The use of levodopa is contraindicated in patients with psychosis order altace 10 mg online hypertension follow up, narrow-angle glaucoma discount 10 mg altace visa blood pressure chart 5 year old, and peptic ulcer disease order generic altace on line blood pressure medication voltaren. Characteristics (1) Pramipexole is a relatively selective dopamine D3-receptor agonist; ropinirole is a relatively selective dopamine D2-receptor agonist; bromocriptine is a dopamine D2- (and D1-) receptor agonist. Adverse effects (1) These drugs have the same adverse effects, cautions, and contraindications as levodopa, although the severity of their effects may differ. Adverse effects (1) Amantadine is associated with a reversible occasional headache, insomnia, confusion, hallucinations, and peripheral edema. Selegiline causes an occasional mild am- phetamine-like stimulating action (amphetamine is one of the metabolites). It decreases metabolism of levodopa to make more available to the brain; Tolcapone acts in the periphery and the brain. Entacapone, in a combined product (Stalevo), is used to augment the effect of carbidopa/ levodopa. Entacapone is preferred because tolca- pone has been associated (rarely) with acute, fatal hepatic failure. These drugs can exacerbate dysphoria, nausea, and other adverse effects of levodopa; downward dose adjustment of levodopa is necessary. They have a significant effect on tremor and rigidity but little effect on bradykinesia and postural reflexes. Adverse effects, contraindications, and drug interactions (1) These drugs are associated with occasional restlessness, sedation, confusion, mood changes, dry mouth, mydriasis, constipation, tachycardia, and arrhythmias. These drugs have only a short-term, modest effect and do nothing to halt the progression of neurodegeneration. It may take weeks to establish adequate drug plasma levels and to determine the adequacy of therapeutic improvement. Addition of a second drug to the therapeutic regimen should be gradual, as should discon- tinuance of the initial drug before the substitution of an alternative drug, because seizures may occur on withdrawal. This may call for the reduction or termination of ther- apy during pregnancy or before planned pregnancy. Epilepsies are characterized by either focal or generalized abnormal neuronal discharges. Drug selection, based on seizure classification, is listed below in the order of general choice. Complex: Localized discharge that becomes widespread; accompanied by loss of consciousness (1) Phenytoin, carbamazepine, lamotrigine (2) Valproic acid, phenobarbital 2. Absence (petit mal): Sudden onset of altered consciousness that lasts 10–45 seconds, with up to hundreds of seizures per day; begins in childhood or adolescence (1) Ethosuximide (2) Valproic acid (when absence seizures coexist with tonic-clonic seizures) (3) clonazepam, lamotrigine, topiramate c. Status epilepticus: Prolonged seizure (>20 min) of any of the types previously described; the most common is life-threatening generalized tonic-clonic status epilepticus. Phenytoin, carbamazepine, valproic acid, and lamotrigine block sodium channels and inhibit the generation of action potentials. Ethosuximide reduces the low-threshold T-type Ca2+ current that provides the pacemaker ac- tivity in the thalamus. Phenytoin is absorbed well after oral administration, but its rate and extent of absorption can be altered considerably by its formulation. Phenytoin is metabolized by microsomal enzymes and excreted primarily as glucuronide. In some patients, meta- bolic enzymes become saturated at low doses, and half-life increases as the dose and plasma concentration increase, resulting in a steady-state mean plasma concentration that varies disproportionately with dose (Fig. A steep dose response and low therapeutic index require that phenytoin plasma levels be carefully monitored. Fosphenytoin is available for parenteral administration as a replacement for phenytoin. Common: Nystagmus (occurs early), diplopia and ataxia (most common), slurred speech, blurred vision, mental confusion, hirsutism (an issue particularly for females), gingival hyperplasia (can be minimized with good dental hygiene) b. Rare: With long-term use, coarsening of facial features, with mild peripheral neuropathy, and osteomalacia; idiosyncratic reactions requiring drug discontinuance (e. Fetal malformation (‘‘fetal hydantoin syndrome’’) includes growth retardation, microence- phaly, and craniofacial abnormalities (e. The plasma concentration of phenytoin is increased by drugs that inhibit its hepatic