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STUDENT DIGITAL NEWSLETTER ALAGAPPA INSTITUTIONS |
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This one example demonstrates the importance of employing a battery of models in an initial screening protocol to avoid inadvertently "missing" a potentially important new therapy erectile dysfunction over 40 buy silagra 50mg line. However erectile dysfunction doctors in st. louis buy generic silagra 100 mg line, clinical experience has shown that this is an invalid prediction; for example erectile dysfunction causes tiredness order 100mg silagra overnight delivery, phenobarbital list all erectile dysfunction drugs order silagra 100 mg with mastercard, gabapentin what causes erectile dysfunction yahoo discount silagra 50mg otc, pregabalin erectile dysfunction what age does it start purchase silagra 50mg visa, and tiagabine are not only ineffective, they all aggravate spikeÂwave seizure discharge. These results suggest that pharmacodynamic factors were responsible for the severe adverse effects observed in patients with epilepsy. Thus, this phenomenon appears to represent a permanent reactivity specific for limbic kindling because it has not been observed after chemical kindling (20). This information should be used to guide decisions regarding the advancement of one analog over another when testing a series of structurally related molecules. Regardless of the approach by which a new drug is synthesized, the first proof-of-concept study almost always involves testing it in one or more of the animal models described above;. A further evaluation found levetiracetam to possess anticonvulsant properties in the amygdala kindled rat and to display a marked and persistent ability to inhibit kindling acquisition (15,22,23). Levetiracetam was also shown to be active in the mouse 6 Hz psychomotor seizure model (13). Levetiracetam further exemplifies that it is important to use a battery of models during random screening of new chemical entities that include animal models with (i) an acquired, kindled, alteration in seizure threshold and (ii) induced or natural mutations associated with an altered seizure threshold or spontaneous seizure expression (26). Fortunately for the patient with epilepsy, these models have yielded several new drugs that have proven to be effective for the treatment of their seizures. Clinical experience has demonstrated that they are effective for a large fraction of the patients with partial, generalized, and secondarily generalized seizures. Unfortunately, there still remains a substantial need for the identification of therapies for the patient with refractory seizures. Thus, the identification and characterization of one or more model systems that would predict efficacy in the pharmacoresistant patient population would be a valuable asset to the epilepsy community. The experimental epilepsy community will not know which model is the most relevant until the time a drug is found that markedly reduces the incidence of therapy-resistant epilepsy. Only then will we be able to retrospectively determine which model predicts efficacy against refractory seizures. At the present time, there are a number of potentially interesting model systems of therapy resistance available. In recent years, there have been a number of in vivo model systems characterized that display a phenotype consistent with pharmacoresistant epilepsy (see Ref. This is not to imply that other approaches using in vitro systems are of any less value and the reader is referred to Refs. The lowfrequency, long-duration stimulus results in a seizure that is characterized by immobility, forelimb clonus, Straub tail, and facial automatisms and is thought to more closely model human limbic seizures (13,50,51). Interestingly, the pharmacological profile of the 6 Hz model is somewhat dependent on the intensity of the stimulation (Table 41. Importantly, the use of these models has led to the development of novel drugtesting protocols in animals that more closely resemble human clinical protocols. The poststatus epileptic rat provides an investigator with the opportunity to evaluate the efficacy of a given treatment on seizure frequency, seizure type. Unfortunately, drug trials in rats with spontaneous seizures take on another level of complexity. They are extremely laborious and time-consuming and require a greater level of technical expertise. Fortunately, this leads to excellent seizure control in the majority of patients with epilepsy. The availability of predictive biomarkers would be useful for avoiding ineffective treatments and dose-related or idiosyncratic side effects. Chapter 41: Antiepileptic Drug Development and Experimental Models 511 Lastly, each of the models of pharmacoresistance described so far provide a biological system that will likely lead to a greater understanding of the mechanisms underlying pharmacoresistant epilepsy. As such, they can be used to test novel approaches designed to overcome or reverse therapy resistance, and to perhaps identify appropriate surrogate markers of pharmacoresistance. One can envision the day when we will be able to identify the patient at risk for developing therapyresistant epilepsy and institute a prophylactic therapy that prevents the emergence of pharmacoresistance. Those drugs that were discovered with this approach that displayed a favorable therapeutic window and showed no significant preclinical toxicity were advanced into