, 277], whereas chy- motrypsin cleaves at hydrophobic residues such as Phe, Tyr, and Trp [277]. Therefore, modifcation of the primary structure of peptide drug lead to minimize reactivity is an important consideration in the design of peptide therapeutics. Alternatively, amino acid substitution is frequently employed to enhance affnity for receptors by alteration of amino acids involved in binding interactions [278]. The cost of production is important in pharmaceutical development and a residue modifcation strategy is one way that can be used to reduce the cost of synthesis. For example, substitution of γ-carboxyl glutamic acid, common in conotoxins, with an unmodifed glutamic acid, often does not induce a loss of activity but substantially decreases production costs [272]. However, it is important to consider that altering amino acids can sometimes infuence the conformation of peptides, which can impact on their stability and binding properties. Thus, substitutions should be done to ensure that no loss of biological activity or undesirable side effects occurs. These peptides have better stability [96] and higher antimicrobial activity against some bacterial strains [98] than their all l-analogs. In this case a single d-amino acid substitution was an approach developed by nature to modulate not only the solubility [101] but also the biostability of a peptide [98]. The use of d-amino acids has also been adapted by the pharmaceutical industry and is now common in peptide-based drug design [83, 280]. Another possible strategy is the incorporation of β-amino acids, which also generally increases resistance to enzymatic degradation [281] while maintaining a stable secondary structure [282], and the functional properties of the natural peptide [281]. Capping by N-acetylation or C-amidation reduces susceptibility to carboxy-peptidases, improving the stability of natural peptides [283, 284]. Cyclic peptides are particularly important due to their resistance to enzymatic degradation, pH and temperature [286]. Linear peptides are often less stable, and more fexible, leading to reduced binding affnity and lower biological activity than their cyclic counterparts. This pathfnder study has been followed up with a number of other examples of the cyclization of conotoxins [290–293], the most successful of which resulted in the development of a cyclic analog of conotoxin Vc1. Thus in this case cyclization not only improved stability but led to oral activity that was not present in the parent linear conotoxin. A cyclic melittin analog exhibited increased antibacterial activity, with reduced hemolytic propensity, whereas a cyclic magainin 2 derivative was not so successful and had reduced antibacterial activity and increased hemolytic propensity [294]. The proper design of bioactive cyclic peptides requires detailed knowledge of the role of each amino acid residue, so that for example, cyclization should be designed to not affect residues that are crucial for activity [278]. Another consideration is the selection of a correctly sized linker, which must span the distance between the N and C termini. The adverse effects of removing stabilizing charge-charge interactions between the termini have to be overcome with linkers of correct length [287]. Nevertheless, with due consideration of these potential caveats peptide cyclization is a widely applied technique in the pharmaceutical industry, which decreases proteolytic degradation, prolongs half-life and stability and can improve binding effciency [278]. They are very important for the folding and stability of proteins, and in peptides they introduce conformational con- straints that confer a bioactive and thermodynamically stable conformation [296]. Disulfde-rich peptides can be used as stable scaffolds to graft exogenous peptide epitopes onto their stable structure, giving them new, and desired properties. Such scaffolds include the cyclotides [202], the defensins [297, 298], and the conotoxins [299] already described in this article. Because of their various disulfde connectiv- ities and a wide range of activities, these natural peptides offer a large diversity of stable molecular scaffolds. To supplement this natural set of scaffolds, the engineering of new intramolecular disulfde bonds into peptide structures is a valuable strategy for the design of peptidic compounds with desired structural and active properties [300]. For example, nonnative disulfde bonds have been used to induce a constrained and stable structure in peptides, such as an amphipathic α-helix [301–303] or β-hairpin [279, 300]. Peptides with potential antimicrobial activity were shown to possess bet- ter membrane binding, and enhanced antimicrobial potency, when a nonnative bond was introduced [279, 303, 304]. The use of diselenide bonds in place of disulfde bonds has been a particularly popular approach as the surrogate is almost isosteric but is more resistant to reduction [306–308]. The potency and selectivity of these natural compounds, including peptides, has made them of interest in the feld of drug design. In some cases, natural peptides have already been approved and are used as drugs or as food preservatives, while many others are in the pipeline of pharmaceutical com- panies. In this review, some examples of peptides isolated from different organisms with potential as therapeutic compounds have been illustrated. Such applications are facilitated by chemical modifcations and peptide engineering to improve drug-like properties of peptides. Although only limited examples have been described, the future appears to be bright for applications of natural peptides as drug leads. The value of Nature’s natural product library for the discovery of New Chemical Entities: the discovery of ingenol mebutate. Combinatorial peptide libraries in drug design: lessons from venomous cone snails. Recent progress towards pharmaceutical applica- tions of disulfde-rich cyclic peptides. Chemical re-engineering of chlorotoxin improves bioconjugation properties for tumor imaging and targeted therapy. Chemical and genetic characterization of bacteriocins: antimi- crobial peptides for food safety. Capacity of human nisin- and pediocin-producing lactic acid bacteria to reduce intestinal colonization by vancomycin-resistant enterococci. Antibacterial activity evalua- tion of microcin J25 against diarrheagenic Escherichia coli. Biosynthesis and insecticidal prop- erties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affnis. Cyclotides as grafting frameworks for protein engineering and drug design applications.

