By M. Emet. Fayetteville State University.

As is evident from the case studies presented purchase 25 mg acarbose amex, much reliance has been placed on reporter assays buy cheap acarbose 50mg on-line, particularly luciferase-based systems purchase acarbose 25mg on-line, rather than assays in which direct readout of either a mechanistic or pharmacological endpoint is measured. Much critique has been presented in the literature on luciferase assays, and potential confounding factors. It is also vital that appropriate deconvolution tests are carried out to rule out false-positives associated with compounds having a direct effect on luciferase such as inhibition or stabilisation. Assuming these precau- tionary measures are adequately accounted for, these along with (re) emergent technologies such as phenotypic and high-content screening57,288 and newer drug discovery platforms which comprise more physiological/ pathologically relevant systems such as patient-derived stem cell models are anticipated to be critical in providing more disease- and patient- relevant models. Whatever the assays chosen within projects, it is critical that appropriate validation occurs to determine (for example) the extent of modulation (level and duration) required of a new target in order to establish therapeutic benet in the clinic. Of the examples described here, the compounds that View Online 326 Chapter 11 have progressed to clinical studies are rst generation, and so will provide valuable information on these pharmacodynamic aspects. Coupled with the increase in disease-relevant screening systems, rene- ment of corporate screening sets in order to remove problem compounds must continue. While this will restrict the number of compounds screened it should also improve the quality of hits obtained, thereby reducing down- stream attrition. All too frequently within drug discovery programmes, and despite the greater emphasis in modern pharmaceutical and biotechnology companies on improving compound quality, problems with molecules which are either false-positives or unsuitable for further development persist. Appropriate forward-thinking synthetic strategies within medicinal chem- istry teams will widen the structural diversity of molecules tested, while oen the incorporation of relatively simple cross-checks into screening cascades can help ensure rapid elimination of unsuitable molecules that would otherwise lead to project and clinical trial failures, and potentially setting back discovery efforts in rare diseases many years. Otherwise the disturbing possibility exists that the failure of an ‘unsuitable’ compound in clinical trials may discourage further efforts on an otherwise feasible mechanism for the treatment of a particular disease. The two case studies described here, as well as being representative of the rapid and merciless progression of both diseases present in a paedi- atric population, and it is critically important to establish as soon as possible the appropriate clinical trial inclusion criteria so that the chances of seeing therapeutic benet are maximised. Cohort size, as with any clinical trial, will also play a crucial role, as will availability of the appropriate patient groups – by denition the diseases are rare and so the patient numbers will be limited. What is clear at this stage is that there are two clear emergent paradigms for curative treatment of rare neuromuscular disease, as opposed to the development of improved symptomatic treatments. The rst of these is predicated on inventing a therapy to treat the disease’s underlying cause, in these cases this being a genetic mutation. Approaches using oligonucleotides to enable exon skipping, or employing small-molecule read-through agents, have made fantastic progress, and are starting to deliver encouraging results in later stage clinical trials. However, the possibility of the disease encom- passing a more heterogeneous group of sufferers with multiple mutations limits the applicability of each specic therapy to a smaller subset of patients. The alternative is, through a detailed knowledge of the disease in question, to identify a therapeutic approach which is independent of the primary lesion. While this may be more technically challenging, and relies on the existence of an appropriate redundant/compensatory mechanism to target, the advantages are hugely signicant, in that the opportunity for treatment of all patients becomes potentially viable. View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 327 There is of course a middle ground, in which a combination of drugs, each addressing a specic point in progression of the disease is used, or simply one in which an established symptomatic treatment is partnered with an emerging disease-modifying drug; examples of both of these paradigms having been summarised in the preceding text. In reality, this latter approach is likely to be the rst to be reduced to clinical practice and receive regulatory approval, with combinations of disease-modifying agents coming next, subject of course to the appropriate combination clinical