By K. Sven. Pennsylvania State University at Altoona. 2018.
Theoretical chemistry quality 20mg tadacip, combined with modern compu- tational methods tadacip 20 mg lowest price, offers a powerful solution to this prediction dilemma 20 mg tadacip overnight delivery. The docking of a drug with its receptor site is a precise interaction between two mole- cules. The success of this interaction is dependent upon the geometry, conformation and electronic properties of the two molecules. Designing drugs requires techniques for deter- mining and predicting the geometry, conformation, and electronic properties of both small molecules (i. Molecular modeling is the evaluation of molecular properties and structures using computational chemistry and molecular graphics to provide three-dimensional visu- alization and representation of molecules. Quantum pharmacology is the application of the methods of modern computational chemistry to understanding drug action at the molecular and atomic level of structural refinement. A review of drug design papers in the Journal of Medicinal Chemistry and of pharmaceutically relevant papers in the Journal of the American Chemical Society, covering the year 2000, reveals that 43% of these papers included computational chemistry techniques in their design and analyses of drug molecule action. Clearly the dawn of the 21st century has emphasized the exponentially growing importance of molecular modeling and quantum pharmacology in drug design. Accordingly, a basic understanding of medicinal chemistry in the modern era requires an appreciation of the fundamentals of quantum mechanics, molecular mechanics, and the other techniques of computational chemistry as applied to drug design. The medicinal chemist who uses com- mercially available computer programs to design drugs should not treat them as merely “black boxes,” and should have some insight into their conceptual basis. This is best achieved by using a “mechanics” method that permits the geometry of a molecule to be expressed as a function of energy. By minimizing this energy function, one can ascertain the optimal geometry of the molecule. Quantum mechanics and molecular mechanics are the dominant “mechanics” methods in quantum pharmacology (see figure 1. Once the wavefunction is known for a particular system, then any physical property may in principle be determined for that system. However, ψ is just a normal mathematical function; it has no special mathematical properties. If the system being studied is a simple hydrogen atom with a single electron outside of a positively charged nucleus, the Schrödinger equation may be solved exactly. The wavefunctions which satisfy the Schrödinger equation for this simple hydrogen atom are called orbitals; a hydrogenic atomic orbital is therefore the three-dimensional mathe- matical function from which one may calculate the energy and other properties of a single electron. For single atoms that contain multiple electrons (polyelectronic mono-atomic systems), the wavefunction for the atom (ψ) is a product of one-electron wavefunctions (χi), one for each electron. Drug molecules may have their properties ascertained by either experimental or theoretical methods. Although experimental meth- ods, especially X-ray crystallography, are the “gold standard” methods, calculational approaches tend to be faster and do provide high quality information. Nonempirical techniques, such as ab initio quantum mechanics calculations, provide accurate geometries and electron distribution properties for drug molecules. In quantum pharmacology, the goal is to determine the wavefunction Ψ for the drug molecule so that the energy and properties of the drug may be calculated. It is not possible to provide an exact mathematical solution for the wavefunction of an entire molecule. Accordingly, quantum mechanics calculations that provide approximate, but not exact, solutions for the drug molecule wavefunction are employed; these approxi- mate methods are called molecular orbital calculations. In molecular orbital calculations, the molecular orbitals φ are represented as a linear combination of atomic orbital functions (χi). A variety of different mathematical func- tions may be used to represent these atomic orbital functions. If a very sophisticated mathematical function is used, then the resulting answer is higher in quality, providing very accurate energies and geometries for the drug molecule being studied; however, such calculations may be extremely expensive in terms of computer time required. Classically, the most obvious types of mathemati- cal functions used to represent atomic orbitals are called Slater-type orbitals. The