clinical add-on epilepsy trials with patients with refractory partial seizures. Since 1993, 12 new therapies have been brought to the market for the treatment of epilepsy. It is not clear whether we will be able to identify a therapy that will provide a greater level of efficacy in this patient population using the current approach. As such, there is a clear need to move beyond the conventional animal models and to explore other animal models and molecular targets by which neuronal hyperexcitability may be reduced. Levetiracetam demonstrated that a new therapy does not have to be effective in the traditional seizure models to be effective in the patient with epilepsy. This implies that the community interested in developing a drug for this patient population will need to take a substantial risk when advancing a novel drug into a clinical trial. Only then will we likely find a therapy that provides the level of efficacy for which patients continue to hope. Experimental determination of the anticonvulsant properties of some phenyl derivatives. The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. The National Institutes of Health Anticonvulsant Drug Development Program: Screening for Efficacy. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and models with spontaneous recurrent seizures. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine, gabapentin, and topiramate against human absence seizures. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Kindling increases the sensitivity of rats to adverse effects of certain antiepileptic drugs. Profile of ucb-L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. Pharmacological characterization of phenytoin-resistant amygdala-kindled rats, a new model of drug-resistant partial epilepsy. Anticonvulsant efficacy and adverse effects of phenytoin during chronic treatment in amygdala-kindled rats. Lamotrigine treatment during amygdalakindled seizure development fails to inhibit seizures and diminishes subsequent anticonvulsant efficacy. Effect of lamotrigine, carbamazepine and sodium valproate on lamotrigine-resistant kindled rats. Carbamazepine, but not valproate, displays pharmaco-resistance in lamotrigine-resistant amygdala kindled rats. Retigabine decreases behavioral and electrographic seizures in the lamotrigine-resistant amygdala kindled rat model of pharmacoresistant epilepsy. Phenytoin potently increases the threshold for focal seizures in amygdala-kindled rats. Development and reversal of contingent inefficacy and tolerance to the anticonvulsant effects of carbamazepine. Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy. The effect of carbamazepine on spontaneous seizures in freely-behaving rats with kainate-induced epilepsy. Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytointreated chronic epileptic rats. Effects of antiepileptic drugs on induced epileptiform activity in a rat model of dysplasia. The pharmacokinetic parameters determine the relationship between an administered dose and the concentration of the drug in the body. The main pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the study of the factors that relate to the efficacy and safety of the drug, and determines the relationship between concentration and effect. The relationship between pharmacokinetics and pharmacodynamics is illustrated in Figure 42. Bioavailability (F) is the amount of the administered drug that reaches the systemic circulation. Other drugs are absorbed by a combination of passive and active transport by proteins that can increase and/or decreased absorption depending on their location and whether they are influx or efflux transporters. Rate of absorption is generally a first-order process, where the rate of absorption is dependent on the amount of drug; however, some drugs can follow zero-order kinetics with a constant release of drug independent of the amount of drug. Extended release formulations are used to decrease the frequency of dosing for drugs with rapid elimination to improve convenience and compliance. For extended release drugs, the rate-limiting step in drug elimination is the absorption rate of the drug and not the actual elimination rate. Use of the extended release products can decrease the peak-to-trough fluctuation in serum concentrations and theoretically improve the therapeutic benefit of the drug by decreasing adverse events associated with higher peak concentrations. The enteric coating improves tolerability by decreasing absorption within the stomach and delaying absorption until the formulation reaches the intestines. Bioequivalence is defined as chemical, when the drug meets the same chemical and physical standards; biologic, when the administered drug yields similar concentrations in blood; and therapeutic, when the drug provides equal therapeutic benefits in clinical trials. Carbamazepine meets two of three criteria due to its low water solubility and narrow therapeutic range. The nonlinearity due to autoinduction will not influence generic formulation problems. A drug is considered to have high solubility when the highest dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1 to 7. Of the older drugs, carbamazepine, clonazepam, primidone, and phenytoin are not Class I drugs. Gabapentin is not a Class I drug, due to the transporter-mediated saturable absorption. However, as transport processes occur after dissolution, there is no reason to expect a difference in transporter efficiency with generic products of