metab- olism (e. The plasma concentration of phenytoin is decreased by drugs that stimulate hepatic metab- olism (e. Carbamazepine has good oral absorption although there is significant interpatient variabil- ity in its rate of absorption. Nonlinear accumulation and variable serum levels of phenytoin dosage among different patients. Carbamazepine induces microsomal enzymes and increases its own hepatic clearance (autometabolism), thus reducing its half-life from more than 30 hours to less than 20 hours. Carbamazepine is the drug of choice to treat trigeminal neuralgia and other pain syndromes (phenytoin is occasionally used); it is also used to treat bipolar affective disorder. Oxcarbazepine is a prodrug whose actions are similar to those of carbamazepine; it has a short half-life of 1–2 hours. It may have a better adverse effect profile and be a less potent inducer of hepatic microsomal enzymes than carbamazepine. Carbamazepine induces microsomal enzymes and increases the hepatic clearance of numerous drugs including phenytoin and valproic acid. Plasma concentration of carbamazepine is increased by numerous drugs that inhibit he- patic metabolism. Valproic acid is also used to treat bipolar affective disorder and is used for migraine prophylaxis. Valproic acid inhibits the metabolism of other drugs including phenytoin and carbamazepine. Divalproex sodium (Depakote) is a 1:1 enteric formulation of valproic acid and valproate so- dium that is absorbed more slowly than valproic acid and is often preferred by patients. Rare: Idiosyncratic hepatotoxicity; may be fatal in infants and in patients using multiple anticonvulsants. Fetal malformations: Spina bifida; orofacial and cardiovascular anomalies have been reported. Although it is effective in fewer patients with absence seizures than valproic acid, ethosuxi- mide is often the drug of choice because of its greater safety. Phenobarbital at less than hypnotic doses is used most often as a first-line drug for neonatal seizures and for maintenance control of status epilepticus. Benzodiazepines: Diazepam, lorazepam, clonazepam, and clorazepate (see also I B) 1. Diazepam and lorazepam are highly effective in short-term treatment of status epilepticus. Other anticonvulsant agents (for partial and generalized tonic-clonic seizures) 1. Adverse effects include headache, ataxia, dizziness, and (rarely) a rash that may be life- threatening, particularly in children. It suppresses weight loss and has been used to treat patients with eating disorders.
Control of epilepsy with phenytoin can be a difﬁcult and lengthy process because of the wide range of doses required by different patients and the drug’s narrow therapeutic index purchase altace us arrhythmia 18 years old. Similarly best 5 mg altace hypertension kidney pain, appropriate doses of carbamazepine take time to deter- mine because of the drug’s variable effects on patient metabolism and its potential neurologic side effects safe altace 2.5 mg sinus arrhythmia icd 10. People with epilepsy are genetically different from one another, and some of those differences affect their responses to drugs in a predict- able manner. Detection of these gene variants might identify in advance, which patients will need the higher dose and enable a more optimal dose schedule at the start. These new ﬁndings provide a direction for a dosing scheme that could be tested in a clinical trial to assess whether pharmacogenetic testing can improve dosing decisions. Transcranial magnetic stimulation is useful for investigating the effects of genetic variants on cortical excitability and pharmacoresponse. Pharmacogenetic factors have been implicated in immune-mediated or hypersensitivity reactions. Drug Resistance in Epilepsy One of the problems with current therapy of epilepsy is development of drug resis- tance. One third of patients with epilepsy develop resistance to drugs, which is associated with an increased risk of death and debilitating psychosocial conse- quences. Multiple seizures prior to diagnosis, correlated with epilepsy type as well as intrinsic severity, are risk factors for development of drug resistance. Universal Free E-Book Store 432 12 Personalized Management of Neurological Disorders Neuroinﬂammation also plays a key role of in the pathophysiology of resistant epi- lepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance. Further studies in this direction might eventually enable the drugs to be tailored to the patient’s proﬁle. These data suggest that study of changes in ion channel pharmacology and their contribution to the loss of anticonvulsant