Rather skin care 27 year old female 20 gm betnovate free shipping, ethanol appears to modulate the function of a number of signaling proteins acne vulgaris icd 10 discount betnovate 20 gm fast delivery. Other organ systems-Ethanol acne 39 weeks pregnant discount 20gm betnovate overnight delivery, even at relatively low blood concentrations skin care summer cheap 20 gm betnovate visa, significantly depresses the heart skin care solutions betnovate 20gm without a prescription. Vascular smooth muscle is relaxed acne 2 week order betnovate 20 gm with visa, which leads to vasodilation, sometimes with marked hypothermia. Liver-Liver disease is the most common medical complication of chronic alcohol abuse. Progressive loss of liver function occurs with reversible fatty liver progressing to irreversible hepatitis, cirrhosis, and liver failure. Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. Gastrointestinal system-Irritation, inflammation, bleeding, and scarring of the gut wall occur after chronic heavy use of ethanol and may cause absorption defects and exacerbate nutritional deficiencies. More rarely, thiamine deficiency, along with alcohol abuse, leads to Wernicke-Korsakoff syndrome, which is characterized by ataxia, confusion, and paralysis of the extraocular muscles. Endocrine system-Gynecomastia, testicular atrophy, and salt retention can occur, partly because of altered steroid metabolism in the cirrhotic liver. Cardiovascular system-Excessive chronic ethanol use is associated with an increased incidence of hypertension, anemia, and dilated cardiomyopathy. Fetal alcohol syndrome-Ethanol use in pregnancy is associated with teratogenic effects that include mental retardation (most common), growth deficiencies, microcephaly, and a characteristic underdevelopment of the midface region. Neoplasia-Ethanol is not a primary carcinogen, but its chronic use is associated with an increased incidence of neoplastic diseases in the gastrointestinal tract and a small increase in the risk of breast cancer. Immune system-Chronic alcohol abuse has complex effects on immune functions because it enhances inflammation in the liver and pancreas and inhibits immune function in other tissues. Thiamine administration is used to protect against Wernicke-Korsakoff syndrome, and correction of electrolyte imbalance may be required. The withdrawal syndrome is managed by correction of electrolyte imbalance and administration of thiamine and a sedative-hypnotic. A long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is preferred unless the patient has compromised liver function, in which case a short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is preferred. Treatment of alcoholism-Alcoholism is a complex sociomedical problem, characterized by a high relapse rate. The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain (see Chapters 31 and 32). The aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs. Methanol Methanol (wood alcohol), a constituent of windshield cleaners and "canned heat," is sometimes ingested intentionally. Intoxication causes visual dysfunction, gastrointestinal distress, shortness of breath, loss of consciousness, and coma. Methanol is metabolized to formaldehyde and formic acid, which causes severe acidosis, retinal damage, and blindness. A freshman student (weight 70 kg) attends a college party where he rapidly consumes a quantity of an alcoholic beverage that results in a blood level of 500 mg/dL. Assuming that this young man has not had an opportunity to develop tolerance to ethanol, his present condition is best characterized as (A) Able to walk, but not in a straight line (B) Alert and competent to drive a car (C) Comatose and near death (D) Sedated with increased reaction times (E) Slightly inebriated Questions 5 and 6. A homeless middle-aged male patient presents in the emergency department in a state of intoxication. He tells you that he has recently consumed about a pint of a red-colored liquid that his friends were using to "get high. Which of the following most accurately describes the therapeutic purpose of the fomepizole administration Fomepizole, an inhibitor of alcohol dehydrogenase, is used in methanol or ethylene glycol poisoning to slow the rate of formation of toxic metabolites. This level of drinking is much higher than his regular habit of drinking 1 alcoholic drink per day. His only significant medical problem is mild hypertension, which is adequately controlled by metoprolol. With this history, this man is at significant risk for (A) Bacterial pneumonia (B) Cardiac arrhythmias (C) Hyperthermia (D) Tonic-clonic seizures (E) Wernicke-Korsakoff syndrome 2. A 42-year-old man with a history of alcoholism is brought to the emergency department in a confused and delirious state. A 23-year-old pregnant woman with alcoholism presented to the emergency department in the early stages of labor. This pattern of "binge drinking" does put him at increased risk of cardiac arrhythmia. The condition results from thiamine deficiency but is rarely seen in the absence of alcoholism. The blood level of ethanol achieved in this individual is extremely high and likely to result in coma and possibly death due to respiratory arrest in a person who lacks tolerance to ethanol. Behavioral disinhibition is a feature of early intoxication from ethanol and most other alcohols but not the solvent, hexane. Ocular dysfunction, including horizontal nystagmus and diplopia, is also a common finding in poisoning with alcohols, but the complaint of "flickering white spots before the eyes" or "being in a snowstorm" is highly suggestive of methanol intoxication. This appears to be the explanation for the increased susceptibility to acetaminophen-induced hepatotoxicity found in individuals who regularly ingest alcohol. The nausea, hypotension, and ill feeling that result from drinking ethanol while also taking disulfiram stems from acetaldehyde accumulation. Disulfiram inhibits acetaldehyde dehydrogenase, the enzyme that converts acetaldehyde to acetate. Naltrexone, a competitive inhibitor of opioid receptors, decreases the craving for alcohol in patients who are recovering from alcoholism. Ethanol elimination follows zero-order kinetics because the drug is metabolized at a constant rate irrespective of its concentration in the blood (see Chapter 3). The pharmacokinetic relationship between elimination halflife, volume of distribution, and clearance, given by t1/2 = 0. Its rate of metabolism is constant, but its clearance decreases with an increase in blood level. The arithmetic plot of ethanol blood level versus time follows a straight line (not exponential decay). Outline the