gabapentin, a highly soluble compound. Albumin concentrations are decreased in the neonate, the elderly, in hepatic and renal disease, during pregnancy, and after trauma. For the majority of the drugs, protein binding is linear and the percent unbound is a constant within the range of concentrations used clinically. Valproate is highly protein bound and due to its high molar concentration, valproate saturates albumin-binding sites within the therapeutic range. An increase in the percent unbound as the dose increases results in total valproate concentrations increasing less than proportional with increasing doses. Conversely, unbound valproate concentrations will increase linearly with increasing dose, and total valproate concentrations will no longer reflect unbound or active concentrations. For the large majority of drugs, elimination is linear; the elimination rate if proportional to the amount of drug present. For drugs following linear kinetics, clearance is constant and serum concentrations increase proportionally with increasing doses. Unlike other drugs, phenytoin is unique in that its elimination is nonlinear due to saturation of metabolism within the normal dosage range. This saturation of metabolic processes results in a decreased clearance with increasing doses. For drugs like phenytoin with nonlinear elimination, serum concentrations will increase more than expected with increasing doses. Clearance is the most useful pharmacokinetic parameter for evaluating an elimination mechanism and in estimation of average steady-state concentrations (Cave,ss). Physiologically, clearance is the loss of drug across an organ of elimination and is determined by the blood flow to the organ that metabolizes or eliminates the drug and the efficiency of the organ in extracting the drug. Clearance (Cl) is described in terms of the eliminating organ; hepatic clearance (ClH) and renal clearance (ClR) with total clearance (Cl) determined by the sum of all the partial clearances. After multiple dosing, Cave,ss is dependent on the dose/interval (D/), Cl, and F (Eq. Cave,ss F D Cl (4) Distribution Distribution is the process of reversible transfer of drug to and from the site of measurement. The volume of distribution (Vd) is a measure of the apparent space in the body available to contain the drug. Vd relates the amount of drug in the body to the concentration of drug in the plasma. Therefore, the initial concentration (C0) attained after administration of a single or bolus dose (D) is dependent on the Vd of the drug.
Somatic parameters impotence prozac discount silagra 100mg online, diseases and psychomotor development in the offspring of epileptic parents erectile dysfunction doctor pune silagra 50mg. Fetal head growth retardation associated with maternal phenobarbitone/primidone and/or phenytoin therapy [letter] erectile dysfunction causes emotional cheap silagra 100 mg on-line. Head circumference in children of epileptic mothers: contributions of drug exposure and genetic background buy erectile dysfunction pills online uk order 50 mg silagra fast delivery. Psychiatric comorbidity is common among patients with epilepsy erectile dysfunction korea purchase silagra 50 mg line, the clinical presentation is frequently atypical erectile dysfunction viagra not working buy generic silagra 100mg on line, and there is often a temporal relationship with seizures. This chapter reviews four of the most commonly encountered psychiatric illnesses in patients with epilepsy: depression, anxiety, psychosis, and personality disorders. Symptoms resemble those of dysthymia, but occur intermittently, precluding the formal diagnosis of dysthymia. Patients may have intermittent irritability, depressed or euphoric moods, anergia, insomnia, atypical pains, anxiety, and fears in the setting of clear consciousness. They may recur every few days to every few months and last from a few hours to upto 2 days or more. A similar presentation in the setting of limbic lesions, but without overt seizures, has been termed "subictal dysphoric disorder. Many patients experience an increase in dysphoria over the 12 to 18 months following temporal lobectomy, after which symptoms resolve. The relationship between seizures and depression is bidirectional, in that the presence of one predicts the other (3). Depression is a better predictor of quality of life in patients with epilepsy than are verbal memory, psychomotor function, cognitive processing speed, mental flexibility, seizure frequency, and seizure severity (6,7). Depression has a negative effect and is associated with more disability, greater social difficulties, more drug side effects, lower employment rates, cognitive dysfunction and subjective memory complaints, and greater use of the medical system (8,9). In patients with epilepsy, morbidity, mortality, and overall prognosis are poorer in those with comorbid depression. Potential risk factors for depression in patients with epilepsy include frequent seizures (1 per month), symptomatic focal epilepsy, younger age, psychosocial difficulties with learned helplessness, and polypharmacy (12). The effect in focal epilepsies appears to be independent of lateralization of the seizure focus, although studies are conflicting with some indicating left predominance (13). Symptoms may arise prior to seizure onset (preictal), as an expression of the seizure (ictal), following seizures (postictal), or, most commonly, unrelated to seizure occurrence (interictal). Preictal