trials taking place rst. This pathway parallels established development pathways, which have taken place in other therapeutic areas such as the oncology and anti-infective elds. Over the past decades pioneering work has taken place to elucidate the underlying pathological mechanisms of many rare neuromuscular diseases. This in turn has inspired the development of several truly innovative thera- peutic strategies aimed at correcting the underlying pathology. Acknowledgements The authors wish to thank Professor Dame Kay Davies, Professor Steve Davies and Dr Robert Westwood for helpful advice and comments, and for proof- reading this manuscript. Databases: Chemical Abstracts and PubMed; searched using the search terms ‘Duchenne Muscular Dystrophy’ and ‘Spinal Muscular Atrophy’ respectively. Bivona, Duchenne Muscular Dystrophy Drug could Unlock Huge Potential for this Pharmaceutical, http://beta. Tatem, View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 329 K. Summit Outlines Clinical Development Plans For Utrophin Modulator Programme For Duchenne Muscular Dystrophy, http://www. Dansette, in The Practice of Medicinal Chemistry, 3rd edition Academic Press, 2008, pp. Summit Outlines Clinical Development Plans for Utrophin Modulator Programme for Duchenne Muscular Dystrophy, http://www. Janssen, Identication of Compounds Enhancing Utrophin Expression in Primary Human Skeletal Muscle Cells, http://www. Pzer Licenses Families of Spinal Muscular Atrophy Quinazoline Drug Program from Repligen, http://www. Improved precision in isolation, purication, char- acterisation and production have increased the availability of these secondary metabolites to explore their inherent chemical and biological diversity.

Blocks myocardial excitability by reducing membrane conductance of sodium and potassium ions effective acarbose 25mg. Adjustment of dosage • Kidney disease: Creatinine clearance <30 mL/min: 50% of normal dose should be administered buy acarbose 50mg low cost. Warnings/precautions • Use with caution in patients with heart failure discount acarbose 50mg line, kidney or liver disease. Advice to patient • Take missed drug as soon as remembered if within 4 hours of previous drug. Clinically important drug interactions: Drugs that increase effects/ toxicity of tocainide: lidocaine, metoprolol, rifampin. Editorial comments • Tocainide is not often used because its side effects overshadow its efficacy as an antiarrhythmic. If the patient develops any signs of infection or excessive bruising or bleeding, complete blood counts should be performed promptly. If a hematologic disorder has been identified as being responsible, tocainide should be discontinued. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effective- ness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Stimulates release of insulin from pancre- atic beta cells; decreases glucose production in liver; increases sensitivity of receptors for insulin, thereby enhancing effec- tiveness of insulin. Dose is best administered before breakfast or, if taken twice a day, before the evening meal. Contraindications: Hypersensitivity to the drug, diabetes com- plicated by ketoacidosis. Editorial comments • This drug is listed without details in the Physician’s Desk Reference, 54th edition, 2000. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Indications/dosage/route • Rheumatoid arthritis, osteoarthritis Ð Adults: 400 mg t. Mechanism of action: Inhibits sodium and chloride reabsorp- tion in proximal part of ascending loop of Henle. Contraindications: Hypersensitivity to sulfonamides, anuria, hepa- tic coma, severe electrolyte depletion. Editorial comments • Torsemide has the advantage of a safer pregnancy category than other loop diuretics. Mechanism of action: Most likely produces analgesia by binding to opioid receptors. Adjustment of dosage • Kidney disease: Creatinine clearance <30 mL/min: 50–100 mg q12h. Contraindications: Hypersensitivity to tramadol or opioids; acute intoxication with alcohol; other analgesics, opioids, hypnotics, or psychotropic agents. There is an increased risk in patients with conditions that predispose to seizures, eg, head injury. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Adverse reactions • Common: dizziness, vertigo, headache, nausea, constipation, somnolence. In some clinical trials, tramadol was comparable or superior to adult dosages of codeine with/without acetaminophen. Use caution if administering to individuals with a prior history of opioid dependence or abuse of other drugs. Chronic dosage should be at lowest effective dose; downward titration is suggested. American Aca- demy of Pediatrics expresses concern regarding use of trazadone while breastfeeding. Warnings/precautions: Use with caution in patients with car- diac disease, risk of suicide. Adverse reactions • Common: dry mouth, dizziness, drowsiness, fatigue, insomnia, anxiety, nausea. Clinically important drug interactions: Trazodone increases effects/ toxicity of digoxin, phenytoin. Mechanism of action: Acts on distal renal tubules to inhibit sodium– potassium exchange.