pharmacotherapy of (1) the alcohol withdrawal syndrome and (2) alcohol-use disorders. Chronic, damage to many systems, including liver, pancreas, gastrointestinal tract, and central and peripheral nervous systems. However, they vary in terms of their mechanisms of action and in their effectiveness in specific seizure disorders. Antiseizure drugs Myoclonic seizures Back-up & adjunctive drugs Felbamate Gabapentin Lamotrigine Levetiracetam Phenobarbital Tiagabine Topiramate Vigabatrin Zonisamide Clonazepam Lamotrigine Valproic acid Epilepsy comprises a group of chronic syndromes that involve the recurrence of seizures (ie, limited periods of abnormal discharge of cerebral neurons). For some of these drugs (eg, phenytoin), determination of plasma levels and clearance in individual patients may be necessary for optimum therapy. In general, antiseizure drugs are well absorbed orally and have good bioavailability. Most antiseizure drugs are metabolized by hepatic enzymes (exceptions include gabapentin and vigabatrin), and in some cases active metabolites are formed. Resistance to antiseizure drugs may involve increased expression of drug transporters at the level of the blood-brain barrier. In the presence of drugs that inhibit antiseizure drug metabolism or displace anticonvulsants from plasma protein binding sites, plasma concentrations of the antiseizure agents may reach toxic levels. On the other hand, drugs that induce hepatic drug-metabolizing enzymes (eg, rifampin) may result in plasma levels of the antiseizure agents that are inadequate for seizure control. Several antiseizure drugs are themselves capable of inducing hepatic drug metabolism, especially carbamazepine and phenytoin. Phenytoin the oral bioavailability of phenytoin is variable because of individual differences in first-pass metabolism. Phenytoin metabolism is nonlinear; elimination kinetics shift from first-order to zeroorder at moderate to high dose levels. Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine. Fosphenytoin is a water-soluble prodrug form of phenytoin that is used parenterally. Carbamazepine Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs including clonazepam, lamotrigine, and valproic acid. Carbamazepine metabolism can be inhibited by other drugs (eg, propoxyphene, valproic acid). A related drug, oxcarbazepine, is less likely to be involved in drug interactions. Valproic Acid In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug. Other Drugs Gabapentin, pregabalin, levetiracetam, and vigabatrin are unusual in that they are eliminated by the kidney, largely in unchanged form. Tiagabine, topiramate, and zonisamide undergo both hepatic metabolism and renal elimination of intact drug. Sodium Channel Blockade At therapeutic concentrations, phenytoin, carbamazepine, lamotrigine, and zonisamide block voltage-gated sodium channels in neuronal membranes. This action is rate-dependent (ie, dependent on the frequency of neuronal discharge) and results in prolongation of the inactivated state of the Na+ channel and the refractory period of the neuron. The enzyme is irreversibly inactivated by vigabatrin at therapeutic plasma levels and can also be inhibited by valproic acid at very high concentrations. Calcium Channel Blockade Ethosuximide inhibits low-threshold (T type) Ca2+ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge. Other Mechanisms In addition to its action on calcium channels, valproic acid causes neuronal membrane hyperpolarization, possibly by enhancing K+ channel permeability. Valproic acid is particularly useful in patients who have concomitant generalized tonic-clonic or myoclonic seizures. Clonazepam is effective as an alternative drug but has the disadvantages of causing sedation and tolerance. Lamotrigine, levetiracetam, and zonisamide are also effective in absence seizures. Myoclonic and Atypical Absence Syndromes Myoclonic seizure syndromes are usually treated with valproic acid; lamotrigine is approved for adjunctive use, but is commonly used as monotherapy. Levetiracetam, topiramate, and zonisamide are also used as backup drugs in myoclonic syndromes. Felbamate has been used adjunctively with the primary drugs but has both hematotoxic and hepatotoxic potential. Status Epilepticus Intravenous diazepam or lorazepam is usually effective in terminating attacks and providing short-term control. For prolonged therapy, intravenous phenytoin has often been used because it is highly effective and less sedating than benzodiazepines or barbiturates. However, phenytoin may cause cardiotoxicity (perhaps because of its solvent, propylene glycol), and fosphenytoin (watersoluble) is a safer parenteral agent. In very severe status epilepticus that does not respond to these measures, general anesthesia may be used. Other Clinical Uses Several antiseizure drugs are effective in the management of bipolar affective disorders, especially valproic acid, which is now often used as a first-line drug in the treatment of mania. Carbamazepine and lamotrigine have also been used successfully in bipolar disorder. Carbamazepine is the drug of choice for trigeminal neuralgia, and its congener oxcarbazepine may provide similar analgesia with fewer adverse effects. Gabapentin has efficacy in pain of neuropathic origin, including postherpetic neuralgia, and, like phenytoin, may have some value in migraine. Which of the mechanisms of action of antiseizure drugs have theoretical implications regarding their activity in cardiac arrhythmias Recall any clinical uses of antiseizure drugs in the management of cardiac arrhythmias Drug choice is usually made on the basis of established efficacy in the specific seizure state that has been diagnosed, the prior responsiveness of the patient, and the anticipated toxicity of the drug. Treatment may involve combinations of drugs, following the principle of adding known effective agents if the preceding drugs are not sufficient. Generalized Tonic-Clonic Seizures Valproic acid, carbamazepine, and phenytoin are the drugs of choice for generalized tonic-clonic (grand mal) seizures. Phenobarbital (or primidone) is now considered to be an alternative agent in adults but continues to be a primary drug in infants. Lamotrigine and topiramate are also approved drugs for this indication, and several others may be used adjunctively in refractory cases. Partial Seizures the drugs of first choice are carbamazepine (or oxcarbazepine) or lamotrigine or phenytoin. Many of the newer anticonvulsants can be used adjunctively, including gabapentin and pregabalin, a structural congener. Absence Seizures Ethosuximide or valproic acid are the preferred drugs because they cause minimal sedation.