depression is characterized by a dysphoric mood that precedes a seizure by hours or days (18) and usually ends with the seizure. Psychiatric symptoms occur in 25% of auras, 15% of which involve affective changes (19). The mood alterations with ictal depression are stereotypical and occur out of context. In one series, postictal depression was evident in 43% of patients with partial seizures. Postoperative depression often begins acutely within the first month after surgery. Risk factors include those with fear auras, especially those rendered seizure-free by surgery. Treatment Depression is both under-recognized and undertreated in patients with epilepsy. An estimated 80% of neurologists (24) do not screen for depression in patients with seizure disorders, perhaps due to unease with its management. Difficulty in recognition of symptoms may also play a role, as many patients present atypically or have confounding side effects of medications. A further limiting factor is the lack of controlled trials for depression in patients with epilepsy. When screening for depression, an initial, simple step is to inquire about anhedonia, which is the inability to experience pleasure. This is an excellent indicator of depression and generally unaffected by drug side effects or underlying medical issues. Referral to a psychiatrist, especially one who is knowledgeable about epilepsy, is advisable for diagnosis and initiation of treatment. Phenobarbital exerts particularly negative effects on mood, with 40% of those treated developing depression (26). If iatrogenic issues are a factor, their correction should be the first step in treatment. In addition, prior to initiation of therapy, patients should be screened for evidence of bipolar disorder to avoid precipitating a manic episode. For those with peri-ictal depression, improved seizure control may be a sufficient treatment. In the absence of controlled trials, the choice of antidepressant should be based upon safety, tolerability, and ease of use. If a particular antidepressant was successful in the past for the patient or family member, another trial of this agent should be considered. A common misconception is that all antidepressants significantly lower seizure threshold and should be avoided. These fears are largely based upon seizures associated with overdoses, which have little predictive value when levels are within therapeutic range (27,28). Patients with primary generalized epilepsy may have a greater propensity for seizure exacerbation secondary to antidepressants; depression in such patients appears to respond well to low doses of these agents (15). The medications with substantial risk are few; however, it is prudent to avoid bupropion, maprotiline, clomipramine, and amoxapine because of their potential for exacerbating seizures (29). The immediate-release preparation presents a particular concern, with a seizure incidence of 0. The epileptogenicity of clomipramine varies by dose, with seizures in up to 3% of patients taking 250 mg/day. Women tend to be more responsive than men, however, and sexual dysfunction and weight gain are common adverse reactions. Kanner and associates used sertraline to treat depression in 100 patients with epilepsy. Depressive symptoms improved in the majority of subjects, with seizures definitely worsening in only one patient (16). Starting with the lowest dose is recommended, with a gradual dose increase at 1- to 2-week intervals. If a more rapid increase is necessary due to severe symptoms, closer observation is required. Also of concern are the potential for cardiac conduction abnormalities and the greater tendency to induce mania. The anticholinergic effects may exacerbate memory dysfunction in patients with Alzheimer disease as well. Finally, these medications have been shown to increase the risk of seizures in the general population in up to 0. This class of medications is contraindicated in children with epilepsy due to the seizure risk. Imipramine and amitriptyline at dosages 200 mg/day, however, do not generally provoke seizures in adults. DrugÂdrug interactions may be quite complex, at times with increased formation of toxic metabolites but decreased activity of parent compounds. They are not often prescribed due to their side effect profile, however, which includes hypertensive crises due to interactions with tyraminecontaining foods. Although useful for atypical features of depression, these are third-line agents and should be prescribed only by psychiatrists. Dosages as high as 225 mg/day have been demonstrated to be safe in depressed patients with epilepsy. The goal of treatment for depression is symptom remission; those with any residual symptoms have a greater likelihood for relapse. If a patient has three or more episodes of depression, residual symptoms, suicidality, psychosis, or an otherwise severe episode, long-term prophylaxis is indicated. Children tend to have high relapse rates, with continuation of symptoms into adulthood (30). Psychotherapy can help patients cope with limitations imposed by epilepsy and may result in significant improvements in rating scales of depression and anxiety, as well as seizure frequency (31). A medication from a different class than that used in Stages 1 or 2 should be administered. Chapter 93: Psychiatric Comorbidity of Epilepsy 1041 When transitioning between drugs, an overlap and taper strategy should be used to avoid withdrawal symptoms. Patients with seizures are also