Using the article below, summarize Drug Development and Approval process 76 I • Foundations of

Using the article below, summarize Drug Development and Approval process 76 I • Foundations of Pharmacology and Prescribing Target identification 1-2 years Target validation 0.5-1 year Lead identification 0.5-1 year Lead optimization 1-3 years Preclinical development 1-2 years Clinical studies 5-6 years Registration 1-2 years FIGURE 7.1 De novo drug discovery process and timeline. THE PROCESS OF NEW DRUG DEVELOPMENT AND U.S. FOOD AND DRUG ADMINISTRATION APPROVAL The process of drug discovery and development in- volves the identification of a target that causes the disease, followed by modeling of that target (e.g., a pro- tein, an antigen, or a receptor type) to design a drug candidate.3 To develop a new therapeutic agent, a phar- maceutical company must bring together appropriate cross sections of scientists, clinicians, statisticians, regulatory agencies, marketing, and even economists as well as attorneys. Furthermore, preclinical investi- gations involve toxicology, pharmacodynamics (PD), and pharmacokinetics (PK) studies, as well as optimi- zation of the drug delivery system. 3 Once a selection of a candidate molecule for clinical development has been identified, an FDA Investigational New Drug (IND) ap- plication will be filed. Figure 7.1 shows the de novo drug discovery process and the approximate timeline during each of the steps. TARGET IDENTIFICATION Typically, researchers begin the drug discovery process by thoroughly examining the critical pathways within a cell, which may directly regulate a phase of the dis- ease. It is crucial to identify a potential drug target in a pathway since there may be multiple metabolic sites of action that can impact the metabolic flow. 5 These po- tential targets may include enzymes, receptors, or oli- gonucleotides. A promising drug target may have the following properties: 1. A defined role in the pathophysiology of a disease and/or one that is disease-modifying 2. Not evenly distributed throughout the body 3. Easily “assayable” enabling high-throughput screening 4. Possesses potential adverse effects that can be predicted using phenotypic data TARGET VALIDATION Drug-target validation is a critical step before mov- ing onto the developmental stage. 6 A new drug often takes more than 10 years to develop with a cost close to $1 billion. 3, 6 Furthermore, more than 50% of failures in clinical phase 2 and 3 trials are due to insufficient efficacy. Consequently, an in-depth understanding of a molecular target is required, since later success or failure of the potential drug candidate is dependent on this early step. While the validation of a drug’s ef- ficacy and toxicity in numerous disease-relevant cell and animal models is highly valuable, the ultimate test is whether the drug works in a clinical setting. The tar- get-validation process may be summarized in three key steps: 1. Once a drug candidate is identified via a specifi c technique, procedure, or review of literature, a confirmatory experiment is repeated to confirm if the data are successfully reproducible. 2. Modulation of the activities of the drug candidate or the binding sites are performed. By varying different parameters, such as introducing mutations into the binding domain or using a different cell or tissue type, researchers are able to further determine the characteristics of the potential drug target. In other words, the introduction of manipulations of either the environment, the ligand, or the binding sites helps to further characterize the potential drug target. 3. Establishment of the druggable toxicities and pharmacological profile is achieved. ASSAY DEVELOPMENT One of the first steps in drug development and toxic- ity testing is creating assays, which evaluate the effects of chemical compounds on cellular, molecular, or bio- chemical processes of interest. An assay is defined as a method by which the activity of a compound is mea- sured. When active compounds are identified, they may become potential therapeutic candidates in the drug development pipeline. LEAD GENERATION A chemical lead is defined as a synthetically feasible, stable, and druglike molecule active in primary and secondary assays with acceptable specificity and selec- tivity for the target. The characteristics of a chemical lead include:7 • Drug Development and Approval 77 1. A defined structure-activity relationship (SAR) 2. Druggability 3. Synthetic feasibility 4. Selective mechanistic assays 5. In vitro assessment of drug resistance and efflux potential 6. Evidence of in vivo efficacy of chemical class 7. Pharmacokinetics/toxicity of the