Mechanism of action-Two types of antisera directed against lymphocytes are available acne complex cheap 20gm betnovate free shipping. Antibodies in these preparations bind to human T cells involved in antigen recognition and initiate their destruction by serum complement acne gluten purchase 20gm betnovate visa. These antibodies selectively block cellular immunity rather than antibody formation acne rosacea cheap betnovate 20 gm with visa, which accounts for their ability to suppress organ graft rejection acne laser treatment buy betnovate 20 gm otc, a cell-mediated process acne needle betnovate 20 gm generic. They are also used in combination with other immunosuppressants for solid organs transplantation skin care jakarta timur purchase betnovate 20gm without a prescription. In combination with methotrexate, infliximab improves symptoms in patients with rheumatoid arthritis. It also is effective in the treatment of ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis. Etanercept is used in arthritis, psoriasis, and ankylosing spondylitis, and it is being investigated in other inflammatory diseases. It is used in combination with other immunosuppressants to prevent renal transplant rejection. In contrast to cyclosporine, tacrolimus, or cytotoxic immunosuppressants, the adverse effects of daclizumab are equivalent to those of placebo. Basiliximab is a chimeric human-mouse IgG with an action that is equivalent to that of daclizumab. Aldesleukin is indicated for the adjunctive treatment of renal cell carcinoma and malignant melanoma. Cytokine inhibitors An important application of immunomodulation therapy involves the use of cytokine inhibitors for inflammatory diseases (see Chapter 36). Type I (Immediate) Drug Allergy this form of drug allergy involves IgE-mediated reactions to animal and plant stings and pollens as well as to drugs. When linked to carrier proteins, small drug molecules can act as haptens and initiate B-cell proliferation and formation of IgE antibodies. On subsequent exposure, the antigenic drug cross-links the IgE antibodies on the surface of mast cells and basophils and triggers release of mediators of vascular responses and tissue injury, including histamine, kinins, prostaglandins, and leukotrienes. The recombinant form is used to decrease the incidence and severity of infections in patients with chronic granulomatous disease. Hypoxemia can contribute to cardiac events, including arrhythmias and myocardial infarction. Drugs used to treat anaphylaxis mainly target the receptors used by neurotransmitters of the sympathetic nervous system. Which of the following is a widely used drug that suppresses cellular immunity, inhibits prostaglandin and leukotriene synthesis, and increases the catabolism of IgG antibodies She is now in her ninth month of pregnancy and is in the labor room having frequent contractions. A 36-year-old man presents with swollen, painful heels, nail changes, and left lower back pain that wakes him from sleep. Within a few minutes of the antibiotic injection, he developed severe bronchoconstriction, laryngeal edema, and hypotension. Unfortunately, a year later he was treated with an antipsychotic drug and developed agranulocytosis. Modification of Drug Allergies Drugs that modify allergic responses to other drugs or toxins act at several steps of the immune mechanism. For example, corticosteroids inhibit lymphoid cell proliferation and reduce tissue injury and edema. However, most drugs that are useful in type I reactions (eg, epinephrine, H1 antagonists, corticosteroids) block mediator release or act as physiologic antagonists of the mediators. Which of the following most accurately describes the immunosuppressant action of cyclosporine She was successfully treated with tacrolimus and a second drug that targets both B and T lymphocytes. Which of the following is an immunosuppressant that suppresses both B and T lymphocytes via inhibition of de novo synthesis of purines Recombinant interleukin-2 has proved useful in the treatment of which of the following diseases Although sirolimus and cyclosporine have similar immunosuppressant effects, their toxicity profiles differ. Which of the following toxicities is more likely to be associated with sirolimus than with cyclosporine Which of the following is an immune modulator that increases phagocytosis by macrophages in patients with chronic granulomatous disease Agranulocytosis (and systemic lupus erythematosus) are autoimmune syndromes that can be drug-induced. The patient was probably treated with clozapine for his psychosis (see clozapine toxicity, Chapter 29). Mycophenolic acid, formed from mycophenolate mofetil, inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme in the de novo pathway of purine synthesis. It has shown efficacy in renal cell carcinoma and malignant melanoma, 2 cancers that respond poorly to conventional cytotoxic anticancer drugs. Cyclosporine and tacrolimus both are associated with renal toxicity and hypertension. In contrast, sirolimus appears to spare the kidney and instead is more likely to cause gastrointestinal disturbance, hypertriglyceridemia, and myelosuppression, especially in the form of thrombocytopenia. Interferon- is approved for use in chronic granulomatous disease, a condition that results from phagocyte deficiency. The corticosteroid prednisone is used extensively as an immunosuppressant in autoimmune diseases and organ transplantation. Therefore, she has no memory B cells that can activate upon subsequent pregnancies with an Rho(D)positive fetus. Epinephrine activates all adrenoceptors, whereas norepinephrine has minimal agonist activity at b2 adrenoceptors. This difference is important in anaphylaxis because b2 adrenoceptor activation is needed to provide a bronchodilatory effect that will oppose the anaphylaxis-induced airway obstruction. The 1 adrenoceptor agonist effect of epinephrine opposes the anaphylaxis-induced vasodilation and, to some extent, the vascular leak (administration of fluid is also a cornerstone of the treatment of anaphylaxis), whereas the b1 adrenoceptor agonist effect helps maintain cardiac output. If bronchospasm is predominant, then administration by inhalation of a b2-selective agonist such as albuterol may be useful. If cardiovascular collapse is predominant and does not respond adequately to fluid resuscitation, then vasopressor drugs may be helpful; these include adrenoceptor agonists such as phenylephrine and b1-adrenoceptor agonists