睿学教育Wisdome Education

Apostolos Christopoulos, MD, MSc, FRCSC

• Assistant Professor, Department of Otorhinolaryngology
• Centre Hospitalier de l?niversit? de Montr?al
• Montr?al, Qu?bec, Canada

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These include alcohol and certain intravenous anesthetics (etomidate symptoms 10 dpo order genuine prothiaden online, propofol) in addition to thiopental medication 3 checks discount 75mg prothiaden amex. Central nervous system excitatory agents that act on the chloride channel include picrotoxin and bicuculline medicine 3202 order prothiaden american express. Sedation—Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative- hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the tricyclic antidepressants and antihistamines. However, the disinhibition of previously suppressed behavior may be more related to behavioral disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of self-control, which can occur at dosages in the range of those used for management of anxiety. The benzodiazepines also exert dose-dependent anterograde amnesic effects (inability to remember events occurring during the drug’s duration of action). The effects of sedative-hypnotics on the stages of sleep depend on several factors, including the specific drug, the dose, and the frequency of its administration. Despite possible reductions in slow-wave sleep, there are no reports of disturbances in the secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used as hypnotics. The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns. However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administration, a characteristic favoring their use for the induction of anesthesia. Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia. Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. Several benzodiazepines—including clonazepam, nitrazepam, lorazepam, and diazepam—are sufficiently selective to be clinically useful in the management of seizures (see Chapter 24). Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures, though not the drugs of first choice. Muscle relaxation—Certain drugs in the sedative-hypnotic class, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Effects on respiration and cardiovascular function—At hypnotic doses in healthy patients, the effects of sedative- hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative- hypnotics can produce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative- hypnotics. At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, possibly via facilitation of the actions of adenosine, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. Tolerance: Psychologic & Physiologic Dependence Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep.

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Nonpharmacologic therapies that are useful for sleep problems include proper diet and exercise symptoms zollinger ellison syndrome buy generic prothiaden 75 mg, avoiding stimulants before retiring symptoms your period is coming cheap prothiaden 75mg buy line, ensuring a comfortable sleeping environment symptoms 5 days past ovulation purchase cheapest prothiaden, and retiring at a regular time each night. In some cases, however, the patient will need and should be given a sedative-hypnotic for a limited period. It should be noted that the abrupt discontinuance of many drugs in this class can lead to rebound insomnia. The newer hypnotics, zolpidem, zaleplon, and eszopiclone, are less likely than the benzodiazepines to change sleep patterns. However, so little is known about the clinical impact of these effects that statements about the desirability of a particular drug based on its effects on sleep architecture have more theoretical than practical significance. The drug selected should be one that provides sleep of fairly rapid onset (decreased sleep latency) and sufficient duration, with minimal “hangover” effects such as drowsiness, dysphoria, and mental or motor depression the following day. Older drugs such as chloral hydrate, secobarbital, and pentobarbital continue to be used, but benzodiazepines, zolpidem, zaleplon, or eszopiclone are generally preferred. Daytime sedation is more common with benzodiazepines that have slow elimination rates (eg, lorazepam) and those that are biotransformed to active metabolites (eg, flurazepam, quazepam). If benzodiazepines are used nightly, tolerance can occur, which may lead to dose increases by the patient to produce the desired effect. Eszopiclone, zaleplon, and zolpidem have efficacies similar to those of the hypnotic benzodiazepines in the management of sleep disorders. Favorable clinical features of zolpidem and the other newer hypnotics include rapid onset of activity and modest day-after psychomotor depression with few amnestic effects. Zolpidem, one of the most frequently prescribed hypnotic drugs in the United States, is available in a biphasic release formulation that provides sustained drug levels for sleep maintenance. Zaleplon acts rapidly, and because of its short half-life, the drug appears to have value in the management of patients who awaken early in the sleep cycle. At recommended doses, zaleplon and eszopiclone (despite its relatively long half-life) appear to cause less amnesia or day-after somnolence than zolpidem or benzodiazepines. The drugs in this class commonly used for sedation and hypnosis are listed in Table 22–3 together with recommended doses. Note: The failure of insomnia to remit after 7–10 days of treatment may indicate the presence of a primary psychiatric or medical illness that should be evaluated. Drugs used in the management of seizure disorders and as intravenous agents in anesthesia are discussed in Chapters 24 and 25. For sedative and possible amnestic effects during medical or surgical procedures such as endoscopy and bronchoscopy —as well as for premedication prior to anesthesia—oral formulations of shorter-acting drugs are preferred. Long-acting drugs such as chlordiazepoxide and diazepam and, to a lesser extent, phenobarbital are administered in progressively decreasing doses to patients during withdrawal from physiologic dependence on ethanol or other sedative- hypnotics. Meprobamate and the benzodiazepines have frequently been used as central muscle relaxants, though evidence for general efficacy without accompanying sedation is lacking. A possible exception is diazepam, which has useful relaxant effects in skeletal muscle spasticity of central origin (see Chapter 27). Psychiatric uses of benzodiazepines other than treatment of anxiety states include the initial management of mania and the control of drug-induced hyperexcitability states (eg, phencyclidine intoxication). Relatively low doses may lead to drowsiness, impaired judgment, and diminished motor skills, sometimes with a significant impact on driving ability, job performance, and personal relationships. Benzodiazepines may cause a significant dose-related anterograde amnesia; they can significantly impair ability to learn new information, particularly that involving effortful cognitive processes, while leaving the retrieval of previously learned information intact. This effect is utilized for uncomfortable clinical procedures, eg, endoscopy, because the patient is able to cooperate during the procedure but amnesic regarding it afterward. The criminal use of benzodiazepines in cases of “date rape” is based on their dose-dependent amnestic effects. Because elderly patients are more sensitive to the effects of sedative-hypnotics, doses approximately half of those used in younger adults are safer and usually as effective. The most common reversible cause of confusional states in the elderly is overuse of sedative- hypnotics. At higher doses, toxicity may present as lethargy or a state of exhaustion or, alternatively, as gross symptoms equivalent to those of ethanol intoxication. The physician should be aware of variability among patients in terms of doses causing adverse effects. An increased sensitivity to sedative-hypnotics is more common in patients with cardiovascular disease, respiratory disease, or hepatic impairment and in older patients.