chemical class that are known based on preliminary toxicity or in silico studies To increase the success rate from the compound candidates during the drug development process, a druggability assessment is conducted. This assessment is crucial in transforming a compound from a lead mol- ecule to a drug. For a compound to be considered drug- gable, it should have the potential to bind to a specific target at high affinity. Other assay screenings such as the Ames test and cytotoxicity assay may be applied to evaluate the potential toxicity of the new compound. Of note, when compounds are being developed, a posi- tive result in the cytotoxicity assays may not necessar- ily limit the development of the compound. In fact, the other more relevant druggability factors (such as the PK profi le) would be the potential determining factors for a drug development. LEAD OPTIMIZATION Once a lead structure is identified, a detailed SAR can be carefully constructed to increase the activity of the lead compound. Subsequently, an optimized lead molecule will enter IND-enabling studies in compliance with good laboratory practices (GLP) and good manufacturing practices (GMP). 7 The criteria for selecting optimized candidates are as follows: 1. Acceptable in vivo PK and toxicity 2. Feasible formulation 3. In vivo preclinical effi cacy (properly powered) 4. Dose range finding (DRF) pilot toxicology 5. Scale up feasibility of chemistry assessment 6. Regulatory and marketing assessments3, 8 When a promising compound for development is identified, various experiments are conducted to deter- mine how it is absorbed, distributed, metabolized, and excreted. Its potential benefits, best dosage, and mecha- nisms of action are determined. The best route of admin- istration (e.g., by mouth or injection) is described. Side effects, adverse events, or toxicities are also recorded. Furthermore, the effects of how the optimized com- pound has influenced different populations by gender, race, or ethnicity and how it interacts with other drugs and treatments are observed. Additionally, its effective- ness as compared with similar drugs is also noted. NEW CHEMICAL ENTITY SOURCES New chemical entity (NCE) is a new molecule with a physiological or pharmacological bioactive response that has not been used before as a medicinal product. NCEs can be obtained from various sources, which may be natural, semi-synthetic, or synthetic. The NCEs are the major contributors to the new drug discovery process that may take up to 10 years depending on the advance of technology employed.9, 10 Natural products are biologically active chemical compounds found in nature of biological organisms or systems regardless of modes of preparation (e.g., by extraction or total synthesis). These compounds are generally secondary metabolites that are not cru- cial for the growth, development, or reproduction of the organism. 11 They are often a product of defense mechanisms against predators or adaptation of the organism to its environment. 12,13 The NCEs from nat- ural products are highly potent and selective because they result from an “optimized” biological process to help the organism cope with its environment. They are generally an important source of NCEs throughout history and continue to deliver a great variety for drug discovery. 13-15 Plants as a Source of a New Chemical Entity Many drugs are derived from plants. For example, artemisinin was isolated from wormwood , Arte- misia annua, in 1972. It has been used for centuries in traditional Chinese medicine to treat malaria and fevers. Artemisinin and its derivative, artemether, have been used until today to effectively treat chloro- quine-resistant malaria. 16,17 In 2006, the FDA-approved sinecatechins, which was extracted from green tea leaves, Camellia sinensis, containing more than 95% catechins, which is used for the treatment of external genital or perianal warts. In 2012, another botanical drug, crofelemer, extracted from “dragon’s blood,” Croton lechleri, was approved for the treatment of non-infectious diarrhea. 18 Microorganisms as a Source of a New Chemical Entity Screening of microorganisms for NCEs has resulted in many important pharmaceutical products. 19-21 In 1928, Alexander Fleming discovered penicillin from the fila- mentous fungus Penicillium notatum, and in 1943 Sel- man Waksman and colleagues discovered streptomycin from the soil bacteria Actinomycete, Streptomyces gri- seus. 22 These discoveries have transformed the drug discovery industry and the search for NCEs in biolog- ical systems. Up to 2013, 69% of all antibacterial agents approved by the FDA originated from natural products, of which 97% were isolated from microorganisms. 