such as dobutamine or dopamine. Name 7 immunosuppressants and, for each, describe the mechanism of action, clinical uses, and toxicities. Describe the mechanisms of action, clinical uses, and toxicities of antibodies used as immunosuppressants. Identify the major cytokines and other immunomodulating agents and know their Describe the different types of allergic reactions to drugs. A 56 C H A P T E R Solvents Halogenated aliphatic hydrocarbons, aromatic hydrocarbons number of chemicals in the environment (eg, atmosphere, home, workplace) pose important health hazards. Classification and Prototypes the major air pollutants in industrialized countries include carbon monoxide (which accounts for about 50% of the total amount of air pollutants), sulfur oxides (18%), hydrocarbons (12%), particulate matter (eg, smoke particles, 10%), and nitrogen oxides (6%). Air pollution appears to be a contributing factor in bronchitis, obstructive pulmonary disease, and lung cancer. Headache occurs first, followed by confusion, decreased visual acuity, tachycardia, syncope, coma, seizures, and death. It is higher for shorter periods than for longer periods Environmental toxicology Occupational toxicology Threshold limit value when approximately 40% of hemoglobin has been converted to carboxyhemoglobin. Prolonged hypoxia can result in irreversible damage to the brain and the myocardium. Conjunctival and bronchial irritation (especially in individuals with asthma) is the primary sign of exposure. Farm workers exposed to high concentrations of the gas within enclosed silos may die rapidly of acute pulmonary edema. Ozone Ozone (O3) is a bluish irritant gas produced in air and water purification devices and in electrical fields. Chronic exposure leads to bronchitis, bronchiolitis, pulmonary fibrosis, and emphysema. Aliphatic Hydrocarbons this group includes halogenated solvents such as carbon tetrachloride, chloroform, and trichloroethylene. The acute effects of excessive exposure are nausea, vertigo, locomotor disturbances, headache, and coma. Aromatic Hydrocarbons Benzene, toluene, and xylene are important aromatic hydrocarbons. Long-term exposure to benzene is associated with hematotoxicity (thrombocytopenia, aplastic anemia, pancytopenia) and various types of hematologic cancers, especially leukemia. Most national and international organizations classify benzene as a known human carcinogen. Treatment-No specific treatment is available for the acute toxicity caused by chlorinated hydrocarbons. Because of their extremely long half-lives in organisms and in the environment (years), their use in North America and Europe has been curtailed. Cholinesterase Inhibitors the carbamates (eg, aldicarb, carbaryl) and organophosphates (eg, dichlorvos, malathion, parathion) are effective pesticides with short environmental half-lives. Effects-As described in Chapter 7, cholinesterase inhibitors increase muscarinic and nicotinic cholinergic activity. Treatment-Atropine is used in large doses to control muscarinic excess; pralidoxime is used to regenerate cholinesterase (see Chapter 8). Mechanical ventilation may be necessary until sufficient cholinesterase has been regenerated. Rotenone-This plant alkaloid pesticide causes gastrointestinal distress when ingested and conjunctivitis and dermatitis after direct contact with exposed body surfaces. Pyrethrum-The most common toxic effect of this mixture of plant alkaloids is contact dermatitis. If a new drug is destined for chronic systemic administration, what animal toxicity testing is required Chlorinated Hydrocarbons these agents are persistent, poorly metabolized, lipophilic chemicals that exhibit significant bioaccumulation. Effects-Chlorinated hydrocarbons block physiologic inactivation in the sodium channels of nerve membranes and cause uncontrolled firing of action potentials. Chlorophenoxy Acids the 2 most important members of this group are 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid, the compound in Agent Orange. Glyphosate Glyphosate is the principle ingredient in Roundup brand weed killer and is now the most widely used herbicide in the world. Its target, 5-enolpyruvylshikimate-3-phosphate synthase, a key enzyme involved in aromatic amino acid biosynthesis in plants. Effects-Glyphosate exposure causes significant eye and skin irritation and can be fatal when ingested in large quantities. Paraquat Paraquat, a bipyridyl herbicide, is used extensively to kill weeds on farms and for highway maintenance. After ingestion, the initial effect is gastrointestinal irritation with hematemesis and bloody stools. Within a few days, signs of pulmonary impairment occur and are usually progressive, resulting in severe pulmonary fibrosis and often death. Gastric lavage is not recommended, as it may promote aspiration from the stomach into the lungs. Once the paraquat is absorbed, treatment is successful in fewer than 50% of cases. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical-scavenging, anti-inflammatory actions. The dioxins have appeared in the environment as unwanted by-products of the chemical industry. In humans, the most common signs of toxicity are dermatitis and chloracne, which are cystic acneiform lesions that typically form on the face and upper body. Epidemiologic evidence suggests that the dioxins also have carcinogenic and teratogenic effects in humans. Source-Asbestos is a group of naturally occurring long, flexible mineral fibers, most commonly containing silicon. Because it is poorly metabolized and lipophilic, it is highly persistent in the environment and accumulates in the food chain. Many countries have banned all use of asbestos because of its toxicity and strictly regulate handling of preexisting asbestos building products. Effects-Inhalation of asbestos fibers can cause a fibrotic lung disorder called asbestosis, which is characterized by shortness of breath. Asbestos is also associated with several cancers including lung cancer, mesothelioma, and cancers of the gastrointestinal tract. The light brownish color of smog often apparent in a major metropolitan area on a hot summer day is mainly due to (A) Carbon monoxide (B) Hydrocarbons (C) Ozone (D) Nitrogen dioxide (E) Sulfur dioxide 2. You are stuck in traffic in New York City in summer for 3 or 4 h and you begin to get a headache, a feeling of tightness in the temporal region, and an increased pulse rate. A farm worker was accidentally in the field during the aerial spraying with parathion.