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What is the most crew has complained of being light-headed and likely adverse outcome if the woman began taking tired occasionally at work and that if it occurs medications xl 75mg prothiaden free shipping, it the drug at this time? Exposure to one such pollutant treatment 8th feb discount prothiaden line, (B) Insecticide packaging area carbon monoxide medicine you take at first sign of cold buy genuine prothiaden, can result in which of the follow- (C) Label printing area ing conditions? You have been told there has been a large spill at to the epithelium the chemical company but in the confusion you (B) An increased susceptibility to respiratory in- weren’t told where it occurred. The exposed work- fection due to impairment in phagocyte function ers were agitated and irritable and said to be having (C) Exacerbation of asthmatic episodes because of difficulty walking in a coordinated manner. Some bronchoconstriction feel quite hot as if they are burning up, and one had (D) Hypoxia due to displacing oxygen from hemo- a seizure. A 4-year-old boy is taken to the emergency depart- (B) Insecticide packaging area ment by his parents in the afternoon the first (C) Label printing area Saturday in June. The symptoms are characteristic of a person generally low in toxicity and few poisonings have chronically exposed to vapors released from ele- been reported; however, seizures are a symptom. While the tech- clear up after work are often due to inhalation ex- nician may be exposed to solvent vapors released posure of volatile or aerosol materials. The solvents from dental adhesives, the symptoms are not char- used in printing inks cause light-headedness and se- acteristic of this type of exposure. The symptoms are not those of herbicide ex- would not be expected because these are not symp- posure and insecticide exposure. The tient and not the technician would be most likely symptoms are referable to an acute high exposure exposed to quantities high enough to cause any to an organochlorine or pyrethroid insecticide. The technician has little exposure to li- While organochlorine pesticides are not used in this docaine, and the symptoms are not typical of lido- country, they are manufactured for export. Ellenhorn’s Medical Toxicology: tion of the fetus is the principal outcome if expo- Diagnosis and Treatment of Human Poisoning (2nd sure to drugs occurs during the last 6 months of ed. Clinical impairing the erythrocyte’s ability to release oxy- Management of Poisoning and Drug Overdose (3rd gen. Casarett and Doull’s Toxicology, the lungs, while exposure to sulfur dioxide can exacer- Basic Science of Poisons (6th ed. Poisoning Materials Toxicology: Clinical Principles of with compound 1080 (fluorocitrate) inhibits mito- Environmental Health. The paint used originally in older because compared to her kindergarten classmates, homes usually contains lead. Recently the child has complained of abdominal Small children may exhibit pica, which is the pain and has had occasional constipation. About 3 compulsive eating of nonfood items, and this can years ago the parents moved into a 75-year-old occur during times of stress, such as the separa- house in the inner city and have been renovating it tion of parents. Within the past year, the parents adequately after removing the paint, it is proba- separated and the father moved out of the house. There is evidence that at blood lead levels of about 10 g/dL, children are at risk for devel- opmental impairment. Other tests that may be useful include examination for microcytic anemia and erythrocyte stippling and radiographic exam- ination of the long bones for lead lines. This negatively affect others, individuals with the capacity to chapter provides a conceptual framework for bioethical make their own decisions should be free to do as they analysis, presents some cases that illustrate ethical prob- wish, even if their choices are risky or harmful to them- lems, and delineates some guidelines for consideration. The principle also entails that persons with di- Bioethics is the study of ethical issues associated with minished autonomy, such as those who are illiterate or providing health care or pursuing biomedical research. Most approaches to bioethics in the United States are Many moral obligations for professionals engaged in secular in nature and presuppose no particular religious scientific research or health care are derived from or theological perspective. While one’s religious beliefs the principle of autonomy, such as the physician– may play an important role in determining personal researcher’s obligation to fully inform potential re- morality, the broader endeavor of bioethical analysis at- search subjects and respect the individual’s informed tempts to be devoid of any particular religious perspec- consent or informed refusal. Similarly, bioethical analysis stands independent of on the principle that individuals are the appropriate de- legal analysis. As the primary moral principle to reflect a societal consensus on issues and are estab- quoted in medical codes and oaths, the principle of lished to set a minimum standard of behavior. For example, concerns about acceptable actions, religious beliefs, and knowledge of beneficence motivate physicians, pharmacologists, phar- the law are frequently insufficient to guide moral ac- macists, and clinical investigators, all of whom share the tion, in the realm of health care. Solving problems that goal of conducting studies that will ultimately benefit arise in the scientific and clinical contexts requires society by producing or refining effective treatments. While bioethical analysis is multifac- sionals have an obligation to prevent harm or if harm is torial, four moral principles play key roles in establish- unavoidable, minimize that harm. Thus the principles of beneficence and non- • Researchers must ensure subjects’ privacy and maleficence dictate that the overall goal of scientific confidentiality.