drug efﬁcacy in human epilepsy may provide an important impe- tus for the development of novel anticonvulsants speciﬁcally targeted to modiﬁed ion channels in the epileptic brain. It is possible to use human tissue for the demon- stration of drug resistance in an in vitro preparation, providing a unique tool in the search for novel, more efﬁcient anticonvulsants. Another mechanism underlying drug resistance in epilepsy may be the same as in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic substances by actively exporting the offending compounds. Use-dependent blockade of the fast Na current in dentate granule cells by carbamazepine is lost in hippocampi resected from patients with carbamazepine-resistant temporal-lobe epilepsy, although this ﬁnding does not extend to lamotrigine, which has a pharmacologic action similar to that of carbamazepine. Whether these changes result in reduced sensitivity to antiepileptic drugs that Universal Free E-Book Store Personalized Management of Epilepsy 433 act on the receptor is unknown. The hypothesis cannot account for the observation that patients often have epilepsy that is resistant to multiple drugs with different modes of action, although it cannot be ruled out that alteration in drug targets may play a contributory role. Once a patient’s epilepsy is recognized to be drug resistant, a personalized treat- ment plan should be formulated to limit any cognitive deterioration or psychosocial dysfunction. Conditions commonly associated with treatment-resistant epilepsy, such as anxiety, depression, and cognitive and memory disturbances, should be rec- ognized and treated. Surgery is considered as an option in drug-resistant epilepsy and the decision to offer surgical treatment requires an individualized risk-beneﬁt assessment. Several surgical procedures can be performed, depending on the indication (Kwan et al. Corpus callosotomy is usually performed in children with clinically signiﬁcant learning disabilities and severe generalized epilepsy. In hemispherectomy an extensively diseased and epileptogenic cerebral hemi- sphere is removed or functionally disconnected. An Algorithm for Personalized Management of Epilepsy Several stratiﬁcation approaches to address the therapeutic challenges in epilepsy, take into consideration several investigations including pharmacogenomic and pharmacogenetic studies (Walker et al. An algorithm used by the author for personalized management of epilepsy is shown in Fig. Future drugs may be designed speciﬁcally according to the electrophysiological dysfunction as personalized medicines for epilepsy. Several new drugs are in development but there is still need for better drugs and strategies to overcome drug resistance. The knowl- edge that multidrug transporters are increased in epileptogenic areas opens potential new avenues for therapeutic intervention. Drugs can be developed to inhibit or bypass overexpressed transporters or implantable devices can be used to deliver high concentrations of drugs directly into the epileptogenic brain parenchyma. However, there is a lack of good correspon- dence between results from different laboratories, and more recent ﬁndings are awaiting attempts at conﬁrmation. Different neuroimaging techniques may provide combined measurements that may become these biomarkers. Personalized Management of Migraine Migraine is a paroxysmal neurological disorder affecting up to 12 % of males and 24 % of females in the general population. Improvements in prophylactic treatment of migraine patients are desirable because the drugs currently available are not effec- tive in all patients, allow recurrence of the headache in a high percentage of patients and sometimes have severe adverse side effects. Genes involved in neurological, vascular, and hormonal pathways have been implicated in predisposing individuals to migraine. Genetic proﬁling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. Pharmacogenomics of Migraine The development of International Hap Map project could provide a powerful tool for identiﬁcation of the candidate genes in this complex disease and pharmacoge- nomics research could be the promise for individualized treatments and prevention of adverse drug response (Piane et al. The pathophysiology of migraine is not well understood, and although some gene mutations have been associated with special forms of migraine, genetic inﬂu- ences on common migraine at the population level were previously unknown. These two genes are not associated with more common migraine syndromes and are not the most common hemiplegic migraine