Randomization the subjects are allocated to either group using a preselected random number table or computer programme so that any subject has equal chance of being assigned to the test or the control group acne en la espalda purchase betnovate 20gm with visa. Discretion (and likely bias) of the investigator/subject in treatment allocation is thus avoided skin care websites proven 20 gm betnovate. For this purpose the two medications have to appear similar in looks acne under microscope trusted 20 gm betnovate, number acne rosacea pictures 20gm betnovate fast delivery, weight acne oral medication cheap 20 gm betnovate visa, taste acne 5 year old buy betnovate 20 gm overnight delivery, etc. End point the primary and secondary (if any) end points (cure, degree of improvement, symptom relief, surrogate marker, avoidance of complication, curtailment of hospitalization, survival, quality of life, etc. Sample size: Both financial and ethical considerations demand that the number of subjects in the trial be the minimum needed for a valid result. The minimum number of subjects for obtaining a decisive conclusion (test better than control/ control better than test/no difference between the two) must be calculated statistically beforehand. Because the trial is conducted on a sample of the whole patient population, there is always a chance that the sample was not representative of the population. Two types of errors are possible: Type I error: a difference is found between the two groups while none exists. The sample size of the trial depends on the desired level of significance and power. Also, higher the significance and power level desired, greater is the number of subjects. The variability of response in terms of the primary end point also affects the sample size. Responses that show greater individual variation need larger number of subjects to achieve the desired significance and power levels. Many large scale trials are subjected to interim analysis from time to time as the trial progresses by an independent committee which can order an early termination if a decisive result (positive or negative) is obtained; because it would be unethical to subject some of the remaining patients to a treatment (test or control) which has been found inferior. Sequential trial this design attempts to detect a significant result as soon as it is achieved, minimizing the number of subjects. This design is applicable only to certain types of drugs and diseases for which clinical end points are achieved quickly and paired comparisons are possible. Meta-analysis this is an exercise in which data from several similarly conducted randomized controlled clinical trials with the same drug (or class of drugs) examining the same clinical end point(s) is pooled to bring out the overall balance of evidence by enlarging the number of test and control subjects and increasing the significance and power of the conclusions. Nevertheless, meta-analysis is a useful tool to arrive at conclusions that may influence medical practice. For example, meta-analysis of trials has strongly supported the use of -adrenergic blockers in heart failure and use of statins to reduce risk of coronary artery disease. In the retrospective cohort study, health records of a population are scrutinized for exposure to the study drug and the subsequent beneficial/adverse events. Its value is questionable because many events may have been missed in the records and several unknown factors may have contributed to the findings. Though case control studies can be performed rather quickly because the number of patients analysed is small compared to the cohort design, they do not prove causality. Also, the causative drug and the adverse event have to be suspected first to plan the study, whereas cohort study can reveal unsuspected adverse events. Cohort study this is a type of observational study in which no intervention for the sake of the study is done. In the context of drug research, the common feature is that all study subjects have taken a particular drug. Occurrence of events (beneficial or adverse) in users and nonusers of the drug is compared. A matching group of patients who have not received the drug is identified and followed up to serve as control. The discovery of penicillin (1941) opened the flood-gates of a vast source-microorganisms-of a new kind of drugs (antibiotics). Though few drugs are now produced from plants, animals or microbes, these sources of medicines are by no means exhausted. Random or targeted chemical synthesis Synthetic chemistry made its debut in the 19th century and is now the largest source of medicines. Though some useful drugs (barbiturates, chlorpromazine) have been produced serendipitously by this approach, it has very low probability of hitting at the right activity in the right compound; rarely employed now. Lead optimization A more practical approach is to synthesize chemical congeners of natural products/synthetic compounds with known pharmacological activity in the hope of producing more selective/superior drugs. As such, invention and development of new drugs is now possible only in the set up of big pharmaceutical houses that alone have the resources, infrastructure and dedicated teams of scientists to carry out the multiple specialized stages of the process. Though the pharmaceutical industry is often regarded cunning, greedy, unscrupulous and deceptive, there is no denying that it is responsible for most of the progress in therapeutics as well as pharmacological knowledge of today. Approaches to drug discovery/ invention Exploration of natural sources Plants are the oldest source of medicines. Clues about these have been obtained from traditional systems of medicine prevalent in various parts of the world; Opium (morphine), Ephedra (ephedrine), Cinchona (quinine), curare (tubocurarine), belladonna (atropine), Quinghaosu (artemisinin) are the outstanding examples. Study of several congeners of the lead compound can delineate molecular features responsible for a particular property. Application of this structure-activity relationship information has proven useful on many occasions. More commonly now, as described later in the rational approach, identification of the target biomolecule is the starting point for new drug invention. A lead compound capable of interacting with the target is searched by applying diverse approaches described above and below. It is then chemically modified to optimise these parameters as well as pharmacokinetic, pharmaceutical, toxicological and other characteristics. Because pharmacological activity depends on three dimensional interaction of drug molecules with their target biomolecules, the enantiomers (R and S forms or d and l isomers) of chiral drugs differ in biological activity, metabolic degradation, etc. Approval is withheld unless the pure enantiomers are shown to be no better than the racemate. Several drugs, originally introduced as