term basis set applies to a set of mathematical functions used to describe the shape of the orbitals in an atom. Molecular orbital calculations may be broadly divided into two types: ab initio and semi-empirical. The term ab initio is an unfortunate choice of words since it gives a mistaken idea of quality; nevertheless, it is used universally for molecular orbital wave- function calculations that explicitly consider all electrons within the drug molecule. The higher the basis set level, the more likely will the calculation reproduce experimental observations, such as bond lengths determined from X-ray crystallographic methods. Not surprisingly, the current medicinal chemistry literature contains numerous examples in which quantum pharmacology calculations using ab initio methods have been employed to understand the properties of drug molecules. Despite the length of time required for their completion, ab initio calculations are themselves not always successful in reproducing experimental observations and do require prolonged calculational times. To address these potential problems, consider- able effort has been expended to devise the so-called semi-empirical molecular orbital calculations. Semi-empirical methods employ a variety of approximations and assump- tions to reduce the complexity of the mathematics and thus the time required for a cal- culation. Core electrons, such as 1s electrons, are ignored under the assumption that they play little if any role in biological and biochemical processes. To compensate for ignoring core electrons, empirically derived parameters are incorporated into the calculations; these “fudge factors” help the semi-empirical calculation to reproduce experimental results while neglecting to calculate a number of difficult integral equations that would be present in the ab initio mathematical formulation. It is not uncommon for semi- empirical calculations to run 2 to 3 times faster than ab initio calculations. These first methods were somewhat crude and proved to be of little value in medicinal chemistry and quantum pharmacology. In molecular mechanics, atoms are regarded as distensible balls, bearing charge, and connected to other distensible balls via springs. The mathe- matics of molecular mechanics is thus rapid and trivial, which makes the technique ideal for the treatment of pharmaceutically relevant macromolecules.
At least 6 hours must have elapsed since the last administration of dinoprostone before oxytocin can be given order tadacip 20 mg overnight delivery. The % w/w is not equal to the % v/v because the mixture of water and alcohol produces a reduction in volume generic 20 mg tadacip free shipping. For example: 40% v/v = 70° proof (British system) = 80° proof (American system) = 40° in French speaking countries order tadacip 20 mg visa. Preparation – Use 70% v/v ethanol, which is more effective than higher concentrations. To obtain 1 litre of 70% v/v ethanol: • take 785 ml of 90% v/v ethanol, or 730 ml of 95% v/v ethanol, or 707 ml of 99% v/v ethanol; • add distilled or filtered water to make up a volume of 1 litre; • leave to cool and top up with water again to bring the volume back to 1 litre (mixing water and ethanol together produces a reaction whereby volume is reduced). Precautions – Do not apply to mucous membranes, wounds or burns: it is painful, irritating and slows the healing process. Remarks – Ethanol can be used for disinfection of non-critical medical items (items that are in contact with intact skin only) that are not soiled by blood or other body fluids. Contra-indications, adverse effects, precautions – May cause: local allergic reaction (rare). However, preferably use the cream on moist lesions and the ointment on dry and scaly lesions. Contra-indications, adverse effects, precautions – Use with caution and under medical supervision in children under 2 years. The first signs of poisoning after accidental ingestion are gastrointestinal disturbances (vomiting, diarrhoea). Preventive treatment of non- infected persons is ineffective and increases the risk of resistance. As a precaution, this product should not be used in humans if an alternative is available. Therapeutic action – Antifungal, weak antiseptic, drying agent Indications – Oropharyngeal candidiasis, mammary candidiasis in nursing mothers – Certain wet skin lesions (impetigo, dermatophytosis oozing lesions) Presentation – Powder to be dissolved Preparation – Dissolve 2. Use – 2 applications/day for a few days Contra-indications, adverse effects, precautions – Do not apply to wounds or ulcerations. In the event of mammary candidiasis, clean the breast before nursing and apply cream after nursing. Remarks – For the treatment of vulvovaginal candidiasis, miconazole cream may complement, but does not replace, treatment with clotrimazole or nystatin vaginal tablets. Therapeutic action – Antibacterial Indications – localized non bullous impetigo (less than 5 lesions in a single area) Presentation – 2% ointment, tube Dosage and duration – Child and adult: 3 applications/day for 7 days, to clean and dry skin The patient should be reassessed after 3 days. Contra-indications, adverse effects, precautions – May cause: pruritus and burning sensation; allergic reactions. Contra-indications, adverse effects, precautions – Use with caution and under medical supervision in children under 6 months. Preventive treatment of non- infected persons is ineffective and increases the risk of resistance. Contra-indications, adverse effects, precautions – Do not use in children under 2 months (safety not established). In the event of secondary bacterial infection, administer an appropriate local (antiseptic) and/or systemic (antibiotic) treatment 24 to 48 hours before applying permethrin. Remarks – Close contacts should be treated at the same time regardless of whether there have symptoms or not. Decontaminate clothes and bed linen of patients and close contacts simultaneously. The treatment may be repeated if specific scabies lesions (scabious burrows) are still present after 3 weeks. Dosage – Adult: 1 drop into the conjunctival sac 4 times daily Duration – life-long treatment Contra-indications, adverse effects, precautions – Do not administer to children. Duration – 3 consecutive days per week, for a maximum of 4 weeks Contra-indications, adverse effects, precautions – Do not use to treat genital warts in children. Use – Always apply a protective layer of vaseline or zinc ointment on the surrounding skin prior to treatment. Contra-indications, adverse effects, precautions – Do not use to treat genital warts in children. Another advantage is that the patient may apply the solution to the warts himself; whereas the resin must always be applied by medical staff. The skin should be cleaned beforehand if soiled or if the procedure is invasive (lumbar puncture, epidural/spinal anaesthesia, etc. Contra-indications, adverse effects, precautions – Do not use with other antiseptics such as chlorhexidine (incompatibility) or mercury compounds (risk of necrosis). Use – Antiseptic hand wash Wet hands; pour 5 ml of solution, rub hands for 1 min; rinse thoroughly; dry with a clean towel. Spread again 5 ml of solution on hands and forearms and rub for 2 min; rinse thoroughly; dry with a sterile towel. Contra-indications, adverse effects, precautions – Do not use with others antiseptics such as chlorhexidine (incompatibility) or mercury compounds (risk of necrosis). Contra-indications, adverse effects, precautions – Do not use: • in patients with hypersensitivity to sulfonamides; • in infants less than one month. The risk is limited for good quality stainless steel instruments if concentration, contact time (20 minutes maximum) and thorough rinsing recommendations are respected. Caution: some formulations used for disinfecting floors contain additives (detergents, colouring, etc. Remarks – Tetracycline eye ointment replaces silver nitrate 1% eye drops for the prevention of neonatal conjunctivitis. When systemic treatment cannot be given immediately, apply tetracycline eye ointment to both eyes every hour until ceftriaxone is available.
Inhibitory effects of par- oxetine and sertraline on desipramine pharmacokinetics have also been compared (135) order 20mg tadacip with mastercard. After 10 d of cotreatment discount 20mg tadacip overnight delivery, desipramine concentrations in plasma increased greater than fourfold cheap tadacip 20mg fast delivery, from 38 to 173 ng/mL, in the paroxetine/desipramine group but only by approximately half, from 36 to 52 ng/mL, in the sertraline/desipramine group. The experiments were consistent with a greater pharmacokinetic interaction by paroxe- tine than by sertraline. A similar small effect by sertraline on nortriptyline accumulation has also been reported (136). Each of these reports again supports the original assignment of relative inhibi- tory actions decreasing in the order fluoxetine/paroxetine/sertraline. After conversion, four of the five subjects achieved therapeutic levels of nortriptyline. In one report, prior treatments with fluvoxamine (100 mg/d, 10 d) prolonged the elimination half-life of imipramine from 23 to 40 h and reduced apparent oral clearance (141). In another instance, fluvoxamine, administered at a dose of 100 mg/d for 14 d, increased the elimination half-life of imipramine from 23 to 39 