genes. However, the work on migraine can also have implications for the increasing number of additional neurological episodic dis- orders with the common denominator of channelopathy. Individualization of Use of Triptans for Migraine With a large number of triptans now available, it may be possible to match indi- vidual patient needs with the speciﬁc characteristics of the individual triptans to optimize therapeutic beneﬁt. Pharmacogenetics provides the possibility of tailoring the therapeutic approach to individual patients, in order to maximize treatment efﬁ- cacy while minimizing the potential for unwanted side-effects (Buzzi 2008 ). Pain relief by triptans is signiﬁcantly modulated by a common genetic variant − G protein beta3 (Schürks et al. Genetic proﬁling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. Pharmacogenomics will most likely provide a stronger scientiﬁc basis for optimiz- ing triptan therapy on the basis of each patient’s genetic constitution (Tfelt-Hansen and Brøsen 2008; Tfelt-Hansen 2009 ). Pharmacogenomics may help in rationalizing triptan administration according to characterization of an individual’s genomic proﬁle. Although some genetic factors inﬂuence drug response, prediction of therapy response with adequate predictive power requires a systematic approach to genetic association studies due to complexity of the ﬁeld (Gentile et al. Multitarget Therapeutics for Personalized Treatment of Headache Migraine is a special type of headache.
Another advantage of this approach is that the same nanoparticles used to detect the tumors can be used to deliver stronger doses of anticancer drugs directly to the tumor site without systemic toxicity order 2.5mg altace overnight delivery heart attack high the honeymoon is over. This fulﬁlls some of the important components of personalized cancer therapy: early detection proven 2.5 mg altace hypertension 2 nigerian movie, combi- nation of diagnostics with therapeutics and monitoring of efﬁcacy of therapy order altace without prescription blood pressure medication for young adults. Specialized chemistry techniques enable precise control over the physical and chemical properties of the dendrimers. They are most useful in drug delivery but can also be used for the development of new pharmaceuticals with novel activities. Design of Future Personalized Cancer Therapies A better understanding of cancer biology would enhance the design of future thera- pies for cancer. Future targets for cancer therapies may include defective proto-oncogenes or the tumor suppressor genes themselves. A gene therapy strategy might be employed to correct or replace the defective gene. In cancers with multi- factorial etiology, it may be possible to interrupt one or two steps in the complex pathways, thereby hindering the overall evolution of the tumor. Studies using serial analysis of gene expression have shown that tumor and normal endothelium are distinct at the molecular level, a ﬁnding that may have signiﬁcant implications for the development of antiangiogenic therapies. Mutant mice lacking cyclin D1 are entirely resistant to breast tumors induced by neu and ras, genes implicated in most human breast cancers, but are susceptible to those tumors caused by the other oncogenes c-myc and Wnt-1. Although it remains to be seen whether these ﬁndings translate to humans, the results suggest that human breast cancers caused by neu and ras could be treated with anti-cyclin D1 therapy. Use of emerging technologies in early clinical trials is allowing quick assessment of the efﬁcacy of anticancer agents. Cyclacel Ltd has introduced the concept of assembling a toolkit that will allow rational drug development rather than a “trial and error” method. Identiﬁcation of speciﬁc biomarker molecules in tumor tissue will permit prediction of clinical outcomes in response to drug treatment. The cancer clinical trial toolkit, including biomarkers that can detect antitumor activity of anticancer agents, can guide selection of patients for speciﬁc drug treatments. Universal Free E-Book Store 258 10 Personalized Therapy of Cancer Personalized Therapy of Cancer Based on Cancer Stem Cells Cancers may rely on “cancer stem cells” that share the self-renewal feature of nor- mal stem cells. This has changed the perspective with regard to new approaches for treating cancer. Cancer stem cells are slow-dividing and inherently drug- resistant, and their eradication would be necessary for long-term success in cancer treatment. The cancer stem cell concept could be used to better tailor treatment strategies to individual