racemates, have now been made available as single enantiomer preparations as well (see box). The purine, pyrimidine, folate antimetabolites were introduced in cancer chemotherapy after elucidation of key role of these metabolites in cell proliferation. Preclinical studies After synthesizing/identifying a prospective compound, it is tested on animals to expose the whole pharmacological profile. As the evaluation progresses unfavourable compounds get rejected at each step, so that only a few out of thousands reach the stage when administration to man is considered. These also are preliminary tests to detect specific activity, such as antihistaminic, antisecretory, vasodilator, antibacterial, etc. Tests on animal models of human disease Such as kindled seizures in rats, spontaneously (genetically) hypertensive rats, experimental tuberculosis in mouse, alloxan induced diabetes in rat or dog, etc. Confirmatory tests and analogous activities Compounds found active are taken up for detailed study by more elaborate tests which confirm and characterize the activity. Systemic pharmacology Irrespective of the primary action of the drug, its effects on major organ systems such as nervous, cardiovascular, respiratory, renal. Quantitative tests the dose-response relationship, maximal effect and comparative potency/efficacy with existing drugs is ascertained. Pharmacokinetics the absorption, tissue distribution, metabolism, excretion, volume of distribution and halflife of the drug are quantified. Animals are examined for overt effects, food intake, body weight, haematology, etc. To minimize any risk, initially few subjects receive the drug under close supervision. Adherence to these provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected as enunciated in the Helsinki Declaration of the World Medical Association. The requirements and regulations for the conduct of clinical trials on a new drug in India have been laid down in the schedule Y of the Drugs and Cosmetics Rules. The emphasis is on safety, tolerability, and to detect any potentially dangerous effects on vital functions, such as precipitous fall/ rise in bloof pressure or heart rate, arrhythmias, bronchospasm, seizures, kidney/liver damage, etc. Unpleasant side effects are noted and an attempt is made to observe the pharmacodynamic effects in man. Phase 0: Microdosing study this is a new strategy being developed to reduce the cost and time of the drug development process. The rate of rejection of candidate drugs at various stages of clinical development has progressively increased recently, discouraging pharmaceutical companies to venture into the risky business of new drug invention. Many candidate drugs fail during clinical trials due to sub-optimal human pharmacokinetics. These subpharmacological doses are not expected to produce any therapeutic or toxic effects, but yield human pharmacokinetic information. These studies may obviate the need for animal pharmacokinetic studies and can be undertaken before extensive animal toxicity tests. Thus, elaborate animal studies and costly phase 1 human trials could be avoided for candidate drugs which would have later failed due to unsuitable human pharmacokinetics. Moreover, the pharmacokinetic 0 phase data could be useful in more precise selection of doses for phase 1 study. The phase 0 studies have not yet been technically fully developed or adequately evaluated. However, they are promising, and most regulatory authorities are willing to allow and consider them. The primary aim is establishment of therapeutic efficacy, dose range and ceiling effect in a controlled setting. The candidate drug may get dropped at this stage if the desired level of clinical efficacy is not obtained. Safety and tolerability are assessed on a wider scale, while pharmacokinetic studies may be conducted on some of the participants to enlarge the population base of pharmacokinetic data. Patients treated in the normal course form the study population: numbers therefore are much larger. Uncommon/idiosyncratic adverse effects, or those that occur only after long-term use and unsuspected drug interactions are detected at this stage. Modified release dosage forms, additional routes of administration, fixed dose drug combinations, etc. He responded with brisk diuresis, but on the 3rd day he was found to be talking irrelevant, was weak and partly disoriented. Predictable (Type A or Augmented) reactions (mechanism based adverse reactions) these are based on the pharmacological properties of the drug, which means that they are augmented, but qualitatively normal response to the drug; include side effects, toxic effects and consequences of drug withdrawal. They are less common, often non-dose related, generally more serious and require withdrawal of the drug. Severity of adverse drug reactions graded as: has been All drugs are capable of producing adverse effects, and whenever a drug is given a risk is taken. The magnitude of risk has to be considered along with the magnitude of expected therapeutic benefit in deciding whether to use or not to use a particular drug in a given patient. One may divide them into: Minor: No therapy, antidote or prolongation of hospitalization is required. Severe: Potentially life-threatening, causes permanent damage or requires intensive medical treatment. It has an important role in the rational use of medicines, as it provides the basis for assessing safety of medicines. Voluntary reporting depends on the initiative and willingness of the health professionals. Though even rare reactions can be detected by this method, it does not provide incidence of the reaction. Changes in the labelling of medicines indicating restrictions in use or statuary warnings, precautions, or even withdrawal of the drug, by the regulatory decision making authority. Causality assessment When a patient undergoing drug therapy experiences an adverse event, it may be due to the drug, or the disease or some other causes. Poisoning In a broad sense, poisoning implies harmful effects of a chemical on a biological system. Generally, they are not serious, can be predicted from the pharmacological profile of a drug and are known to occur in a given percentage of drug recipients. Glyceryl trinitrate relieves angina pectoris by dilating peripheral vasculature which is also responsible for postural hypotension and throbbing headache. Secondary effects these are indirect consequences of a primary action of the drug. Maintain blood pressure and heart beat by fluid and crystalloid infusion, pressor agents, cardiac stimulants, pacing, defibrillation, etc, as needed. Maintain blood sugar level by dextrose infusion, especially in patients with altered sensorium. Termination of exposure (decontamination) by removing the patient to fresh air (for inhaled poisons), washing the skin and eyes (for poisons entering from the surface), induction of emesis with syrup ipecac or gastric lavage (for ingested poisons).