18 Furthermore, during the 2000 to 2013 time period, 77%78 I • Foundations of Pharmacology and Prescribing of antibiotics approved by the FDA were natural prod- ucts, and all were derived from microorganisms. 18 To date, less than 1% of microorganisms available in na- ture have been screened thus far for NCEs. 20 This sug- gests there is much potential for further discoveries of microbe-derived therapeutic agents. Other Sources of a New Chemical Entity Other sources of NCEs may include the synthesis or purification of bioactive peptides acting against a dis- ease process. Exenatide and lepirudin are examples of bioactive peptide-derived drugs that may be classified under this category. Exenatide, a peptide extracted from the saliva of the Gila monster lizard, Heloderma suspectum, is a well-known glucagon-like peptide-1 analog approved for the treatment of type 2 diabetes mellitus.20,23 In addition, the hirudin was produced from the salivary gland of the medical leech, Hirudo medici- nalis . Hirudin is a potent thrombin inhibitor, which acts as a potent anticoagulant. The gene encoding for this protein was later identified and cloned. In 1998, a re- combinant product of this protein (i.e., hirudin) known as lepirudin was approved by the FDA as an alternative anticoagulant for patients who developed heparin-in- duced thrombocytopenia (HIT) with heparin.24 Over the past decades, the drug discovery paradigm has shifted toward rational design. This target-based ap- proach involves specific proteins or “targets,” which are often chosen according to the current understandings of the pathophysiology of the disease process. Although the application of rational design has systematically outlined and identified new drugs, serendipity still plays a significant role in the new entity discoveries.25 CLINICAL TRIALS Once a promising NCE has been identified, clinical trials are the ultimate step to translate laboratory-re- search findings to patient-oriented applications. Sim- ply, new treatments that work in laboratory animal studies (i.e., preclinical trials) need to be tested in humans to determine if the treatment would provide benefits or harms. Generally, clinical trials are con- trolled by ethical principles of respect for the persons, benefi cence of the patient, and justice. These principles are presented in the form of informed consent, which has to be explained and signed by every participant in the study. Additionally, all clinical trials are overseen by the Institutional Review Boards (IRBs) ensuring that human research conforms to local and national stan- dards of safety and ethics. 25-27 Study populations are properly selected based on two major characteristics: (a) a sound “internal validity” with predefined charac- teristics; and (b) a high degree of “external validity” to represent a general patient population.27 Before initiating a clinical trial on humans, all data from preclinical studies must be first submitted to the FDA in the form of IND application. If the IND is approved, the new drug may be studied in human in phases 1 to 3. If a drug showed high safety and efficacy, a second application referred to as New Drug Appli- cation (NDA) may be also submitted to the FDA to determine if it can be prescribed and marketed for the intended population. Subsequently, the drug continues to be studied and monitored post marketing as a phase 4 trial.28 PHASE 1 CLINICAL TRIALS Phase 1 clinical trials are the first stage during drug testing on human subjects. The purpose of this phase is to test the safety and dosage ranges, as well as poten- tial toxicity of the new drug. Phase 1 trials are usually designed as “open-labeled” studies where the clinician and the participant are aware of the given drug. This phase is often conducted on a small number of healthy volunteers for a few months. PHASE 2 CLINICAL TRIALS Phase 2 clinical trials evaluate the efficacy and side ef- fects of the new drug. In this phase, the safety and dos- age specifications are conducted on patients affected with the condition for which the drug is intended to treat, rather than on healthy volunteers. These trials are designed as “controlled” studies that involve one group of patients who receive the new drug and a control group who receives a placebo or gold-standard treat- ment. They are usually carried out in “double-blinded” fashion in which neither the clinicians nor the patients know if the given therapy is the new drug or a placebo. PHASE 3 CLINICAL TRIALS Phase 3 clinical trials are studies of the new drug prior to getting the final FDA approval for marketing. The purposes of this phase are to determine the efficacy and to