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In unstable angina symptoms kidney stones prothiaden 75 mg buy on line, vigorous measures are taken to achieve both—increase oxygen delivery (by medical or physical interventions) symptoms right after conception purchase prothiaden from india, and decrease oxygen demand treatment jock itch 75mg prothiaden visa. The effects of arterial blood pressure and venous pressure are mediated through their effects on myocardial wall stress. As a consequence of its continuous activity, the heart’s oxygen needs are relatively high, and it extracts approximately 75% of the available oxygen even in the absence of stress. The myocardial oxygen requirement increases when there is an increase in heart rate, contractility, arterial pressure, or ventricular volume. These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. A small, late component of sodium current helps to maintain the long plateau and prolong the calcium current of myocardial action potentials. Drugs that block this late sodium current can indirectly reduce calcium influx and consequently reduce cardiac contractile force. Therefore, drugs that shift myocardial metabolism toward greater use of glucose (fatty acid oxidation inhibitors) have the potential, at least in theory, to reduce the oxygen demand without altering hemodynamics. Determinants of Coronary Blood Flow & Myocardial Oxygen Supply In the normal heart, increased demand for oxygen is met by augmenting coronary blood flow. Because coronary flow drops to negligible values during systole, coronary blood flow is directly related to the aortic diastolic pressure and the duration of diastole. Therefore, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia. Resistance is determined mainly by intrinsic factors, including metabolic products and autonomic activity, and can be modified—in normal coronary vessels— by various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance. Determinants of Vascular Tone Peripheral arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress (Table 12–1). In systole, intraventricular pressure must exceed aortic pressure to eject blood; arterial blood pressure thus determines the systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Contraction is triggered (red arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Interaction with the Ca -calmodulin complex reduces their interaction with myosin during the contraction cycle. Nitric oxide is an effective activator of soluble guanylyl cyclase and acts mainly through this mechanism. Important molecular donors of nitric oxide include nitroprusside (see Chapters 11 and 19) and the organic nitrates used in angina. Decreasing intracellular Ca : Calcium channel blockers predictably cause vasodilation because they reduce 2+ intracellular Ca , a major modulator of the activation of myosin light chain kinase (Figure 12–1) in smooth muscle. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability. Certain agents used elsewhere and under investigation in the United States (eg, nicorandil) may act, in part, by this mechanism. This appears to be the mechanism of vasodilation caused by β agonists, drugs that are not used in angina2 (because they cause too much cardiac stimulation), and by fenoldopam, a D agonist used in hypertensive emergencies. In some patients, the nitrates and the calcium channel blockers may cause a redistribution of coronary flow and increase oxygen delivery to ischemic tissue. In variant angina, these two drug groups also increase myocardial oxygen delivery by reversing coronary artery spasm. Although nitroglycerin is used in the manufacture of dynamite, the systemic formulations used in medicine are not explosive.

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When tricyclic antidepressants are administered to patients taking guanethidine symptoms 5dpiui 75mg prothiaden for sale, the drug’s antihypertensive effect is attenuated medications of the same type are known as cheap generic prothiaden uk, and severe hypertension may follow medicine express purchase generic prothiaden on-line. Reserpine Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large scale in the treatment of hypertension. This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days. Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms. At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance. High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0. Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson’s disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears. Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The pharmacologic properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations. Propranolol Propranolol was the first β blocker shown to be effective in hyper-tension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol. All β-adrenoceptor-blocking agents are useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions (see Chapter 13). Mechanism and Sites of Action Propranolol’s efficacy in treating hypertension as well as most of its toxic effects result from nonselective β blockade. Other β blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities. It is likely that1 propranolol’s effect is due in part to depression of the renin-angiotensin-aldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol’s β- blocking effect, and changes in these parameters may be used as guides for regulating dosage. Toxicity The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β receptors and are described in more detail in Chapter 10. The most important of these predictable extensions of the β -blocking action occur1 in patients with brady-cardia or cardiac conduction disease, and those of the β -blocking action occur in patients with2 asthma, peripheral vascular insufficiency, and diabetes. When β blockers are discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Although the incidence of these complications is probably low, β blockers should not be discontinued abruptly. Metoprolol & Atenolol Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in the treatment of hypertension. Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of β adrenoceptors such as those in the1 heart but 50- to 100-fold less potent than propranolol in blocking β receptors.