Vasopressin may compromise mesenteric blood flow best acarbose 50 mg, and some studies suggest its use concomitantly with dobutamine (with or without norepinephrine) to antagonize this effect order acarbose 25 mg on-line. Dosing Vasopressin is to be administered exclusively parenterally as a bolus or as a continuous infusion and should be titrated within the therapeutic range and to the minimal effective dose until the desired response is achieved proven acarbose 25mg. Furthermore, fluid intake and output, urine specific gravity, and urine and serum osmolality should be carefully monitored. After 12 hours of stability, withdraw over 24 to 48 hours Ventricular Fibrillation or Tachycardia Unresponsive to Initial Defibrillation Adults: a single dose of 40 units, I. Pharmacokinetics Onset of action: 1 hour Duration: 2 to 8 hours Metabolism: most of the drug is rapidly metabolized in the liver and kidneys Protein binding: 10 to 40% Half-life: 10 to 20 minutes Drug Interactions Chlorpropamide, carbamazepine, hydrocortisone, clofibrate, and tricyclic anti- depressants may increase vasopressin effect. Demeclocycline, heparin, lithium, epinephrine, and alcohol may decrease vasopressin effect. Adverse Effects Cardiovascular: hypertension, bradycardia, arrhythmia, venous thrombosis, vasoconstriction, angina, heart block, cardiac arrest (all of the above with high doses); pallor Central nervous system: vertigo, headache, fever, seizures (careful use in case of background of epileptic activity) 58 Eduardo da Cruz and P. Rimensberger Cutaneous: tissue necrosis (extravasation), urticaria Endocrine and metabolic: water intoxication, hyponatremia Gastrointestinal: abdominal cramps, nausea, vomiting, diarrhea; vaso- pressin may induce vasoconstriction of the splanchnic region that may be compensated by dobutamine97 Neuromuscular and skeletal: tremor Respiratory: wheezing, bronchospasm Renal: careful use in patients with renal dysfunction, chronic nephritis Hepatic: patients with chronic liver disease might require a downward dose adjustment Others: diaphoresis Poisoning Information Adverse effects caused by excessive doses or altered pharmacokinetics of vaso- pressin may be observed. In these circumstances, it is recommended to decrease temporarily or even withdraw the drug and treat symptomatically (significant individual variability). In case of extravasation, local administration of phen- tolamine or papaverine should be considered. It should be administered into a central vein, except in urgent scenarios, with an infusion device allowing proper and reliable titration. Phenylephrine Indication Phenylephrine is an α-adrenergic agonist agent with a sympathomimetic effect in various systems, mainly circulatory, ophthalmic, and nasal. In the cardio- vascular patient, it is used as a pure vasoconstrictor drug to treat hypotension and low vascular resistance in distributive shock98–100, to treat supraventricu- lar arrhythmias101–103, and it is particularly useful for the treatment of hypoxic spells in tetralogy of Fallot patients unresponsive to sedation, volume loading, and/or β-blockade104, 105. It may also be used as a vasoconstrictor in regional anesthesia, for symptomatic relief of nasal and nasopharyngeal mucosal conges- tion, and as a mydriatic agent for ophthalmic procedures. Mechanisms of Action Phenylephrine is a potent α agonist (α-adrenergic stimulator) with a very mild β-adrenergic activity. Therefore, it produces systemic arterial vasoconstriction, causes vasoconstriction of the nasal and conjunctival arterioles, and stimulates the dilator muscle of the pupil producing mydriasis. Inotropic and Vasoactive Drugs 59 Dosing Phenylephrine is to be used as a bolus or as a continuous infusion and should be titrated within the therapeutic range and to the minimal effective dose until the desired response is achieved. Severe Hypotension, Hypoxic Spells in Tetralogy of Fallot, and Vasoplegic Shock