monitor adverse reactions. In this stage, the safety, efficacy, and dosage modification of the new drug compared to the current gold-standard treatment or placebo are intensively evaluated in thousands of participants. Although only one-third of new drugs successfully progress to phase 3 clinical trials, approx- imately 80% of those that enter phase 3 receive an NDA approval and move on to phase 4 clinical trials.29 PHASE 4 CLINICAL TRIALS Phase 4 clinical trials are conducted after getting the FDA approval for NDA and post marketing to identify and evaluate the long-term effect of new drugs over a7 • Drug Development and Approval 79 lengthy period on a massive number of “real-world” pa- tients. Through phase 4 clinical studies, new drugs can be tested continuously post marketing approval to un- cover more information about efficacy, safety, and side effects. Approximately 20% of new drugs in the market acquire new Black-Box Warnings post marketing, and approximately 4% of drugs are ultimately withdrawn from the market for safety reasons. GENERIC VERSUS BRANDNAME DRUGS The initial therapeutic agents developed and approved for marketing are referred to as brand name drugs. Once the current patents of the brand-name products have expired, their generic counterparts may become available. The FDA requires that the generic drugs have the same performance and quality as their brand-name counterparts. Approved generic drugs must meet rigor- ous standards established by the FDA in terms of their identity, purity, strength, quality, and efficacy. Since they carry the same active ingredients as the brand, they are expected to provide the same therapeutic ef- fects. In clinical practice, prescribers often use generic drugs interchangeably with the innovator brand prod- ucts. As reported by the Intercontinental Marketing Statistics (IMS) Institute for Healthcare Informatics, generic drugs now account for approximately 88% of prescriptions dispensed in the United States. From 2005 to 2014, generic medications saved Americans $1.68 trillion—a rate of more than $1 billion in savings every other day. THE U.S. FOOD AND DRUG ADMINISTRATION APPROVAL OF GENERIC DRUGS Over the last several decades, the numbers of abbre- viated new drug applications (ANDAs) have grown substantially. In the United States, drug companies can submit an ANDA for approval to market a generic drug that is bioequivalent to the brand-name version. Manufacturers seeking an approval of a generic drug product must submit data to demonstrate that it has the same active ingredient(s), strength, type of prod- uct, route of administration, use of indication(s), strict manufacture standard, and the same rate and extent of absorption (i.e., bioequivalence) as the innovator drug product. In other words, the generic drug has to show that it is the same type of product and uses the same time-release technology, such as immediate-release or extended-release. Nevertheless, the inactive ingredi- ents from the generic version, which do not affect the active drug function, can be different from the copied brand drug. 30 Generic manufacture rs must provide evidence that the ingredients used in their product are safe. Drug label information for generic should also be the same as for the brand -name drug. In addition, the FDA must evaluate the container information to make sure it is appropriate for storage. 30 However, the ANDA process does not require the drug appli- cant to repeat the costly animal and pre- or clinical research on ingredients or dosage forms already proven safe and effective. Consequently, the generic formulations are brought to the market more quickly and at much lower cost, which allows increased medication accessibility to the public. 30 BIOEQUIVALENCE STUDY OF GENERIC MEDICATIONS As part of developing and approving generic drugs, manufacturers must provide proof of bioequivalence. This involves submitting data demonstrating that the generic drug has the same rate and extent of absorp- tion as the innovator drug product. Bioequivalence measures drug peak plasma concentration (Cmax ) and area under the plasma drug concentration versus time curve (AUC). These measurements are expressed as geometric mean ratios (GMRs) of generic to innovator Cmax and AUC. Both Cmax and AUC (average bioequivalence) must be within the limits of 80% to 125%.31 In 2000, the FDA guidance for ANDA applicants recommended that age, sex, and race be considered while selecting patients to represent the general population. To support the valid- ity of the FDA bioequivalence approach, post market- ing safety and efficacy data of approved generic drug products also need to be followed and analyzed.30 THE IMPACT OF SWITCHING TO GENERIC DRUGS In clinical settings, prescribers usually switch between branded drugs to generic formulations. This practice has become a common cost-containment measure in the United States. However, generic substitution con- tinues to be a topic of debate among government of- ficials, consumers, pharmaceutical companies, and healthcare professionals; particularly, the controversy is over the methods of evaluation of bioequivalence in vivo between the generic and innovator products. 