patients. Most traditional anticancer agents affect primarily bulk tumor cells by disrupting their proliferation and/or survival. Cancer stem cells are less likely to be killed than bulk tumor cells by these approaches. Improved methods will be required to identify, isolate and genetically proﬁle the stem cell population in cancers from individual patients. Cancer stem cells, ampliﬁed from individual clinical specimens, should be tested for gene expression proﬁles and sensitivity to a battery of agents, leading to indi- vidualized decisions on selection of the best therapeutic strategies. The antineoplas- tic agents of the future will have to target the ancient developmental molecular pathways on which stem cells depend on for replication and survival. Thus, an improved understanding of these pathways and their roles in cancer stem cells could lead to a new generation of more selective and effective antineoplastic treatments. Role of Epigenetics in Development of Personalized Cancer Therapies In addition to having genetic causes, cancer is also an epigenetic disease. Epigenetic regulation of gene transcription is emerged a key biological determinant of cellular differentiation and plays a signiﬁcant patho- genic role in a number of human diseases, particularly cancer. Disruption of the activity of disease-associated epigenetic enzymes offers a mechanism-based opportunity for pharmacologic intervention in diseases such as cancer. When used in combination with conventional chemotherapeutic agents, epigenetic- based therapies may provide a means to sensitize drug-resistant tumors to estab- lished treatments. Universal Free E-Book Store Design of Future Personalized Cancer Therapies 259 Epizyme Inc is focused on discovering novel, small molecule drugs that act as selective inhibitors of key epigenetic enzymes. Once the methyl group has been deposited on the histone site, the affected genes continue to be regu- lated (turned on or off) until this chemical unit is removed by other enzymes, known as histone demethylases. Aberrant epigenetic modiﬁcations are frequently associated with distinct cancer types and have potential utility as biomarkers. Selective Destruction of Cancer Cells While Sparing Normal Cells A problem with conventional chemotherapy or radiotherapy is that damage is not limited to cancer cells but involves normal cells as well. It is easy to kill cells in vitro and many new anticancer drugs are being discovered. However, it is difﬁcult to selectively kill cancer cells in vivo without harming normal cells. Even though some success is achieved in animal experiments, it is difﬁcult to translate these ﬁndings into practical management of cancer patients. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from inter- nal sources when external nutrients are unavailable. In contrast, normal cells can adapt to the nutrient stress that kills cancer cells by becoming quiescent and cata- bolic. It is well recognized that hypoxia inﬂuences the response of cells and tissues to radiation and increases the resistance of cancer to radiother- apy requiring higher radiation doses that can normal tissues. Cancer cells adapt to this stress to survive, and may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Therefore, targeting this non-oncogene dependency may result in selective death of cancer cells. A cell-based small-molecule screening and quantitative pro- teomics approach led to the unbiased identiﬁcation of piperlongumine, a small mol- ecule that selectively kills cancer cells but not normal cells (Raj et al. Signiﬁcant antitu- mor effects were observed in mouse xenograft tumor models treated with piper- longumine, but no toxic effects were observed in normal mice. Moreover, piperlongumine inhibits the growth of spontaneous breast cancers in mice. These ﬁndings show that ability a small molecule can selectively induce apoptosis in cells that have a cancer genotype by targeting a non-oncogene dependency acquired through the expression of the cancer genotype in response to oxidative stress induced by malignant transformation. Initial trial with the drug will be a study in patients with breast or ovarian cancers to determine a safe dose. Role of Oncoproteomics in Personalized Therapy of Cancer Clinical proteomics is an exciting new subdiscipline of proteomics that involves the application of proteomic technologies at the bedside, and cancer, in particular, is a model disease for studying such applications. Oncoproteomics is the term used for application of proteomic technologies in oncology.
Y. Deckard. Marymount University.