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The hepatobiliary recy- mechanism is relatively minor medicine you can give cats buy cheap prothiaden on line, however treatment vitiligo cheap prothiaden 75 mg fast delivery, and at high cling of colchicine and its antimitotic effect on cells that dosages these same drugs increase uric acid elimination are rapidly turning over medications via peg tube cheap generic prothiaden canada, such as those of the intestinal by inhibiting its proximal tubular reabsorption. Therefore, it is wise to begin ther- are somewhat similar to urate in structure; therefore, apy with the administration of small amounts of they can compete with uric acid for transport sites. In addition, the initial rise in urinary uric the total excretion of urate by inhibiting its tubular se- acid concentrations during uricosuric drug therapy may cretion. In contrast, low dosages of probenecid appear to com- Sulfinpyrazone is readily absorbed after oral admin- pete preferentially with plasma uric acid for the proxi- istration, with peak blood levels reached 1 to 2 hours af- mal tubule anionic transport system and thereby block ter ingestion. The uricosuric (98–99%) than is probenecid (84–94%) and is a more action of probenecid, however, is accounted for by the potent uricosuric agent. Most of the drug (90%) is elim- drug’s ability to inhibit the active reabsorption of fil- inated through active proximal tubular secretion of the tered urate. Sulfinpyrazone also undergoes Probenecid is rapidly absorbed after oral administra- p-hydroxylation to form a uricosuric metabolite, the tion, with peak plasma levels usually reached in 2 to 4 formation of which undoubtedly contributes to the hours. Its half-life is somewhat variable (6–12 hours) be- drug’s prolonged activity (about 10 hours) and potency cause of both its extensive plasma protein binding and relative to probenecid. Since tubular back- rate of excretion of sulfinpyrazone is not enhanced by diffusion is decreased at alkaline urinary pH ranges, alkalinization of the urine, since the drug is largely ion- probenecid excretion increases with increasing urinary ized at all urinary pH ranges and therefore not a candi- pH. It is not useful in treating acute at- Abdominal pain, nausea, and possible reactivation tacks of gouty arthritis. The drug should be excreted is greater than 800 mg/day, the urine should be used with caution in patients with compromised renal alkalinized to prevent kidney stone formation and pro- function, and adequate fluid intake should always ac- mote uric acid. If these agents are to be given con- comitantly with probenecid, their dosage should be mod- Allopurinol (Zyloprim) is the drug of choice in the treat- ified appropriately. Salicylates interfere with the clinical ment of chronic tophaceous gout and is especially useful effects of both sulfinpyrazone and probenecid and should in patients whose treatment is complicated by renal in- be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distri- bution and hepatic metabolism of a number of drugs. Mechanism of Action Adverse reactions associated with probenecid ther- Allopurinol, in contrast to the uricosuric drugs, reduces apy include occasional rashes, allergic dermatitis, upper serum urate levels through a competitive inhibition of gastrointestinal tract irritation, and drowsiness. The uric acid synthesis rather than by impairing renal urate drug is contraindicated in patients with a history of re- reabsorption. After enzyme inhibition, the urinary and blood concentra- Sulfinpyrazone tions of uric acid are greatly reduced and there is a si- Sulfinpyrazone (Anturane), another uricosuric agent, is multaneous increase in the excretion of the more solu- chemically related to the antiinflammatory and urico- ble uric acid precursors, xanthine and hypoxanthine. This phenomenon contributes to the thera- drugs also metabolized by this system should be done peutic effectiveness of allopurinol in long-term use. Because allopurinol inhibits the oxidation Oxypurinol is probably responsible for the antigout ef- of mercaptopurine and azathioprine, their individual fects of allopurinol. Oxypurinol itself is not adminis- administered doses must be decreased by as much as tered because it is not well absorbed orally. Allopurinol may also increase the toxicity of other cy- Absorption, Metabolism, and Excretion totoxic drugs (e. The actions of allopuri- Allopurinol is largely absorbed after oral ingestion, nol are not antagonized by the coadministration of sal- reaching peak blood levels in about 1 hour. Clinical Uses Indomethacin (Indocin) (see Chapter 36) exerts an- Allopurinol is especially indicated in the treatment of tiinflammatory, antipyretic, and analgesic properties. Its nisms for its efficacy, allopurinol is particularly beneficial antiinflammatory activity and ability to inhibit leuko- for patients who already have developed renal uric acid cytic phagocytosis make it particularly valuable in treat- stones, patients with excessively high urate excretion ing the early stages of gout, because a decrease in the (e. This in- Phenylbutazone (Butazolidin,Tandearil) (see Chapter jury occurs when organs that either have been trans- 36) also displays antipyretic, analgesic, and antiinflam- planted or have had their usual blood perfusion blocked matory activity. In addition, it possesses some uricosuric are reperfused with blood or an appropriate buffer so- potency and therefore is widely used for the treatment lution. The cause of this injury is local formation of free of acute attacks of gouty arthritis, in which it is about radicals, such as the superoxide anion, the hydroxyl free equal to colchicine in effectiveness. These substances are strong does promote the renal excretion of uric acid, its use- oxidants and are quite damaging to tissues. Oxyphenbutazone (Oxalid, Tandearil) is the princi- Adverse Effects pal uricosuric metabolite of phenylbutazone. It has the Common toxicities associated with allopurinol adminis- same indications and toxicities as phenylbutazone. These reactions are of- Corticosteroids ten sufficiently severe to dictate termination of drug therapy. It is advised that therapy not be initiated dur- The use of corticosteroids is often suggested for elderly ing an acute attack of gouty arthritis.