Generic substitutions: A 2005 survey of the acceptance and per- ceptions of physicians in Jamaica order augmentin online. Report of the Expert Committee on a Comprehensive Examina- tion of Drug Regulatory Issues purchase 375 mg augmentin mastercard, Including the Problem of Spurious Drugs purchase augmentin 375 mg with visa. Cross-sectional study of availability and pharmaceutical quality of antibiotics requested with or without prescription (over the counter) in Surabaya, Indonesia. Emerging challenges and opportunities in drug registration and regulation in developing countries. London: Health Systems Resource Centre, Depart- ment for International Development. The drugs stop here: A public health framework to address the drug shortage crisis. The business of health in Africa: Partnering with the private sector to improve people’s lives. Yvonne Chaka Chaka performs “Proud to Be” at Interpol General As- sembly in Vietnam. Ensuring safe foods and medical products through stronger regulatory systems abroad. Local production of pharmaceuticals: Industrial policy and access to medicines—an overview of key concepts, issues and opportunities for future research. Policies to promote use of generic medicines in low and middle income countries: A review of published literature, 2000- 2010. Vaccine supply chains need to be better funded and strengthened, or lives will be at risk. Testimony on protecting the nation’s health and safety before the House Committee on Commerce, Subcommittee on Health and Environment. Infuenza vaccination in German health care workers: Effects and fndings after two rounds of a nationwide awareness campaign. Combating counterfeit medicines and illicit trade in tobacco products: Minefelds in global health governance. New drugs for the treatment of tuberculosis: Needs, chal- lenges, promise, and prospects for the future. From decentralised developmental state towards authoritarian regulatory state: A case study on drug safety regulation in China. Private sector pharmaceutical supply and distribution chains: Ghana, Mali and Malawi. In Millenium development goal 8: Delivering on the global partnership for achieving the millenium development goals. Pharmacovigilance activities in 55 low-and middle-income countries: A questionnaire-based analysis. Brookings Blum Roundtable: The Private Sector in the Fight Against Global Poverty. Procurement strategies for health commodities: An examination of options and mechanisms within the commodity security context. Currently China has about 3,500 drug companies falling from more than 5,000 in 2004, March 18. Medicine prices in urban mozambique: A public health and economic study of pharmaceutical markets and price determinants in low-income set- tings. The price elasticity of demand for pharmaceuticals amongst high-income older Australians: A natural experiment. Model quality assurance system for procurement agencies: Harmonized assessment tool. Journal of Generic Medicines: The Business Journal for the Generic Medicines Sector 9(3):128-143. Practical guidelines on pharmaceutical procurement for countries with small procurement agencies. Safety of medicines: A guide to detecting and reporting adverse drug reactions: Why health professionals need to take action. Annex 6: A model quality assurance system for procurement agencies (rec- ommendations for quality assurance systems focusing on prequalifcation of products and manufacturers, purchasing, storage and distribution of pharmaceutical products). Quality assurance of pharmaceuticals: A compendium of guideines and related materials (volume 2, 2nd updated edition). Assessment of medicines regulatory systems in sub-Saharan African countries: An overview of fndings from 26 assessment reports. Annex 15: Guidelines on submission of documentation for a multisource (generic) fnshed product. General format: Preparation of product dossiers in common technical document format. New global mechanism to combat substandard/spurious/falsely-labelled/ falsifed/counterfeit medical products. The make or buy debate: Considering the limitations of domestic production in Tanzania. Policy note: Improving the competitiveness of the pharmaceutical sector in Bangladesh—draft. Countering the Problem of Falsified and Substandard Drugs 5 Weaknesses in the Drug Distribution Chain The modern pharmaceutical supply chain is complex. Drugs change hands many times between the manufacturer and patient; every transaction is an opportunity for falsifed or substandard products to infltrate the market. Changes to the drug distribution system could improve drug quality around the world. This chapter gives an overview of the drug distribution chain, explain- ing