at greater risk of completing suicide compared to controls: 2. The prevalence of suicide in epilepsy increases with comorbid psychiatric diagnoses, including depression, psychosis, anxiety, personality disorders, and bipolar disorder (33). Ictal and postictal depression, mania, postictal psychosis, and command hallucinations present particular risks. In 90% to 95% of patients who commit suicide, prior psychiatric diagnoses were present (33). Other risk factors include psychosocial stressors, poor physical health, young age in men (25 to 49 years), early age of seizure onset (18 years, particularly during adolescence), presence of brain lesions, inadequate follow-up or treatment of seizures, access to firearms or other methods of self-harm, and interictal behavioral disorders. Furthermore, cognitive impairment carries a 10 to 25 times greater risk than normal cognition. The degree to which these factors are predictive, however, may differ between men and women (36). Time periods for particular concern are in the first 6 months after the diagnosis of seizures (37) and within a few months to years of attaining good seizure control after a long history of refractory epilepsy (38). The risk began as early as 1 week, and continued to at least 24 weeks, at which time most trials ended. Physicians need to document the level of risk, interventions, and plans for monitoring. Antidepressants and psychotherapy are helpful, and referral to a psychiatrist is indicated. Anxiety may lead to significant distress, and the presence of anxiety in a depressed patient with epilepsy increases the risk of suicide (33). Anxiety may occur prior to (preictal), during (ictal), or after (postictal) seizure onset. Ictal anxiety may also be present, however, with frontal, cingulate, or other limbic-onset seizures. While some authors suggest that fear lateralizes to the nondominant hemisphere (41), this is not entirely clear. Postictal anxiety occurs in an estimated 45% of those with refractory partial seizures. Contributing factors include the unpredictability of seizures, psychosocial difficulties, and iatrogenic effects. Anxiety prior to epilepsy surgery is a marker of poorer postresection psychosocial adjustment, perceived memory function, and health-related quality of life. Hence, the importance of screening should be emphasized to aid in appropriate treatment and presurgical counseling. Treatment in patients with epilepsy currently varies little from that of the general population, although no controlled studies have been conducted to date. Benzodiazepines may be used for insomnia and acute, severe distress, although continuous use should probably be limited due to their addictive properties. While buspirone is effective in the general population, this agent should be avoided in patients with epilepsy due to the risk of exacerbating seizures. Nonpharmacologic treatment may be helpful in individual cases, including family counseling, supportive psychotherapy, psychoeducational programs, and self-help groups. Panic Disorder Panic attacks consist of episodic symptoms including lightheadedness, tremor, fear of loss of control or death, paresthesias, shortness of breath, chest pain, palpitations, perspiration, chills, abdominal upset, sensation of choking, derealization, and persistent worry about future attacks. Anecdotally, patients often report that they sense the difference between the two types of spells. Still, seizures may be diagnosed only after a long delay, when progression to more clear complex partial events occurs. When present, ictal panic is most often associated with right midanterior temporal lobe onset. Isolated case reports, however, suggest that ictal panic may occur with left parieto-occipital (48), right parietal (41), and left temporal lobeÂonset seizures (49). Like other forms of postictal anxiety, symptoms last 24 hours on average, and are predicted by psychiatric history and relatively low seizure frequency. These cases underscore the importance of screening and the involvement of neuropsychiatrists in epilepsy clinics. Although one case report documented a 50% improvement in symptoms, many attempts at nonpharmacologic, behavioral treatments have met with limited success in patients with comorbid seizures (53). Underlying cognitive deficits, low self-esteem, depression, family psychiatric history, and lack of social support may predispose to phobias. Rare, and perhaps unique to epilepsy, is a "seizure phobia" in which patients fear future seizures. Patients may specifically fear resultant death or brain damage, and relive prior seizures. Patients may develop agoraphobia or social phobia, stemming from fear that others would observe their seizures if they were to occur in public. While phobias are typically an interictal phenomenon, some patients experience postictal agoraphobia. Caution should be used in the prescription of benzodiazepines, given concerns that they may lead to dependence and avoidance of the deeper cognitive-behavioral issues. The overall frequency of psychosis among patients with epilepsy is approximately 7% to 14%. Reports of an association with other localization-related epilepsies indicate, less commonly, a relationship with left frontal lobeÂonset seizures (60). Symptoms consisted of hallucinations, delusions, affective changes, heightened religiosity, and abusive behavior lasting from 12 hours to 15 days prior to habitual seizures.
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