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There is Two venous systems drain the hemisphere treatment multiple sclerosis purchase prothiaden 75mg amex, one me- considerable variation in its cortical branches treatment 5th finger fracture buy prothiaden 75mg otc. The lateral venous drainage sys- most constant is the pericallosal artery medicine 7767 75 mg prothiaden purchase free shipping, which begins tem can be divided into three groups: anterior, cen- distal to the anterior communicating artery and tral, and posterior convexity ascending systems. The callosal marginal Three veins drain the anterior convexity: the fronto- artery is usually the largest branch of the pericallosal polar, anterior frontal, and middle frontal veins. It is present in 82% of examined brains (Per- arise at the junction between the third and second lmutter and Rhoton 1978). They enter sulcus and has an inverse size relationship with the the subpolar space prior to joining the superior sag- pericallosal artery. These are as follows, tral veins run in their respective sulci in an almost from anterior to posterior: vertical fashion. The orbital frontal artery, most commonly arising noid space lateral to the venous lacuna and then from A-2 and supplying the gyrus rectus. Var- superiorly in the postcentral vein or in the superior ious authors have described landmarks for the local- sagittal sinus; (2) the posterior parietal vein, which ization of the central sulcus. All these methods suffer from then runs posteriorly on the convexity for a few cen- the inability to visualize the full extent of the central timeters, parallel to the superior sagittal sinus, prior sulcus from superior to inferior. This area contains few or no ascending even parallel to the forniceal reference plane as de- veins and is frequently used to access the anterior scribed in Chap. Posteriorly, since the later- my can be easily and precisely displayed, including al occipital vein is directed anteriorly, no large vein the finer morphological details. This approach is enters the superior sagittal sinus for a distance of 4– easily obtainable on nearly all available imaging 5 cm proximal to the torcula. Because the whole extent of the central sulcus is displayed, we think 2 The Mesial Venous Drainage System that this approach might be useful for functional techniques (refer to figures in Sect. Both assume a the reliability of these methods is beyond the scope similar distribution as their lateral counterpart. The reader is referred to selected pa- Those coursing superiorly frequently join the con- pers and reviews on the subject (Berger et al. An indirect approach has relied on skull landmarks and, subsequently, on brain refer- ence coordinates (Horsley 1892; Taylor and Haugh- ton 1900; Rowland and Mettler 1948; Matsui et al. Springer, Berlin Heidelberg New York, J Neuroradiol 23:6–18 pp 2–11 Dusser de Barenne (1924) Experimental researches on sen- Bertrand G (1956) Spinal efferent pathways from the supple- sory localization in the cerebral cortex of the monkey mentary motor area. Smith Elder, Functional activation in motor cortex reflects the direc- London tion and the degree of handedness. Trans St Andrews Bertrand G, Vanier M, Ethier R, Tyler J, de Lotbinière A Med Grad Assoc 3:162–207 (selected writings 1:8–36) (1987) Intégration de l’angiographie numérique, de la Jefferson G (1912) The morphology of the sulcus résonance magnétique, de la tomodensitométrie et de la interparietalis. Neurology 43:2311–2318 Neuroradiol 2:149–155 Rassmussen T (1969) The neurosurgical treatment of focal Matsui T, Kawamoto K, Labarre L, Imai T, Tamotsu O, Hirano epilepsy. In: Niedermeyer E (ed) Epilepsy, recent views on A (1977) Anatomical and pathological study of the brain its therapy, diagnosis and treatment. Anatomical study of the normal brain at (Moderns problems of pharmacopsychiatry, vol 4) various angles. Am J Neuroradiol 17:1699–1706 Einseidel H, Jiddane M, Farnarier P, Habib M, Perot S 138 Chapter 4 (1988) Identification of cortical sulci and gyri using mag- the topography of the convolutions and fissures of the netic resonance imaging: a preliminary study. Appl Szikla G, Bouvier G, Hori T, Petrov V (1977) Angiography of Neurophysiol 50:57–62 the human brain cortex. Springer, Berlin Heidelberg New Waterston D (1907) Complete bilateral interruption of the York fissure of Rolando. Presse Med 28:605–609 during a hand motor task in patients with brain tumor Talairach J, Szikla G, Tournoux P, Prossalentis A, Bordas- and paresis. The cortical regions adjacent to the lateral sulcus The lateral fissure or fissure of Sylvius is the major are the frontal, parietal and temporal opercula, or sulcal landmark on the lateral surface of the brain. During later embryonic stages it assumes a Lying in the depth of the horizontal segment of the horizontal course due to the dramatic expanse of the sylvian fissure is the insular lobe of Reil.

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It has been postulated that the mechanism of action of benzoyl peroxide in acne is related to its antimicrobial activity against P acnes and to its peeling and comedolytic effects medications and grapefruit interactions purchase prothiaden 75 mg online. Fixed-combination formulations of 5% benzoyl peroxide with 3% erythromycin base (Benzamycin) or 1% clindamycin (BenzaClin medicine assistance programs buy prothiaden 75 mg overnight delivery, Duac) medicine man gallery purchase prothiaden master card, and 2. Benzoyl peroxide is a potent contact sensitizer in experimental studies, and this adverse effect may occur in up to 1% of acne patients. Its mechanism of action has not been fully determined, but preliminary studies demonstrate antimicrobial activity against P acnes as well as in vitro inhibitory effects on the conversion of testosterone to dihydrotestosterone. Initial therapy is begun with once-daily applications of the 20% cream or 15% gel to the affected areas for 1 week and twice-daily applications thereafter. Most patients experience mild irritation with redness and dryness of the skin during the first week of treatment. Exacerbation of facial erythema and flushing may occur, ranging from 30 minutes to several hours after application. Alpha agonists can lower blood pressure (see2 Chapter 11); therefore, brimonidine should be used with caution in patients with severe, unstable, or uncontrolled cardiovascular disease. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug’s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. Acitretin must not be used by women who are pregnant or may become pregnant while undergoing treatment or at any time for at least 3 years after treatment is discontinued. Ethanol must be strictly avoided during treatment with acitretin and for 2 months after discontinuing therapy. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy. Adverse local effects include a burning or stinging sensation (sensory irritation) and peeling, erythema, and localized edema of the skin (irritant dermatitis). Potentiation of photosensitizing medication may occur, and patients should be cautioned to minimize sunlight exposure and to use sunscreens and protective clothing. Improvement of psoriasis was generally noted following 2 weeks of therapy, with continued improvement for up to 8 weeks of treatment. However, fewer than 10% of patients demonstrate total clearing while on calcipotriene as single-agent therapy. Adverse effects include burning, itching, and mild irritation, with dryness and erythema of the treatment area. A once-daily two-compound ointment containing calcipotriene and betamethasone dipropionate (Taclonex) is available. This combination is more effective than its individual ingredients and is well tolerated, with a safety profile similar to betamethasone dipropionate. Calcitriol (Vectical) contains 1,25-dihydroxycholecalciferol, the hormonally active form of vitamin D. Clinical studies show comparable safety data regarding adverse cutaneous and systemic reactions between topical calcitriol and calcipotriene ointment. Alefacept is an immunosuppressive agent and should not be administered to patients with clinically significant infection. Because of the possibility of an increased risk of malignancy, it should not be administered to patients with a history of systemic malignancy.