differences between the systems in developed and developing countries. The drug wholesale system is a weak point where the licit and illicit supply chains mix. Better controls on the wholesale market could improve the se- curity of the distribution chain. Drug tracking systems could also improve security by preventing products that leave the legitimate supply chain from returning to it. These solutions can improve drug safety as long as the sup- ply chain does not disintegrate at the point closest to the patient. Disorga- nized drug markets, both real and on the internet, undermine regulatory checks on medicines distribution. For example, in the United States about three-quarters of all pharmaceuticals are bought in retail 197 Copyright © National Academy of Sciences. In developing countries, hundreds, sometimes thou- sands, of frms control tiny shares of the same. These vendors handle a wide variety of products sold in an even wider variety of packaging. Retailers in developed countries would fnd it logistically impossible to buy their stock, in its many different packages, directly from manufacturers (Yadav et al. The drug distribution system in low- and middle-income countries has the same basic steps as that described in Figure 5-1, but with more intermediaries between the manufacturer and patient (Yadav and Smith, 2012).

Adverse reactions to atypical antipsychotics Atypical antipsychotics have fewer ex- blood cells) buy generic augmentin 625 mg on line. Weight gain is common discount augmentin 375 mg with visa, and other atypical antipsychotics discount augmentin 375mg with amex, especially trapyramidal effects than typical anti- seizures may also occur. Olanzapine places the patient at minimal Ziprasidone Aripiprazole risk for extrapyramidal effects. Weight Because ziprasidone may cause electro- Aripiprazole is a newer atypical antipsy- gain is common. Different adverse reactions Many clinicians believe that the phenothiazines should be treated as three distinct drug classes because of the differences in the ad- verse reactions they cause: • Aliphatics primarily cause sedation and anticholinergic effects. Different chemical structure Based on their chemical structure, nonphenothiazine antipsy- chotics can be divided into several drug classes, including: • butyrophenones, such as haloperidol and haloperidol decanoate • dibenzoxazepines such as loxapine • dihydroindolones such as molindone • diphenylbutylpiperidines such as pimozide • thioxanthenes, such as thiothixene and thiothixene hydro- chloride. Pharmacokinetics Although phenothiazines are absorbed erratically, they’re very lipid-soluble and highly protein-bound. Therefore, they’re distrib- uted to many tissues and are highly concentrated in the brain. Like phenothiazines, nonphenothiazines are absorbed errati- cally, are lipid-soluble, and are highly protein-bound. They’re also distributed throughout the tissues and are highly concentrated in the brain. Metabolism and excretion All phenothiazines are metabolized in the liver and excreted in urine and bile. Because fatty tissues slowly release accumulated phenothiazine metabolites into the plasma, phenothiazines may produce effects up to 3 months after they’re stopped. Nonphenothiazines are also metabolized in the liver and ex- creted in urine and bile. Erecting a blockade The antipsychotic effect of phenothiazines is due to receptor blockade in the limbic system. Their antiemetic effect is due to re- ceptor blockade in the chemoreceptor trigger zone located in the brain’s medulla. Sending a charge Phenothiazines also stimulate the extrapyramidal system (motor pathways that connect the cerebral cortex with the spinal nerve pathways). Pharmacotherapeutics Phenothiazines are used primarily to: • treat schizophrenia • calm anxious or agitated patients • improve a patient’s thought processes • alleviate delusions and hallucinations. Phenothiazines are sometimes prescribed Working overtime to quiet mentally challenged children Other therapeutic uses have been found for phenothiazines: and agitated • They’re administered to treat other psychiatric disorders, such geriatric patients. Solo solutions As a group, nonphenothiazines are used to treat psychotic disor- ders. By increasing phenothiazine metabolism, anticholinergic drugs may also reduce the antipsychotic effects of phenothiazines. Antipsychotics with anticholinergic properties Neuroleptic malignant syndrome is a potential- should be avoided in elderly patients. Their dopamine-blocking activity can inhibit levodopa and may cause disorientation in patients receiving both medications. Halo- peridol may boost the effects of lithium, producing encephalopa- thy (brain