Results from either folate or vitamin B12 deficiency A deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally small skin care 90210 order 20gm betnovate mastercard. Iron and Vitamin Deficiency Anemias Microcytic hypochromic anemia skin care trade shows effective betnovate 20 gm, caused by iron deficiency skin care urdu tips betnovate 20gm free shipping, is the most common type of anemia acne vs rosacea purchase 20 gm betnovate visa. Megaloblastic anemias are caused by a deficiency of vitamin B12 or folic acid acne prevention generic betnovate 20 gm with amex, cofactors required for the normal maturation of red blood cells skin care zinc cheap betnovate 20 gm overnight delivery. Pernicious anemia, the most common type of vitamin B12 deficiency anemia, is caused by a defect in the synthesis of intrinsic factor, a protein required for efficient absorption of dietary vitamin B12, or by surgical removal of that part of the stomach that secretes intrinsic factor. Other Blood Cell Deficiencies Deficiency in the concentration of the various lineages of blood cells can be a manifestation of a disease or a side effect of radiation or cancer chemotherapy. Some of these growth factors also play an important role in hematopoietic stem cell transplantation. Although most of the iron in the body is contained in hemoglobin, an important fraction is bound to transferrin, a transport protein, and ferritin, a storage protein. Deficiency of iron occurs most often in women because of menstrual blood loss and in vegetarians or malnourished persons because of inadequate dietary iron intake. Regulation of Iron Stores Although iron is an essential ion, excessive amounts are highly toxic. Since there is no mechanism for the efficient excretion of iron, regulation of body iron content occurs through modulation of intestinal absorption. Excess iron is stored in the protein-bound form in gastrointestinal epithelial cells, macrophages, and hepatocytes, and in cases of gross overload, in parenchymal cells of the skin, heart, and other organs. Role of Iron Iron is the essential metallic component of heme, the molecule responsible for the bulk of oxygen transport in the blood. In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) (section 2) or to hepatocytes for storage as ferritin (section 3). The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. Elimination-Minimal amounts of iron are lost from the body with sweat and saliva and in exfoliated skin and intestinal mucosal cells. Clinical Use Prevention or treatment of iron deficiency anemia is the only indication for iron administration. Iron deficiency can be diagnosed from red blood cell changes (microcytic cell size due to diminished hemoglobin content) and from measurements of serum and bone marrow iron stores. The disease is treated by dietary ferrous iron supplementation with ferrous sulfate, ferrous gluconate, or ferrous fumarate. In special cases, treatment is by parenteral administration of a colloid containing a core of iron oxyhydroxide surrounded by a shell of carbohydrate. Parenteral iron preparations include iron dextran, sodium ferric gluconate complex, and iron sucrose. Iron should not be given in hemolytic anemia because iron stores are elevated, not depressed, in this type of anemia. Ferumoxytol is a super-paramagnetic iron oxide nanoparticle coated with carbohydrate. Signs and symptoms-Acute iron intoxication is most common in children and usually occurs as a result of accidental ingestion of iron supplementation tablets. Depending on the dose of iron, necrotizing gastroenteritis, shock, metabolic acidosis, coma, and death may result. Chronic iron overload, known as hemochromatosis, damages the organs that store excess iron (heart, liver, pancreas). Hemochromatosis occurs most often in individuals with an inherited abnormality of iron absorption and those who receive frequent transfusions for treatment of hemolytic disorders (eg, thalassemia major). Treatment of acute iron intoxication-Immediate treatment is necessary and usually consists of removal of unabsorbed tablets from the gut, correction of acid-base and electrolyte abnormalities, and parenteral administration of deferoxamine, which chelates circulating iron. Treatment of chronic iron toxicity-Treatment of the genetic form of hemochromatosis is usually by phlebotomy. Hemochromatosis that is due to frequent transfusions is treated with parenteral deferoxamine or with the newer oral iron chelator deferasirox. Pharmacokinetics Vitamin B12 is produced only by bacteria; this vitamin cannot be synthesized by multicellular organisms. It is found in many foods and absorbed from the gastrointestinal tract in the presence of intrinsic factor, a product of the parietal cells of the stomach. Vitamin B12 is stored in the liver in large amounts; a normal individual has enough to last 5 yr. The 2 available forms of vitamin B12, cyanocobalamin and hydroxocobalamin, have similar pharmacokinetics, but hydroxocobalamin has a longer circulating half-life. Pharmacodynamics Vitamin B12 is essential in 2 reactions: conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA and conversion of homocysteine to methionine. In vitamin B12 deficiency, folates accumulate as N 5-methyltetrahydrofolate; the supply of tetrahydrofolate is depleted; and the production of red blood cells slows. In addition, vitamin B12 deficiency can cause neurologic defects, which may become irreversible if not treated promptly. Section 1 shows the vitamin B12-dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the "folate trap" in vitamin B12 deficiency. Section 3 shows the pathway by which folate enters the tetrahydrofolate cofactor pool. However, the exogenous folic acid does not correct the neurologic defects of vitamin B12 deficiency. Clinical Use and Toxicity the 2 available forms of vitamin B12-hydroxocobalamin and cyanocobalamin-have equivalent effects. The major application is in the treatment of naturally occurring pernicious anemia and anemia caused by gastric resection. Because vitamin B12 deficiency anemia is almost always caused by inadequate absorption, therapy should be by replacement of vitamin B12, using parenteral therapy. How do these 3 routes compare with regard to onset and duration of drug action and risk of adverse effects In addition, deficiency of folic acid during pregnancy increases the risk of neural tube defects in the fetus. Only modest amounts are stored in the body, so a decrease in dietary intake is followed by anemia within a few months. For this reason, antifolate drugs are useful in the treatment of various infections and cancers. Clinical Use and Toxicity Folic acid deficiency is most often caused by dietary insufficiency or malabsorption. Anemia resulting from folic acid deficiency is readily treated by oral folic acid supplementation. Because maternal folic acid deficiency is