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Pharmacologic factors include (1) the kinetics of absorption 94 medications that can cause glaucoma buy prothiaden with mastercard, distribution medicine 93832 buy generic prothiaden 75mg on line, and elimination; (2) the ability of the drug to be delivered to the site of infection; (3) the potential toxicity of an agent; and (4) pharmacokinetic or pharmacodynamic interactions with other drugs medicine ball order prothiaden american express. Knowledge of the susceptibility of an organism to a specific agent in a hospital or community setting is important in the selection of empiric therapy. Pharmacokinetic differences among agents with similar antimicrobial spectrums may be exploited to reduce the frequency of dosing (eg, ceftriaxone, ertapenem, or daptomycin may be conveniently given once every 24 hours). Finally, increasing consideration is being given to the cost of antimicrobial therapy, especially when multiple agents with comparable efficacy and toxicity are available for a specific infection. Changing from intravenous to oral antibiotics for prolonged administration can be particularly cost-effective. Brief guides to empiric therapy based on presumptive microbial diagnosis and site of infection are given in Tables 51– 1 and 51–2. Sample error, eg, obtaining cultures after antimicrobial agents have been administered, inadequate volume or quantity of specimen obtained, or contamination of specimens sent for culture 2. Noncultivable or slow-growing organisms (Histoplasma capsulatum, Bartonella or Brucella species), in which cultures are often discarded before sufficient growth has occurred for detection 3. Not recognizing the need for special media or isolation techniques (eg, charcoal yeast extract agar for isolation of Legionella species, shell-vial tissue culture system for rapid isolation of cytomegalovirus) Even in the setting of a classic infectious disease for which isolation techniques have been established for decades (eg, pneumococcal pneumonia, pulmonary tuberculosis, streptococcal pharyngitis), the sensitivity of the culture technique may be inadequate to identify all cases of the disease. The results of these tests can then be correlated with known drug concentrations in various body compartments. Beta-Lactamase Assay For some bacteria (eg, Haemophilus species), the susceptibility patterns of strains are similar except for the production of β lactamase. In these cases, extensive susceptibility testing may not be required, and a direct test for β lactamase using a chromogenic β-lactam substrate (nitrocephin disk) may be substituted. Synergy Studies Synergy studies are in vitro tests that attempt to measure synergistic, additive, indifferent, or antagonistic drug interactions. In general, these tests have not been standardized and have not correlated well with clinical outcome. Cultures of specimens taken from infected sites should eventually become sterile or demonstrate eradication of the pathogen and are useful for documenting recurrence or relapse. Clinically, the patient’s systemic manifestations of infection (malaise, fever, leukocytosis) should abate, and the clinical findings should improve (eg, as shown by clearing of radiographic infiltrates or lessening hypoxemia in pneumonia). The duration of definitive therapy required for cure depends on the pathogen, the site of infection, and host factors (immunocompromised patients generally require longer courses of treatment). Precise data on duration of therapy exist for some infections (eg, streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, and cryptococcal meningitis). For recurrent infections (eg, sinusitis, urinary tract infections), longer courses of antimicrobial therapy or surgical intervention are frequently necessary for eradication. Clinical Failure of Antimicrobial Therapy When the patient has an inadequate clinical or microbiologic response to antimicrobial therapy selected by in vitro susceptibility testing, systematic investigation should be undertaken to determine the cause of failure. Errors in susceptibility testing are rare, but the original results should be confirmed by repeat testing. Drug dosing and absorption should be scrutinized and tested directly using serum measurements, pill counting, or directly observed therapy. The clinical data should be reviewed to determine whether the patient’s immune function is adequate and, if not, what can be done to maximize it. For example, are adequate numbers of granulocytes present and is undiagnosed immunodeficiency, malignancy, or malnutrition present? Finally, culture and susceptibility testing should be repeated to determine whether superinfection has occurred with another organism or whether the original pathogen has developed drug resistance. Pharmacodynamic factors include pathogen susceptibility testing, drug bactericidal versus bacteriostatic activity, drug synergism, antagonism, and postantibiotic effects. Together with pharmacokinetics, pharmacodynamic information permits the selection of optimal antimicrobial dosage regimens. Bacteriostatic versus Bactericidal Activity Antibacterial agents may be classified as bacteriostatic or bactericidal (Table 51–3). For agents that are primarily bacteriostatic, inhibitory drug concentrations are much lower than bactericidal drug concentrations. In general, cell wall- active agents are bactericidal, and drugs that inhibit protein synthesis are bacteriostatic. On the other hand, enterococci are inhibited but not killed by vancomycin, penicillin, or ampicillin used as single agents.