h, reduced the appar- ent oral clearance from 1. The maximum concentration of desipramine was halved, in a manner consistent with inhibition of imipramine N-demethylation (142). Effects by amitriptyline on thioridazine metabolism may be more significant, both pharmacokinetically and clinically. Recent studies support the common belief that car- diovascular mortality is greater among psychiatric patients receiving neuroleptics than in the general population (149,150). Other evidence suggests that the risk cardiotoxicity may be greater with thioridazine than other neuroleptics (151) and that cardiac effects such as delayed ventricular repolarization are dose related and due predominantly to unmetabolized thioridazine (152). In a rodent model, treatment with imipramine or amitriptyline increased the blood plasma levels of thioridazine and its metabolites 20- and 30-fold, respectively (153). This observation is consistent with the observations in psychiatric patients that the effect of thioridazine on amitriptyline metabolism varied with the antidepressant/ neuroleptic:dose ratio (153). However, known interactions between ticlopidine and the anticonvulsant, dilantin, might serve as examples (154–155). In addition, since inhibition by ticolidine may be mecha- nism based, which by definition permanently inactivates the metabolizing enzyme, inhibition may be long term (156–157). Carbamazepine is a structural analog of imipramine with anticonvulsant properties (Fig. These contradictory observations of low levels in blood and increased clinical efficacy appear relayed to changes in the amount of drug available for pharmacological action. They also noted that postural sway and short-term memory impairments were increased by the combination. The effects of the combined exposure to ethanol and amitriptyline on skills such as driving have been reviewed (164). In comparison, clinical toxicity has been observed at concentrations over 500 ng/mL (45,84) and severe toxicity at levels over 1000 ng/mL (85–88,165) although in one nonfatal intoxication, amounts of clomipra- mine and N-desmethylclomipramine in plasma exceeded 2000 ng/mL (166). Postmortem concentrations of imipramine and desipramine of 3000 and 9600 ng/mL were determined in blood from an individual treated with a paroxetine/ imipramine combination (167). They observed that, even though amounts of clomipramine in plasma increased to as much as 965 ng/mL, and imipramine to 785 ng/mL, no signs of toxicity were observed in their patients. In these cases, individuals who responded favorably to the combination, experi- enced blood levels that averaged greater than 750 ng/mL (172). Nevertheless, fatalities have been associated with combined fluoxetine/amitriptyline and paroxetine/imipramine therapy (167,173). Pounder and Jones studied this phenomenon of postmortem redistribution and observed diffusion of drugs, along a concentration gradient, out of solid organs and into the blood (177). Highest levels were seen in pulmonary arteries and veins and lowest in peripheral vessels. They reported that amounts of doxepin or clomipramine in postmortem blood collected from different sites ranged from 3. The consequence of postmor- tem redistribution is that reference data are rendered less useful unless a record of the site of collection is available. Some of the interactions may appear small in comparison to a broad range of therapeutic concentrations, but effects in a single patient can be dramatic. It has there- fore been the objective of this chapter to describe these interactions, and to provide a basis on which they can be applied toward interpretation of a toxic response by a single patient. Recognition and management of depression in general practice: consensus statement. A risk-benefit assessment of moclobemide in the treatment of depressive disorders. Line- zolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide. Dangerous monoamine oxidase inhibitor interactions are still occurring in the 1990s. Drug therapy reviews: tricyclic antidepres- sant and monoamine oxidase inhibitor combination therapy. Toxicity secondary to meperidine in patients on monoamine oxi- dase inhibitors: a case report and critical review.