associated with increased risk of neural tube defects in the fetus, folic acid supplementation is recommended before and during pregnancy. Folic acid supplements correct the anemia but not the neurologic deficits of vitamin B12 deficiency. Therefore, vitamin B12 deficiency must be ruled out before one selects folic acid as the sole therapeutic agent in the treatment of a patient with megaloblastic anemia. Through activation of receptors on erythroid progenitors in the bone marrow, erythropoietin stimulates the production of red cells and increases their release from the bone marrow. As an alternative to recombinant human erythropoietin (epoetin alfa), darbepoetin alfa, a glycosylated form of erythropoietin, has a much longer half-life. Methoxy polyethylene glycol-epoetin beta is a long-lasting form of erythropoietin that can be administered once or twice a month. Both growth factors are used to accelerate the recovery of neutrophils after cancer chemotherapy and to treat other forms of secondary and primary neutropenia (eg, aplastic anemia, congenital neutropenia). Romiplostim, a thrombopoietin receptor agonist with a novel peptide structure, is used subcutaneously in patients with chronic idiopathic thrombocytopenia who have failed to respond to conventional treatment. Eltrombopag is an oral agonist of the thrombopoietin receptor that is also used for patients with chronic idiopathic thrombocytopenia that is refractory to other agents. The risk of hepatotoxicity and hemorrhage has restricted eltrombopag use to registered physicians and patients. Toxicity associated with acute iron poisoning usually includes which of the following Correction of acid-base and electrolyte abnormalities and (A) Activated charcoal (B) Oral deferasirox (C) Parenteral deferoxamine (D) Parenteral dantrolene 5. Which of the following is most likely to be required by a 5-year-old boy with chronic renal insufficiency The megaloblastic anemia that results from vitamin B12 deficiency is due to inadequate supplies of which of the following A 23-year-old pregnant woman is referred by her obstetrician for evaluation of anemia. She is in her fourth month of pregnancy and has no history of anemia; her grandfather had pernicious anemia. If this woman has macrocytic anemia, an increased serum concentration of transferrin, and a normal serum concentration of vitamin B12, the most likely cause of her anemia is deficiency of which of the following The laboratory data for your pregnant patient indicate that she does not have macrocytic anemia but rather microcytic anemia. Optimal treatment of normocytic or mild microcytic anemia associated with pregnancy uses which of the following After undergoing surgery for breast cancer, a 53-year-old woman is scheduled to receive 4 cycles of cancer chemotherapy. During the second cycle of chemotherapy, it would be appropriate to consider treating this patient with which of the following Twenty months after finishing her chemotherapy, the woman had a relapse of breast cancer. The decision was made to treat the patient with high-dose chemotherapy followed by autologous stem cell transplantation. The kidney produces erythropoietin; patients with chronic renal insufficiency often require exogenous erythropoietin to avoid chronic anemia. The success of transplantation with peripheral blood stem cells depends on infusion of adequate numbers of hematopoietic stem cells. Like other proteinaceous drugs, the growth factors cannot be administered orally because they have very poor bioavailability. Injections are required for intravenous, intramuscular, and subcutaneous administration. The intravenous route offers the fastest onset of drug action and shortest duration of drug action. Because intravenous administration can produce high blood levels, this route of administration has the greatest risk of producing concentration-dependent drug toxicity. Intramuscular injection has a quicker onset of action than subcutaneous injection, and larger volumes of injected fluid can be given. Because protective barriers can be breached by the needle or tubing used for drug injection, all 3 of these routes of administration carry a greater risk of infection than does oral drug administration. Deficiencies of folic acid or vitamin B12 are the most common causes of megaloblastic anemia. If a patient with this type of anemia has a normal serum vitamin B12 concentration, folate deficiency is the most likely cause of the anemia. Iron deficiency microcytic anemia is the anemia that is most commonly associated with pregnancy. Acute iron poisoning often causes severe gastrointestinal damage resulting from direct corrosive effects, shock from fluid loss in the gastrointestinal tract, and metabolic acidosis from cellular dysfunction. Dantrolene inhibits Ca2+ release from the sarcoplasmic reticulum and is an antidote for malignant hyperthermia induced by inhaled anesthetics. Resection of the stomach does lead to loss of intrinsic factor and the patient will be deficient in vitamin B12. Prevention or treatment of iron deficiency anemia (microcytic cell size) is the only indication for iron administration. Diagram the normal pathways of absorption, transport, and storage of iron in the Name the anemias for which iron supplementation is indicated and those for which it is contraindicated. The first group, the anticlotting drugs, includes some of the most commonly used drugs in the United States. Within the anticlotting group, the anticoagulant and thrombolytic drugs are effective in treatment of both venous and arterial thrombosis, whereas antiplatelet drugs are used primarily for treatment of arterial disease. Three major types of anticoagulants are available: heparin and related products, which must be used parenterally; direct thrombin and factor X inhibitors, which are used parenterally or orally; and the orally 276 active coumarin derivatives (eg, warfarin).
Fairey A, Skinner DG, Groshen S, et al: Effect of Studer pouch versus T-pouch orthotopic ileal bladder substitution on late complications and surgical re-intervention in bladder cancer patients undergoing radical cystectomy: secondary analyses from the USC-STAR randomized trial, J Urol 189(supp4):e579ne580, 2013.
Dolan LM, Dixon WE, Hilton P: Urinary symptoms and quality of life following urogenital fistula repair: a long-term follow-up study, BJOG 115(12):1570n 1574, 2008.
Gill IS, Metcalfe C, Abreu A, et al: Robotic level III inferior vena cava tumor thrombectomy: initial series, J Urol 194(4):929n938, 2015.
Schlomer BJ, Smith PJ, Barber TD, et al: Nephrectomy for hypertension in pediatric patients with a unilateral poorly functioning kidney: a contemporary cohort, J Pediatr Urol 7(3):373-377, 2011.
Bleich SD, Nichols TC, Schumacher RR, et al: Effect of heparin on coronary artery patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;66:1412-1417.