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There is no evidence that there is any increase in pharmacodynamic sensitivity to the therapeutic effects of the cardiac glycosides; in fact treatment laryngitis generic prothiaden 75 mg with visa, animal studies suggest a possible decrease in therapeutic sensitivity medicine jar paul mccartney discount prothiaden on line. Hypokalemia medicines 604 billion memory miracle buy prothiaden 75mg with visa, hypomagnesemia, hypoxemia (from pulmonary disease), and coronary atherosclerosis all contribute to the high incidence of digitalis-induced arrhythmias in geriatric patients. The less common toxicities of digitalis such as delirium, visual changes, and endocrine abnormalities (see Chapter 13) also occur more often in older than in younger patients. Antiarrhythmic Agents The treatment of arrhythmias in the elderly is particularly challenging because of the lack of good hemodynamic reserve, the frequency of electrolyte disturbances, and the high prevalence of significant coronary disease. Disopyramide should probably be avoided in the geriatric population because its major toxicities—antimuscarinic action, leading to voiding problems in men; and negative inotropic cardiac effects, leading to heart failure—are particularly undesirable in these patients. The clearance of lidocaine appears to be little changed, but the half-life is increased in the elderly. Although this observation implies an increase in the volume of distribution, it has been recommended that the loading dose of this drug be reduced in geriatric patients because of their greater sensitivity to its toxic effects. Recent evidence indicates that many patients with atrial fibrillation—a very common arrhythmia in the elderly—do as well with simple control of ventricular rate as with conversion to normal sinus rhythm. Measures (such as anticoagulant drugs) should be taken to reduce the risk of thromboembolism in chronic atrial fibrillation. There appears to be a reduction in host defenses in the elderly, manifested in the increase in both serious infections and cancer. In the lungs, a major age and tobacco-dependent decrease in mucociliary clearance significantly increases susceptibility to infection. In the urinary tract, the incidence of serious infection is greatly increased by urinary retention and catheterization in men. Preventive immunizations should be maintained: influenza vaccine should be given annually, tetanus toxoid every 10 years, and pneumococcal and zoster vaccines once. Since 1940, the antimicrobial drugs have contributed more to the prolongation of life than any other drug group because they can compensate to some extent for this deterioration in natural defenses. The basic principles of therapy of the elderly with these agents are no different from those applicable in younger patients and have been presented in Chapter 51. The major pharmacokinetic changes relate to decreased renal function; because most of the β-lactam, aminoglycoside, and fluoroquinolone antibiotics are excreted by this route, important changes in half-life may be expected. This is particularly important in the case of the aminoglycosides, because they cause concentration- and time-dependent toxicity in the kidney and in other organs. Rheumatoid arthritis is less exclusively a geriatric problem, but the same drug therapy is usually applicable to both types of disease. The basic principles laid down in Chapter 36 and the properties of the anti-inflammatory drugs described there apply fully here. Because they are cleared primarily by the kidneys, these drugs accumulate more rapidly in the geriatric patient and especially in the patient whose renal function is already compromised beyond the average range for his or her age. However, they consistently cause a dose- and duration-related increase in osteoporosis, an especially hazardous toxic effect in the elderly. It is not certain whether this drug-induced effect can be reduced by increased calcium and vitamin D intake, but it would be prudent to consider these agents (and bisphosphonates if osteoporosis is already present) and to encourage frequent exercise in any patient taking corticosteroids. Proprietary oral formulations of vitamins C and E, β-carotene, zinc oxide, and cupric oxide are available. Oral drugs in clinical trials include the carotenoids lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids. Two antibodies are available: bevacizumab (Avastin, used off-label) and ranibizumab (Lucentis), as well as the oligopeptide pegaptanib (Macugen). In long-term care facilities, in which a high percentage of the population is elderly, the average number of prescriptions per patient varies between 6 and 8. Studies have shown that the percentage of patients with adverse reactions increases from about 10% when a single drug is being taken to nearly 100% when 10 drugs are taken. Thus, it may be expected that about half of patients in long-term care facilities will have recognized or unrecognized reactions at some time. Patients living at home may see several different practitioners for different conditions and accumulate multiple prescriptions for drugs with overlapping actions.

Lester, 33 years: The named tributar- The posterior wall is made up of the subscapularis, teres major and ies of the axillary vein correspond to those of the axillary artery. Perform a literature search to assess the efficacy and the potential í Labs role of rifaximin in the treatment of hepatic encephalopathy. At extensive first-pass extraction in the liver, the start of therapy, a prostaglandin-medi- and there hydrolyzed to active metabolites.

Jesper, 64 years: Finally, these drugs reduce the long-term remodeling of the heart and vessels, an effect that may be responsible for the observed reduction in mortality and morbidity (see Clinical Pharmacology). In addition, clinical and entering the lower limb carry fbers from spinal cord signs (such as pain, pins-and-needles sensations, paresthe­ levels 11 to S3 (Fig. Low-dose clonidine (Dixarit 50–75 mg twice brainnoradrenaline/norepinephrineanddopamine,causing daily) also has a minor role in migraine prophylaxis, men- reserpine-like adverse effects (see above).