dysfunction). They include: • dextroamphetamine • lisdexamfetamine • methylphenidate • mixed amphetamine salts • modafinil. They’re help- ful in improving attention, leading to improved school or work performance, and decreasing impulsivity and hyperactivity, if present. Dextroamphetamine and methylphenidate are also used in the treatment of narcolepsy. Dextroamphetamine and Methylphenidate Mixed amphetamine salts Measure up lisdexamfetamine • Dizziness • Restlessness Stimulants may affect growth; • Restlessness • Insomnia • Insomnia children should be monitored • Tremor • Seizures • Hyperexcitability closely for height and weight • Insomnia • Palpitations • Palpitations changes. With the use of the nonbenzodiazepine-nonbarbiturate chlo- ral hydrate, what adverse reactions are most likely? We Drugs and the endocrine system help make up glands, which are a part of The endocrine system consists of glands, which are specialized the endocrine cell clusters, and hormones, the chemical transmitters secreted by system. Keeping well balanced Together with the central nervous system, the endocrine sys- tem regulates and integrates the body’s metabolic activities and maintains homeostasis (the body’s internal equilibrium). The drug classes that treat endocrine system disorders in- clude: • natural hormones and their synthetic analogues • hormonelike substances • drugs that stimulate or suppress hormone secretion. Antidiabetic drugs and glucagon Insulin, a pancreatic hormone, and oral antidiabetic drugs are classified as hypoglycemic drugs because they lower blood glu- cose levels. Glucagon, another pancreatic hormone, is classified as a hyperglycemic drug because it raises blood glucose levels. The disease appears in two primary forms: type 1, previously referred to as insulin-dependent diabetes mellitus type 2, previously referred to as non-insulin-dependent dia- betes mellitus. Insulin Patients with type 1 diabetes require an external source of insulin to control blood glucose levels. Under the skin All insulins, however, may be given by subcutaneous (subQ) injec- tion. Absorption of subQ insulin varies according to the injection site, the blood supply, and degree of tissue hypertrophy at the in- jection site. Distribution, metabolism, and excretion After absorption into the bloodstream, insulin is distributed throughout the body. Insulin is metabolized primarily in the liver and to a lesser extent in the kidneys and muscle, and it’s excreted in stool and urine. How insulin aids glucose uptake These illustrations show how insulin allows a cell to use glucose for energy. Glucose can’t enter the cell without Normally produced by the beta cells These channels allow glucose to the aid of insulin. Insulin and its receptor first move to the inside of the cell, which activates glu- cose transporter channels to move to the surface of the cell. Glucose Glucose Glucose available Insulin transport for receptor channel Insulin metabolism Pharmacodynamics (how drugs act) Insulin can help balance Insulin is an anabolic, or building, hormone that helps: fluids and • promote storage of glucose as glycogen electrolytes! Insulin’s special effects Although it has no antidiuretic effect, insulin can correct the poly- uria (excessive urination) and polydipsia (excessive thirst) associ- ated with the osmotic diuresis that occurs in hyperglycemia by de- creasing the blood glucose level. Insulin also facilitates the move- ment of potassium from the extracellular fluid into the cell. But I don’t have diabetes… tions • lipodystrophy (distur- Insulin is also used to treat severe hyperkalemia (elevated serum bance in fat deposition) potassium levels) in patients without diabetes. Types of available oral antidiabetic drugs include: • first-generation sulfonylureas, which include acetohexamide, chlorpropamide, tolazamide, and tolbutamide • second-generation sulfonylureas, which include gliclazide, glip- izide, glimepiride, and glyburide. Metabolism and excretion Oral antidiabetic drugs are metabolized primarily in the liver and are excreted mostly in urine, with some excreted in bile. Gly- buride is excreted equally in urine and stool; rosiglitazone and pi- oglitazone are largely excreted in both. Pharmacodynamics It’s believed that oral antidiabetic drugs produce actions both within and outside the pancreas (extrapancreatic) to regulate blood glucose. Oral Pancreas partners antidiabetic drugs Oral antidiabetic drugs probably stimulate pancreatic beta cells to work in and out of release insulin in a patient with a minimally functioning pancreas. Most likely, it’s the actions of the oral antidiabetic agents outside of the pancreas that maintain this glucose control.