32-34 In other words, the current FDA standards for ge- neric bioequivalence may not be sufficient for patients treated with drugs that have a narrow therapeutic index. Drugs with variable absorption patterns or with nonlinear pharmacokinetics may also be significantly impacted with generic substitution. 35-37 In general, the potential impacts of switching from brand to generic drugs may be classified into three categories: (a) Clin- ical and safety outcomes, (b) general attitudes toward generic drugs and adherence, and (c) cost and resource utilization. 3880 I • Foundations of Pharmacology and Prescribing Clinical and Safety Outcomes The clinical outcomes of a patient may be affected by the substitution of generic for brand products. There are case reports of breakthrough seizures or increased seizure frequency in patients who were switched from brand to generic or vice versa. 39 Consequently, the American Academy of Neurology (AAN) opposes generic substitution of anticonvulsants for the treat- ment of epilepsy without the approval of the attending physician. 36 Additionally, a retrospective study demon- strated that a higher dose of the generic warfarin was needed to maintain a previously stabilized interna- tional normalized ratio (INR) value when patients were switched from the brand Coumadin. 40 Furthermore, the American Society of Transplantation (AST) has recom- mended that generic immunosuppressive medications should be clearly labeled and distinguished from in- novator drugs. Patients who are taking these medica- tions should inform their physician of any switch to or among generic formulations to prevent disturbances of therapeutic drug levels 41 ; as a result, generic substitu- tion may not be applicable for all patients and condi- tions. It should be evaluated on an individual basis in certain therapeutic areas, such as antiepileptic, immu- nosuppressive, and narrow therapeutic index drugs. General Attitudes Toward Generic Drugs and Adherence Perception and knowledge of generic medications can be influenced by a consumer’s inherent beliefs. Gener- ally, one of the common perceptions that most patients have is the notion that lower drug price equates to lower quality. 42 They usually face generic medication with skepticism due to changes in size and shape of the tab- let. Even the taste of the medicine and packaging of the generic formulation may look very different from the brand, which leads to confusion and stress. Although no such tangible proof exists, generic drugs are usually considered inferior medications. Therefore, switching from branded drugs could negatively impact adher- ence. 38 A study revealed that the generic substitution of risperidone in patients with schizophrenia in Ger- many was not cost-effective due to a reduction in ad- herence rates. Patients with generic substitution had poor adherence, poor symptom control, and increased probability of more intensive and expensive hospital- ization. 43 Ideally, clinicians should prescribe using the international nonproprietary name (INN), leaving it up to the pharmacist to choose the generic best-suited for- mulation for the patient. Cost and Resource Utilization Switching a generic to a branded drug or vice versa may significantly impact the cost and resource use. A large study by Helmers et al. reported that treating pa- tients with generic antiepileptic drugs was associated with higher medical service costs and total costs than the branded drugs.44 In another study, the use of generic topiramate was correlated with a higher utilization of other prescription drugs, higher hospitalization rates, and longer hospital stays compared to branded drugs.45 As a result, the evaluation of economic benefits of switching to and from generic medications may be very complex. Each case, condition, or therapeutic entity may represent a unique situation requiring careful study before identifying its true impacts. Nevertheless, it seems that the current system in place does not offer all the necessary securities regarding pharmacovigilance, notably for the products with narrow therapeutic mar- gin, antiepileptic, and immunosuppressive medications. CONVERSION