Steve, 53 years: They present a serious health (and 22Baber N S 2003 Complementary medicine, clinical pharmacology and economic) problem in countries with weak regulatory therapeutics [editorial]. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. Metabolism Aldosterone is secreted at the rate of 100–200 mcg/d in normal individuals with a moderate dietary salt intake.

Mamuk, 37 years: Enter patient’s demographic, drug dosing, and serum concentration/time data into the computer program. If the forces that bind Adrenaline/epinephrine and theophylline counteract drug to receptor are weak (hydrogen bonds, van der Waals bronchoconstriction produced by histamine released from bonds, electrostatic bonds), the binding will be easily and mast cells in anaphylactic shock by relaxing bronchial rapidly reversible; if the forces involved are strong (covalent smooth muscle (b2-adrenoceptor effect). Category B is for drugs that either prominently featured in the list of standard side have had no well-controlled human studies but show effects.

Ben, 59 years: They are covered in the region into three vertical columns of muscle, each of thoracic and lumbar regions by thoracolumbar fascia and which is further subdivided regionally (lumborum, thora­ the serratus posterior inferior, rhomboid, and splenius cis, cervicis, and capitis), depending on where the muscles muscles. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Toxicity in infants teria from extended antibiotic therapy will result in de- can result in mental and physical retardation, renal fail- creased vitamin K synthesis and possible deficiency.

Larson, 24 years: The function of M and M receptors in the urinary bladder appears to be the same2 3 as in intestinal smooth muscle. Liberation of histamine and other autacoids in the skin also contributes and may be responsible for much of the itch of urticarial allergic reactions. Potassium intake must be reduced, especially bumetanide (Bumex) possess some carbonic anhydrase in outpatients.

Riordian, 41 years: Hence, upper abdominal pathology such as a perfor- of part of the thoracic sympathetic chain (usually for two interspaces) ated duodenal ulcer often results in pain felt at the shoulder tip. It extends across the posterior abdominal wall from the duodenum, on the right, to the • The head of the pancreas lies within the C-shaped spleen, on the left. Reconsideration of this view was driven by recognition that the term “asthma” is applied to a variety of different disorders sharing common clinical features but fundamentally different pathophysiologic mechanisms.

Yokian, 36 years: That is, he had an indication for drug therapy but was Based on the information documented in the care plan, the practi- not receiving treatment. Theophylline increases the lithium clearance/creatinine clearance ratio by as much as 58% resulting in an average decrease of 21% in steady-state lithium concentrations. It is currently in the late stages of clinical development for the treatment of skin and soft tissue infection and health care-associated pneumonia.

Bandaro, 56 years: Progesterone by agent does have some signifcant toxic effects because itself is not used widely as a contraceptive therapy of accumulation of the drug. Because of its effects on A-V nodal and Primary route of Hepatic; active metabolite His-Purkinje conduction, procainamide should be ad- metabolism ministered with caution to patients with second-degree Primary route of 50–60% renal (unchanged) A-V block and bundle branch block. Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders.

Raid, 52 years: Quinidine clearance can be computed using a steady-state quinidine concentration: Cl = [F ⋅ S (D/τ)] / Css = [0. If certain body functions develop hyperreactivity, un- wanted effects can occur even at normal Luellmann, Color Atlas of Pharmacology © 2005 Thieme Undesirable Drug Effects 71 A. Economic evaluation of antide- pressive agents: a systematic critique of experimental and observa- tional studies.

Temmy, 57 years: Approximately 48 hours after exposure, infected William McGhee, PharmD children develop fever, vomiting, and watery diarrhea. He is receiving intravenous (B) Necrotizing enterocolitis pentamidine for suspected Pneumocystis pneumonia. It is important to aspirate fuid from these patients to relieve any respirator impairment and to carr out laborator tests on the fuid to determine its nature.

Phil, 65 years: It has been shown to have a small but significant lowering effect on total cholesterol, but only when dietary controls were not in place. This node receives lym­ lip, the chin, the floor of the mouth, the tip of the phatic drainage from the tongue. The drug is recommended as a 300 mg dose regardless of the patient’s age or weight for administration twice daily in repeated cycles of 28 days on therapy, followed by 28 days off therapy.

Owen, 30 years: Long-term use of ma- enough must be given to maintain a blood plasma level ternal indomethacin is associated with primary pul- of at least 5. When these drugs are administered concurrently with an aminoglycoside, serum creatinine concentrations should be monitored on a daily basis. Alcohol causes sedation, relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness (Table 23–1).

References

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• Abou-Khalil BW, Sackellares JC, Latock JT et al. Magnetic resonance imaging in refractory partial epilepsy. Epilepsia 25: 650, 1984.
• Kinnala A, Suhonen-Polvi H, Aarimaa T, et al. Cerebral metabolic rate for glucose during the first six months of life: an FDG positron emission tomography study. Arch Dis Child Fetal Neonatal Ed 1996;74:F153-7.
• Keskin S, Erdogan N, Kurt A, et al: Bilateral partial ureteral duplication with double collecting system in horseshoe kidney, Adv Med Sci 54:302n304, 2009.
• Boltze J, Nitzsche B, Geiger KD, et al. Histopathological Investigation of Different MCAO Modalities and Impact of Autologous Bone Marrow Mononuclear Cell Administration in an Ovine Stroke Model. Transl Stroke Res 2011;2:279-93.