Mimickers and inhibitors There are two major classes of cholinergic drugs: Cholinergic agonists mimic the action of the neurotransmit- ter acetylcholine order augmentin pills in toronto. Anticholinesterase drugs work by inhibiting the destruction of acetylcholine at the cholinergic receptor sites purchase augmentin 625 mg with amex. How cholinergic drugs work Cholinergic drugs fall into one of two major classes: cholinergic agonists and anticholinesterase drugs buy augmentin 375 mg free shipping. Cholinergic agonists Anticholinesterase drugs When a neuron in the parasympathetic nervous system is stim- After acetylcholine stimulates the cholinergic receptor, it’s de- ulated, the neurotransmitter acetylcholine is released. Anticholinester- choline crosses the synapse and interacts with receptors in an ase drugs inhibit acetylcholinesterase. Cholinergic agonists stimulate cholinergic re- line isn’t broken down and begins to accumulate, leading to ceptors, mimicking the action of acetylcholine. Pharmacokinetics (how drugs circulate) The action and metabolism of cholinergic agonists vary widely and depend on the affinity of the individual drug for muscarinic or nicotinic receptors. Metabolism and excretion All cholinergic agonists are metabolized by cholinesterases: • at the muscarinic and nicotinic receptor sites • in the plasma (the liquid portion of the blood) • in the liver. Pharmacodynamics (how drugs act) Cholinergic agonists work by mimicking the action of acetylcho- line on the neurons in certain organs of the body called target or- gans. Examples include the following: • Other cholinergic drugs, particularly anticholinesterase drugs (such as ambenonium, edrophonium, neostigmine, physostigmine, Adverse and pyridostigmine), boost the effects of cholinergic agonists and reactions to increase the risk of toxicity. Because they bind with • Quinidine also reduces the effectiveness of cholinergic agonists. As acetylcholine builds up, it continues to stimu- fects can include: late the cholinergic receptors. One day at a time: Recognizing a toxic response It’s difficult to predict adverse reactions to an- Enter edrophonium ticholinesterase drugs in a patient with myas- Deciding whether a patient is experiencing a thenia gravis because the therapeutic dose toxic drug response (too much drug) or a my- varies from day to day. Increased muscle asthenic crisis (extreme muscle weakness and weakness can result from: severe respiratory difficulties) can be difficult. When edrophonium is used, suction, oxygen, mechanical ventilation, and emer- gency drugs, such as atropine, must be readily available in case a cholinergic crisis occurs. Pharmacokinetics Here’s a brief rundown of how anticholinesterase drugs move through the body. Because the duration of action for an oral dose is longer, however, the pa- tient doesn’t need to take it as frequently. Distribution Physostigmine can cross the blood-brain barrier (a protective bar- rier between the capillaries and brain tissue that prevents harmful substances from entering the brain). Donepezil is highly bound to plasma proteins, tacrine is about 55% bound, rivastigmine is 40% bound, and galantamine is 18% bound. Depending on the dosage, anticholinesterase Pharmacodynamics drugs can produce a Anticholinesterase drugs promote the action of acetylcholine at stimulant or receptor sites. From minutes to weeks Reversible anticholinesterase drugs block the breakdown of acetylcholine for minutes to hours; irreversible anti- cholinesterase drugs do so for days or weeks. Drug interactions These interactions can occur with anticholinesterase drugs: • Other cholinergic drugs, particularly cholinergic agonists (such as bethanechol, carbachol, and pilocarpine), increase the risk of a toxic reaction when taken with anticholinesterase drugs. Most of the adverse re- actions caused by anti- cholinesterase drugs re- Cholinergic blocking drugs sult from increased ac- tion of acetylcholine at Cholinergic blocking drugs interrupt parasympathetic nerve im- receptor sites. These drugs Adverse reactions are also referred to as anticholinergic drugs because they prevent acetylcholine from stimulating cholinergic receptors. Muscarinic receptors are • diarrhea cholinergic receptors that are stimulated by the alkaloid mus- • shortness of breath, carine and blocked by atropine. Next come their synthetic sisters Synthetic derivatives of these drugs (the quaternary ammonium drugs) include: • glycopyrrolate • propantheline. Atropine may also be used as an antidote for nerve agents (See the appendix, Vaccines and antidotes for biological and chemical weapons. Distribution The belladonna alkaloids are distributed more widely throughout the body than the quaternary ammonium derivatives or dicyclo- mine. The alkaloids readily cross the blood-brain barrier; the other cholinergic blockers don’t. Metabolism and excretion The belladonna alkaloids are only slightly to moderately protein- bound. This means that a moderate to high amount of the drug is active and available to produce a therapeutic response. The bel- ladonna alkaloids are metabolized in the liver and