During the period of ﬂow buy cheap tadacip 20 mg on line, the velocity of the blood is about three times as high as the overall average value calculated in Exercise 8-6 cheap 20mg tadacip with visa. The kinetic energy in the smaller arteries is even less because proven tadacip 20 mg, as the arteries branch, the overall area increases and, therefore, the ﬂow velocity decreases. For example, when the total ﬂow rate is 5 liter/min, the blood velocity in the capillaries is only about 0. The kinetic energy of the blood becomes more signiﬁcant as the rate of blood ﬂow increases. For example, if during physical activity the ﬂow rate increases to 25 liter/min, the kinetic energy of the blood is 83,300 erg/cm3, which is equivalent to a pressure of 62. This energy is no longer neg- ligible compared to the blood pressure measured at rest. In healthy arteries, the increased velocity of blood ﬂow during physical activity does not present a problem. During intense activity, the blood pressure rises to compensate for the pressure drop. Assuming a Reynold’s number of 2000, the critical velocity for the onset of turbulence in the 2-cm-diameter aorta is, from Eq. But as the level of physical activity increases, the ﬂow in the aorta may exceed the critical rate and become turbulent. In the other parts of the body, however, the ﬂow remains laminar unless the passages are abnormally constricted. Laminar ﬂow is quiet, but turbulent ﬂow produces noises due to vibrations of the various surrounding tissues, which indicate abnormalities in the circu- latory system. These noises, called bruit, can be detected by a stethoscope and can help in the diagnosis of circulatory disorders. In the United States, an estimated 200,000 people die annually as a consequence of this disease. In arteriosclerosis, the arterial wall becomes thickened, and the artery is narrowed by deposits called plaque. Sixty to seventy percent is considered severe, and a narrowing above 80% is deemed critical. If, for example, the radius of the artery is narrowed by a factor of 3, the cross-sectional area decreases by a factor of 9, which results in a nine-fold increase in velocity. The increased kinetic energy is at the expense of the blood pressure; that is, in order to maintain the ﬂow rate at the higher velocity, the potential energy due to pressure is converted to kinetic energy. For example, if in the unobstructed artery the ﬂow velocity is 50 cm/sec, then in the constricted region, where the area is reduced by a factor of 9, the velocity is 450 cm/sec. Because of the low pressure inside the artery, the external pressure may actually close oﬀ the artery and block the ﬂow of blood. When such a blockage occurs in the coronary artery, which supplies blood to the heart muscle, the heart stops functioning. Stenosis above 80% is considered critical because at this point the blood ﬂow usually becomes turbulent with inherently larger energy dissipation than is associated with laminar ﬂow. As a result, the pressure drop in the situa- tion presented earlier is even larger than calculated using Bernoulli’s equation. Further, turbulent ﬂow can damage the circulatory system because parts of the ﬂow are directed toward the artery wall rather than parallel to it, as in laminar 112 Chapter 8 The Motion of Fluids ﬂow. The blood impinging on the arterial wall may dislodge some of the plaque deposit which downstream may clog a narrower part of the artery. If such clogging occurs in a cervical artery, blood ﬂow to some part of the brain is interrupted causing an ischemic stroke. The artery has a speciﬁc elasticity; therefore, it exhibits certain springlike prop- erties. Speciﬁcally, in analogy with a spring, the artery has a natural fre- quency at which it can be readily set into vibrational motion. Deposits of plaque cause an increase in the mass of the arterial wall and a decrease in its elasticity. As a result, the natural frequency of the artery is signiﬁcantly decreased, often down to a few hundred hertz. The plaque- coated artery with its lowered natural frequency may now be set into resonant vibrational motion, which may dislodge plaque deposits or cause further dam- age to the arterial wall. We will now compute the power generated by the heart to keep the blood ﬂowing in the circulatory system. Therefore, as shown in Exercise 8-10, the power output of the right ventricle is 0. While in fact the systolic blood pressure rises with increa- sed blood ﬂow, in these calculations we have assumed that it remains at 120 torr. Both abnormally high and abnormally low blood pressures indicate some disorders in the body that require medical attention. High blood pres- sure, which may be caused by constrictions in the circulatory system, certainly implies that the heart is working harder than usual and that it may be endan- gered by the excess load. Blood pressure can be measured most directly by inserting a vertical glass tube into an artery and observing the height to which the blood rises (see Fig. This was, in fact, the way blood pressure was ﬁrst measured in 1733 by Reverend Stephen Hales, who connected a long ver- tical glass tube to an artery of a horse.