Neonates, infants, and children: I. Sympathomimetic agents and halogenated anesthetics may increase the effect of phenylephrine and cause tachycardia or arrhythmia. Rimensberger α- and β-adrenergic blocking agents may decrease the effect of phenylephrine. Adverse Effects Cardiovascular: hypertension, angina, severe reflex sinus bradycardia, arrhythmias, severe peripheral vasoconstriction. Phenylephrine is con- traindicated in cases of severe hypertension, pheochromocytoma, ventricular arrhythmias, and myocardial disease Respiratory: dryness, sneezing, rebound nasal congestion, dyspnea Central nervous system: restlessness, nervousness, headache, anxiety, dizziness Cutaneous: dermal necrosis (extravasation), skin blanching, piloerection Neuromuscular and skeletal: tremor Ocular: blurred vision, lacrimation, photophobia, stinging. Phenylephrine is contraindicated in cases of narrow-angle glaucoma Gastrointestinal: Phenylephrine is contraindicated in cases of pancreatitis, hepatitis, and mesenteric vascular disease106, 107 Renal: Phenylephrine may reduce renal flow and urine output Poisoning Information Adverse effects caused by excessive doses or altered pharmacokinetics of phenylephrine may be observed. In these circumstances, it is recommended to decrease temporarily or even withdraw the drug and treat symptomatically (significant individual variability). In case of extravasation, local administra- tion of phentolamine or papaverine should be considered. Compatible Diluents Phenylephrine is compatible with normal saline, dextrose solutions, and Ringer’s lactate. It should be administered into a central vein, except in urgent scenarios, with an infusion device allowing proper and reliable titration. Metaraminol Indication Metaraminol, also called hydroxynorephedrine or metaradrine, is an α-adrenergic agonist with a weak β-receptor stimulating action used for the prevention or treatment of acute hypotension, throughout cardiopulmonary bypass proce- dures, spinal anesthesia interventions, or in vasoplegic shock states unresponsive to fluid replacement108–113. Inotropic and Vasoactive Drugs 61 Mechanisms of Action Metaraminol stimulates α-adrenergic receptors producing systemic arterial vasoconstriction. It also exerts a weak effect on β1-adrenergic receptors, resulting in increased contractility and heart rate. The increased vagal activity occurring as a reflex to increased blood pressure predominates over the chronotropic effect, because bradycardia may occur. Dosing Metaraminol is to be used as a bolus or as a continuous infusion and should be titrated within the therapeutic range and to the minimal effective dose, until the desired response is achieved. Treatment of Severe Hypotension or Vasoplegic Shock Neonates, infants, and children: loading dose of 0. Adverse Effects Cardiovascular: hypertension, tachycardia, bradycardia, palpitations, car- diac arrhythmias, cardiac arrest Central nervous system: headache, apprehension, dizziness, insomnia Gastrointestinal: nausea, vomiting; careful use in patients with cirrhosis or mesenteric thrombotic disease Metabolic: careful use in diabetes mellitus or thyroid disease Cutaneous: dermal necrosis (extravasation), sloughing or abscess forma- tion at the site of injection Neuromuscular and skeletal: tremors Other: diaphoresis, may activate a relapse in patients with a background of malaria and Mediterranean fever (used for provocation tests) Poisoning Information Adverse effects caused by excessive doses or altered pharmacokinetics of metaraminol may be observed. In these circumstances, it is recommended to decrease temporarily or even withdraw the drug and treat symptomatically (significant individual variability). In case of extravasation, local administration of phen- tolamine or papaverine should be considered. Compatible Diluents Metaraminol is stable for 24 hours when diluted in normal saline, dextrose solutions, or Ringer’s lactate.