excreted by the kidneys as unchanged drug and metabolites. Pharmacodynamics Cholinergic blockers can have paradoxical effects on the body, de- pending on the dosage and the condition being treated. Dual duty Cholinergic blockers can produce a stimulating or depressing ef- fect, depending on the target organ. In the brain, they do both— low drug levels stimulate, and high drug levels depress. Conditional considerations The effects of a drug on your patient are also determined by the patient’s disorder. Parkinson’s disease, for example, is character- ized by low dopamine levels that intensify the stimulating effects of acetylcholine. The quaternary ammo- nium and amine compounds such as propantheline are the drugs of choice for these conditions because they cause fewer adverse reactions than belladonna alkaloids. Before surgery Cholinergic blockers such as atropine are given before surgery to: • reduce oral, gastric, and respiratory secretions • prevent a drop in heart rate caused by vagal nerve stimulation during anesthesia. How atropine speeds the heart rate To understand how atropine affects the heart, first consider inhibits electrical conduction and causes the heart rate to slow how the heart’s electrical conduction system functions. Atropine is the drug of choice to treat: • symptomatic sinus bradycardia—when the heart beats too slow- ly, causing low blood pressure or dizziness (see How atropine speeds the heart rate) • arrhythmias resulting from the use of anesthetics, choline es- ters, or succinylcholine. That means that they: • paralyze the ciliary muscles of the eye (used for fine focusing) • alter the shape of the eye lens. Moreover, cholinergic blockers act as mydriatics to dilate the pupils, making it easier to measure refractive errors during an eye examination or to perform eye surgery. Punishing pesticides The belladonna alkaloids, particularly atropine and hyoscyamine, are effective antidotes to cholinergic and anticholinesterase drugs. Atropine is the drug of choice to treat poisoning from organophosphate pesticides. Atropine and hyoscyamine also counteract the effects of the neuromuscular blocking drugs by competing for the same receptor sites. This increases the amount of the drug that’s absorbed and, therefore, increases the risk of ad- verse effects. Increased effect… Drugs that increase the effects of cholinergic blockers include: • disopyramide • antidyskinetics such as amantadine • antiemetics and antivertigo drugs, such as buclizine, cyclizine, meclizine, and diphenhydramine • antipsychotics, such as haloperidol, phenothiazines, and thio- xanthenes • cyclobenzaprine • orphenadrine • tricyclic and tetracyclic antidepressants. Mixing it up some more Other drug interactions can occur: • The risk of digoxin toxicity increases when digoxin is taken with a cholinergic blocker.

A training program for Kilif shopkeepers more than doubled the proportion of antimalarials sold in adequate dosage (Marsh et al purchase augmentin mastercard. A similar Kenyan program trained mobile wholesalers or wholesaler counter attendants to teach drug retailers about correct malaria drug dosing (Tavrow and Shabahang order 375mg augmentin with amex, 2002) augmentin 625mg without prescription. After 6 months, mystery shoppers were nine times more likely to receive the correct drugs in the correct dose from retailers who had participated in the program (Tavrow and Shabahang, 2002). Giving Incentives to Pharmaceutical Personnel Using workers more effciently could do much to remedy chaotic drug retail in low- and middle-income countries, but there is also a problem of retaining trained staff in underserved posts. Even minimal technical train- ing confers a competitive advantage in the labor market, especially in poor countries (Attanasio et al. Newly minted pharmacy technicians or drug dispensers can easily leave their rural Copyright © National Academy of Sciences. This pattern can undermine the best efforts to improve rural-urban equity and should be discouraged, while respecting the individual right to emigrate. Governments should reward service in underserved areas and attempt to mitigate the hardships of these posts. Scholarships for the children of pharmacy staff in underserved areas could assuage fears that a rural posting puts their children at a disadvantage. Efforts to guarantee good schooling for children, possibly through boarding schools or scholarships, could remove a barrier to rural service (Rao et al. Health workers also have concerns about quality of life and physical hardships in rural posts (Rao et al. Subsidized housing or provi- sion of modern living quarters could help in places where this is a common concern. It is also possible to recruit pharmacy technicians and pharmacy assistants from underserved communities. Training students from rural and remote areas is a known way to reduce attrition in these posts (Rabinowitz et al. The Australian Rural and Remote Pharmacy program has successfully increased service to rural and isolated communities, in part through giving scholarships to students from rural backgrounds (see Box 5-4). Internet Pharmacies