This tissue purchase 20mg tadacip with mastercard, called the "Islets of Langerhans" is named after the German pathologist Paul Langerhans order tadacip 20mg on line, who discovered them in 1869 generic tadacip 20mg mastercard. Through a microscope, Langerhans observed these cells cluster in groups, which he likened to little islands in the pancreas. One such group of cells, the beta cells, produce insulin in response to blood glucose. These beta cells are tiny insulin factories that sense the level of glucose in the blood stream, and produce insulin in precise proportion to that level. Therefore, following a meal, blood sugar levels will rise significantly, and the beta cells will release a large amount of insulin. This insulin will cause body cells to take up the sugar, causing blood sugar to quickly return to its normal range. Once blood sugar is in the normal range, the beta cells will reduce the output of insulin to an idling state. In this way, the beta cells adjust their production of insulin on a minute-by-minute basis, always producing just enough insulin to deal with the amount of blood sugar presently in the blood stream. This self-destructive mechanism is the basis of many so-called autoimmune diseases. Once the islets are killed, the ability to produce insulin is lost, and the overt symptoms and consequences of diabetes begin. Type 2 Diabetes The most common causes of type 2 diabetes are poor diet and/or lack of exercise, both of which can result in insulin resistance. Recent research suggests that the root cause of insulin resistance is a breakdown in intercellular signaling. In the early stages of insulin resistance, the pancreas compensates by producing more and more insulin, and so the "knocking" becomes louder and louder. The message is eventually "heard", enabling glucose transportation into the cells, resulting in the eventual normalization of blood glucose levels. Over time, the stress of excessive insulin production wears out the pancreas and it cannot keep up this accelerated output. This is called "uncompensated insulin resistance" and is the essence of advanced type 2 diabetes. Over time, the pancreas "wears out" and can no longer pump out enough insulin to overcome this insulin resistance. This results in a decreased insulin production and/or increased insulin resistance which propagates the cycle and leads to the onset of diabetes. It is not known if obesity causes insulin resistance; or if insulin resistance causes obesity; or if they develop independently. We also know that physical inactivity contributes to insulin resistance, as does eating too much dietary carbohydrate. Diabetes and Oxidative Stress Most researchers are in basic agreement that the theory of oxidative stress is central to explaining the cause of diabetes. Because it is lacking an electron, it is unstable and very much wants to find one electron to fill its need. This "free radical" will steal an electron from any other molecule it encounters that is more willing to give one up. Antioxidants are molecules which can safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. According to the theory of oxidative stress, free radicals run rampant through the body reeking havoc. This is why it is so important to lower the oxidative stress with better diet, more exercise, improved lifestyle; and to take all the antioxidant supplements known to neutralize the excess free radicals. There is still a lot to learn about the causes of diabetes, but what is known, is that our bodies may begin to malfunction five to seven years before we are ever diagnosed with diabetes. Sometimes we find that just certain foods, just certain stresses just certain times of the month make the diabetes work. Most people consume candy, french fries, potato chips, ice cream, pasta etc on a regular basis. When you consider that so many of us are overfed and so few of us get any regular exercise. The ever increasing number of overweight, out of shape, oxidatively stressed people in todayâ€™s societies around the world, is directly proportional to the epidemic rise of diabetes. Most of these long-term complications are related to the adverse effects diabetes has on arteries and nerves. Complications related to artery damage Diabetes causes damage to both large and small arteries. This artery damage results in medical problems that are both common and serious: Cardiovascular disease. These deaths could be reduced by 30% with improved care to control blood pressure and blood glucose and lipid levels. Foot care programs that include regular examinations and patient education could prevent up to 85% of these amputations. Treatment to better control blood pressure and blood glucose levels could reduce diabetes-related kidney failure by about 50%. Each year, 12,000-24,000 people become blind because of diabetic eye disease, including diabetic retinopathy. Diabetes is the leading cause of new cases of blindness among adults 20-74 years old. Approximately 70% of all adult males with diabetes currently suffer or will experience sexual dysfunction or impotence. Complications related to nerve damage 60 to 70% of people with diabetes have mild to severe forms of nervous system damage. This diabetic neuropathy may result in numbness, tingling, and paresthesias in the extremities and, less often, debilitating, severe, deep-seated pain and hyperesthesias.
Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine generic tadacip 20mg online. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist buy discount tadacip 20mg on line. Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers discount tadacip 20mg amex. Draft guidance for industry: Drug-Drug interactions— study design, data analysis and implications for dosing and labeling. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant admin- istrations of erythromycin. Assessment of single- and multiple-dose interactions between ritonavir and saquinavir. Drug-drug, drug-dietary supplement, and drug- citrus fruit and other food interactions—labeling implications. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. The safety of newly approved medicines: do recent market removals mean there is a problem? What have we learned from the recent market withdrawal of terfenadine and mibefradil? Presentation at the 101st Annual Meeting of American Society of Clinical Pharmacology and Therapeutics, March 15–17, 2000, Beverly Hills, California. Guidance for Industry: Exposure-Response Rela- tionship, Study Design, Data Analysis, and Regulatory Applications, April 2003 (posted May 2003). Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the ‘‘Cocktail’’ Approach. Nelson Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, U. Most adverse drug reactions occur in only a small percentage of patients and are termed idiosyncratic, and many of these reactions are caused by reactive metabolites formed from drugs (2–4). Reactions of reactive metabolites with tissue macromolecules can lead to direct or intrinsic toxic effects and/or cause toxicity by forming haptens that lead to immunotoxic effects. Although new animal models are being developed that provide insights into factors that play a role in these idiosyncratic toxicities (5–7), no generally useful models are yet available. In some cases a new drug may be the precipitator or perpetrator of toxicity of another drug by altering its metabolism and/or disposition, or the new drug may be the object or victim of altered metabolism and/or disposition caused by a drug already on the market. In many instances, the object or victim is a drug with a narrow therapeutic index, window, or ratio (for a discussion, see Ref. Several definitions have been applied to this terminology, including the qual- itatively simple one of a drug ‘‘for which relatively small changes in systemic 687 688 Nelson concentrations lead to marked changes in pharmacodynamic response’’ (9). This chapter will focus on those metabolic drug-drug interactions that have led or can lead to serious toxicological consequences in humans. Most of the chapter will describe examples of metabolic drug-drug interactions that have caused serious toxicities. As discussed in chapter 15, the majority of drug-drug inter- actions of clinical significance have occurred through interactions at the level of cytochromes P450. Since substantial information is now either available or readily obtainable about induction and inhibition of these enzymes as well as the kinetic parameters associated with the metabolism of drugs and other probe substrates, many metabolic drug-drug interactions can be predicted prior to clinical trials. However, because the situation in vivo is complicated by a variety of genetic and environmental factors that affect drug absorption, distribution, and metabolism and because the physiological response to a toxic insult may vary from one individual to another, it is often difficult to predict that a particular drug-drug interaction will lead to a toxic insult. Nonetheless, the results of preclinical studies should provide the basis for more informed planning of clinical studies. Warfarin Because of its narrow therapeutic window and extensive oxidation to inactive metabolites by cytochromes P450, warfarin (and the closely related drug ace- nocoumarol) is subject to many metabolic drug-drug interactions that can place patients at severe risk of either hyper- or hypocoagulability. Several inducers of cytochromes P450, including rifampin, several barbi- turates, aminoglutethimide, primidone, phenytoin, and carbamazepine increase requirements for warfarin dosing, although mechanisms for most of these interactions have not been thoroughly investigated (11–13). Clinically, this effect becomes manifest either when a patient stabilized on warfarin adds one or more of these drugs to his or her therapy or, more commonly, when the patient removes one of these drugs from his or her therapy after stabilization on the combination therapy. Several inhibitors of cytochromes P450 can substantially decrease require- ments for warfarin dosage that, if not attended to, can lead to life-threatening bleeding episodes. Cimetidine contains an imidazole moiety, but it is a much better inhibitor of the metabolism of (R)-warfarin (17), the least potent enantiomer, so that an effect on warfarin therapy is observed only at high doses of cimetidine (18). Although many case reports have appeared of interactions between warfarin and a variety of other drugs with many different drug structures (19), only a few of these have resulted in serious toxic effects, and mechanisms are largely unknown. Because of their increased use, further investigations with some of these drugs, such as tamoxifen (20,21), seems warranted. Theophylline General aspects of the drug-drug interactions involving theophylline are similar to those described for warfarin, because it too is a drug with a narrow therapeutic index. Increases in its rate of metabolism, either by some inducers of cyto- chromes P450 or by removal of an inhibitor of those P450s given concomitantly with theophylline, lead to diminution of therapeutic effect, resulting in increased dyspnea. Conversely, decreases in its rate of metabolism either by inhibitors of P450s involved in the metabolism of theophylline or by removal of an inducer given concomitantly can lead to serious toxicities, including convulsions and heart arrhythmias that can be serious enough to cause death. Some nonselective inhibitors of P450s, such as cimetidine, some b-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. Neither loratadine nor cetirizine, nor the active metabolites of terfena- dine (fexofenadine) and astemizole (norastemizole), cause this cardiotoxic effect to any significant extent (25).