OF DRUGS FROM LEGEND TO OVERTHECOUNTER Millions of Americans rely on over-the-counter (OTC) medications as the first line of therapy for common dis- eases or conditions. Most of these OTC products en- tered the market first as prescription-only medications. Once they demonstrate a proven track record of safety and effectiveness, the drug manufacturer can petition to have them reclassified as OTC and made available to consumers without a prescription. This process is known as an Rx-to-OTC switch. The migration of some prescription medications to the status of OTC takes place on an almost yearly basis. In fact, since 1976 more than 100 formerly prescription ingredients, indications, or dosage strengths have made the switch to OTC, adding up to over 700 OTC products available to the public.46 HISTORY OF PRESCRIPTION VERSUS NONPRESCRIPTION MEDICATIONS The Durham-Humphrey Amendment of 1951 to the Fed- eral Food, Drug, and Cosmetic Act of 1938 classified the existence of two specific categories of medications: Legend prescription (Rx) and OTC.47 Prescription medi- cations are drugs deemed as not safe in self-administra- tion; therefore, they require a physician’s supervision. The amendment went on to stipulate that these drugs bear a label stating “Caution: Federal law prohibits dispensing without prescription.” 47 Meanwhile, OTC became a classification representative of all other drugs that “did not meet the definition of a prescrip- tion drug.” 48 In 1962, the Kefauver-Harris Amendment required manufacturers of prescription medications to also show evidence of drug effectiveness for its in- tended use. 49 As such, any application submitted for a7 • Drug Development and Approval 81 drug conversion from Rx status to OTC must show evi- dence that the drug is safe and effective. THE CONVERSION PROCESS OF PRESCRIPTION TO OVERTHECOUNTER After consumers have used the prescription medica- tion for a period of time and the evidence sufficiently affi rms the drug’s safety and efficacy, the manufacturer may make application to the FDA requesting the pre- scription medication to be moved to the OTC status. There are two main pathways of converting a drug from prescription (Rx) to OTC, namely the NDA and the OTC Monograph Process. For further details of these processes, please visit the FDA website at: www .accessdata.fda.gov/scripts/cder/training/OTC/topic3/ topic3/da_01_03_0190.htm Primarily, most of the Rx-to-OTC switches follow the same NDA process as prescription drug applica- tions. 50 The process may be further complicated if the drug manufacturer requests a change in the indications or a change in drug strength. Nevertheless, changes of indications and/or strength are common in the OTC environment. For example, in the case of several antihistamines, they may be pre- scribed to alleviate allergic reactions or rashes, though they may possess the unwanted side effects of drowsi- ness. These medications are subsequently marketed as OTC drugs for sleep enhancement. As part of the Rx-to-OTC switch application, the FDA examines the safety and effectiveness of the medication and determines if the instructions for the products are written in a way to provide reasonable assurance that the products will be used correctly and safely by the consumers. This information is deter- mined through Label Comprehension Studies. These studies provide insight into the consumer’s ability to understand and properly administer the OTC medica- tion. 47 Ultimately the manufacturer must demonstrate that the drug’s benefits to the general public will out- weigh any potential risks from the Rx-to-OTC switch. LABELING OF OVERTHECOUNTER PRODUCTS The labeling of OTC products must adhere to a stan- dard format regarding minimum type size, bullet lists, and warnings to present the “Drug Facts.”51 BENEFITS OF THE PRESCRIPTIONTO OVERTHECOUNTER SWITCH Once a former Rx is evaluated and approved for OTC classification, the foremost benefit to consumers is im- mediate access in various pharmacies without waiting for appointments.47 Furthermore, the medications may become more affordable after the Rx-to-OTC switch. Although these switched medications may no longer be eligible to be paid by health insurance, the cost of many OTC preparations may be roughly the same amount as many insurance copayments. In general, OTC medica- tions allow millions of patients to access affordable treatments in a timely manner.52 Studies have estimated a combined cost savings of approximately $146 billion annually.53, 54 In other words, for each dollar used to pur- chase an OTC medication, the U.S. Healthcare system realizes $6 to $7 of savings.53 RISKS ASSOCIATED WITH OVER THECOUNTER