in Middle- and High-Income Countries Disorganized medicines retail is not confned to developing countries. The previous section describes the large gray market for medicines in ba- zaars and unlicensed drug shops in low- and middle-income countries. The internet serves the same purpose, but mostly in middle- and high-income countries. Illegitimate internet pharmacies are similar to unlicensed drug shops both in the quality of the products they stock, which is poor, and in the lack of offcial oversight of their operations (Crawford, 2003). And, because the internet facilitates easy international sales, online drug stores have spread the problem of falsifed and substandard drugs “from small, unproftable, markets in developing nations to the [drug] industry’s most lucrative markets” (Lybecker, 2007, p. The program aims to improve access to pharmacy services in rural or remote regions and includes a variety of initiatives to improve recruitment and retention of rural pharmacists. The program also increases pharmacy students’ exposure to rural work during their training. Australian pharmacy students work in com- munity or hospital pharmacies as part of their studies. The program also supports students from rural backgrounds to pursue pharmacy degrees. Another successful initiative to improve retention is the program’s emer- gency locum service. Figure 5-6 shows the geographic breakdown of the 30 countries that have legislation on the operation of internet pharmacies. A few countries have an accreditation process for their own internet pharmacies, but internet commerce is transnational. Perhaps concern about the practicality of enforcing laws against internet drug sales prevents countries from passing them. It may also seem futile to ask internet drug sellers to observe the same stan- dards registered pharmacies do, such as requiring doctor’s prescription for controlled medicines, when “national rules banning the sale of drugs with- out a prescription can be easily overcome” (Levaggi et al. Just as often, restrictions and quality controls for online pharmacies are not, in fact, violated because many internet pharmacies operate out of countries that have no such restrictions. Although regulatory agencies can ask foreign governments to close online drug stores, it is diffcult to prevent them from reopening at a different address (Ivanitskaya et al. Because the products are sent through courier or postal services, customs and border offcers may also stop the imported drugs at the port of entry (Ivanitskaya et al. The Attraction of Internet Pharmacies Some of the more reputable-looking internet drug sellers keep up the pretense of having patients complete a health questionnaire before buying drugs, but many do not (Ivanitskaya et al. Bostwick and Lineberry proposed four main categories of customers at internet pharmacies: bargain hunters, the poor or elderly, the “life- style libertines” who prefer to self-prescribe, and drug addicts (Baert and De Spiegeleer, 2010; Bostwick and Lineberry, 2007). Of these groups, ad- dicts are the least likely to purchase prescription drugs online (Inciardi et al. Internet drug stores cater to people who like to buy drugs with- out, or even against, a physician’s advice (Levaggi et al. Table 5-3 shows other perceived advantages and disadvantages of online pharmacies. Other online shoppers seem motivated by a belief, sometimes a mis- taken one, that internet pharmacies sell cheaper drugs. On average, the investigators paid more for the drugs that never arrived than for those that arrived (€0. Investigators cited other hidden costs, including ship- ping and customs fees, as well as the cost of time spent waiting for the slow transactions to process (Levaggi et al. More importantly, of the 13 pharmacies that flled orders, only two were not of substandard quality (Levaggi et al. They criticized the false economy of online drug sellers in part because the products they bought sell for less in Italian regulated, storefront pharmacies (Levaggi et al. A 2001 study of Parkinson’s disease medications found on- line drug stores offered substantial savings off U. A Forbes magazine contributor explained, “My wife needs the meds to stave off a recurrence of cancer, so avoiding [online pharmacies] is not an option” (Wasik, 2012). The risks of online purchases are, especially in the United States, inextricable from larger questions of affordable drug pricing (Financial Times, 2012). Every year more Americans, and others accustomed to using the internet for bargain shopping, import “incremental amounts” of medicines to their countries though gray market internet purchases (Laven, 2006; Shepherd, 2007b). Distinguishing Rogue Pharmacies from Legitimate Ones In late September 2012, Interpol, an intergovernmental organization for police cooperation, organized an international raid of online pharmacies A GlaxoSmithKline ad campaign about the dangers of online pharmacies purporting to sell Canadian medicines. The operation, known as Pangea V, is part of Interpol’s enforcement against pharmaceutical crime.

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