MEDICATIONS While most OTC medications have proven themselves to be safe and effective for the treatment of many health-re- lated issues, there have been instances of misuse or abuse of these drugs. For example, high doses of the common OTC cough suppressant dextromethorphan (DM) can affect memory cognition and motor function.55 DM packaging gives explicit directions for use with a warning not to exceed 120 mg in a 24-hour period55 ; how- ever, patients with substance use disorder may exceed this maximum in hoping to attain euphoria, leading to dangerous side effects. A dose of 200 to 400 mg may lead to hallucinations; 300 to 600 mg may cause loss of motor coordination and visual distortions; and 500 to 1,500 mg may lead to out-of-body sensations. Additionally, doses exceeding those listed previously may induce breathing problems, heart palpitations, and brain damage.55 CONCLUSION To offer patients the ideal therapies and promote evi- dence-based clinical practice, it is important for clini- cians to understand the key concepts involved in drug development and approval, as well as the involved clini- cal trials. Well-designed and executed clinical trials can contribute significantly to improve the effectiveness and efficiency of healthcare. Constant improvement of the practices applied to new drug candidates will provide a significant boost of patients’ confidence in the treat- ment prescribed. Widespread access to nonprescrip- tion medications has enabled consumers to experience greater convenience and cost savings with treatments, while minimizing associated risks. Although switch- ing branded medications to generic formulations has become a common cost-containment measure, it may potentially impact clinical and safety outcomes, as well as general attitudes of patients and prescribers toward generic drugs. The financial impact of OTC drugs on the healthcare system alone is saving billions of dollars per year, and the trend is not expected to slow down.82 I • Foundations of Pharmacology and Prescribing CASE EXEMPLAR: Patient With Urinary Retention AD is a 42-year-old Asian female complaining that her eczema is becoming severe. She describes a chronic, itchy rash on the hands and arms. She has had this rash for about two months and has tried numerous over-the-counter creams and lotions to no avail. She says she is “going crazy” from the rash. She wants a more powerful steroid cream than the nonprescription treatments she has been using. Past Medical History • Gravida 3 para 3; very active with her kids in school • In good health Medications • OTC hydrocortisone, 1% (“Kind of a lot” she says) • Ibuprofen, 200 mg two to three tabs every 4-6 hours as needed Physical Examination • Well-developed, well-nourished female in mild distress—scratching at her arms • Heart and lungs normal • Skin of arms with numerous excoriations in various stages of healing; some thickening; some areas of epithelial atrophy; some burrow patterns noted between the webs of the fingers, creases of the wrists, and antecubital fossae Labs • Skin scrapings: Sarcoptes scabiei Discussion Questions • Why isn’t AD’s eczema getting better? • How can some of the findings on AD’s skin exam be explained? • What treatment is likely to be more helpful for AD? CASE EXEMPLAR: Patient With Skin Rash BP is a 72-year-old man who presents with the inability to urinate. This is a new symptom for him and started about 1 week ago. It has gotten progressively worse, and now he has a fever. He is very uncomfortable. He recently started over-the- counter diphenhydramine, 25 mg every 6 hours as needed for allergies. Past Medical History • Hypertension • Hyperlipidemia • Allergic rhinitis • Benign prostatic hypertrophy (BPH) Medications • Hydrochlorothiazide, 25 mg once daily • Atorvastatin, 20 mg once daily Physical Examination • Well-developed white male in mild distress • Blood pressure: 152/102; pulse: 84; respiration rate: 16; temperature: 100.2 °F • Lungs clear • Heart regular rate and rhythm • Abdomen obese but with palpable bladder to the umbilicus • Prostate 3+ enlarged on digital rectal exam Labs • Complete blood count: White blood cell (WBC) 12.5k • Urine analysis (catheterized specimen): Innumerable WBC/HPF, 5-10 RBC/HPF Discussion Questions 1. What caused the patient’s acute urinary reten- tion? 2. What is the best approach, after acute man- agement, to managing BP’s urinary outflow ob- struction? 3. Is there a better way to treat BP’s allergies?7 • Drug Devel

******CLICK ORDER NOW BELOW AND OUR WRITERS WILL WRITE AN ANSWER TO THIS ASSIGNMENT OR ANY OTHER ASSIGNMENT, DISCUSSION, ESSAY, HOMEWORK OR QUESTION YOU MAY HAVE. OUR PAPERS ARE PLAGIARISM FREE*******."