Drug therapy strategies in Alzheimer's disease

Treatments in Alzheimer's disease include treatment of cognitive impairment and behavioral manifestations (agitation, depression, anxiety, delusions). It should be noted that many non cognitive behaviors may have some relations to underlying cognitive impairment. In the not too distant future, physicians can expect to see a variety of medications and controversies over the benefits of slowing symptoms with cholinergic therapeutics approved for clinical use and (or) preventing progression of Alzheimer's disease assessed in clinical trials will emerge.     

The difference in mean costs as a pharmacoeconomic outcome variable: power considerations

Significant changes in cholinergic neurotransmission have been described in Alzheimer's disease (AD). These findings led to consider cholinergic deficit as the main disturbance in AD, due to degeneration of presynaptic cholinergic neurons, and that replacement of acetylcholine could restore the cognitive alterations characteristic of AD. Although it was soon demonstrated that cholinergic deficit was not the only change, cholinergic hypothesis has allowed to set several possible therapeutic strategies for these severe disease, the most promising is administration of acetylcholinesterase inhibitors. Of all the compounds investigated, tacrine (tetrahydroamineacridine) has shown in several clinical trials a positive effect on memory in patients with symptoms of slight to moderate severity. Although not all studies have given successful result, probably due to methodological differences, global clinical impression has justified the introduction of tacrine as the first palliative therapy in AD.     

Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.     

Antecedents of dental anxiety: learned responses versus personality traits

Patients recovering from alcohol and other drug addiction have unique medical and pharmacological needs. Careful selection of medications call decrease the risk of relapse. Angiotensin-converting enzyme inhibitors and calcium channel-blocking medications are excellent choices to treat hypertension. Most gastrointestinal problems resolve with abstinence and can be treated nonpharmacologically. In managing pain, physicians should avoid narcotics and use nonpharmacological treatment whenever possible. Treating recovering patients with HIV can be challenging because of the side effects of many of the antiviral medications. The newer antiviral agents have fewer side effects and contraindications. Commonly used remedies for colds and cough can cause a relapse to drug use. Patients with diabetes mellitus need to be monitored very closely in early recovery to prevent hypoglycemia. Frequently a team approach is helpful in managing the medication needs of patients in recovery.     

Treatment of agitation in dementia

Agitation occurs commonly in patients with dementia. Before symptomatic pharmacotherapy is undertaken, it is imperative to perform a sequence of evaluations and interventions to establish whether simpler and safer, nonpharmacologic approaches will be beneficial. When psychotropic medications are used they should be used judiciously, in the lowest effective doses and for the shortest period of time necessary. Ineffective medications should be stopped, and even effective medications should be empirically tapered in most patients to learn whether treatment is still necessary. Antipsychotics probably show the greatest benefit for agitation associated with psychotic features; they have less demonstrated efficacy for agitation not associated with psychotic features. The side effects of typical agents are legion; data are pending regarding atypical agents. The available evidence regarding nonneuroleptic medications ranges from case reports to well-designed, double-blind, placebo-controlled, randomized, parallel group studies. Literature exists describing the use of anticonvulsants, anxiolytics, serotonergic antidepressants, and other agents to manage agitation. Carbamazepine and divalproex sodium (valproate) have demonstrated efficacy in uncontrolled studies, whereas the use of carbamazepine has produced negative results in one small controlled study and positive results in two larger controlled studies. Buspirone has shown benefit in some open trials. Encouraging early findings have been reported for trazodone, including from one controlled trial. Varying results have been obtained using selective serotonin reuptake inhibitors, but with consistently encouraging anecdotes. In the aggregate, the evidence suggests but does not prove that alternatives to traditional antipsychotics exist. Again, none of these agents has yet been approved for this purpose by the FDA. As more studies become available we will have a better idea about which classes of agents are most efficacious. It is likely that there may be a role for "rational" polypharmacy in the management of this distressing complication of dementia. However, no studies that we know of address combination therapy, so the clinician must contemplate this option on a case-by-case basis. Clinical trials data are pending from studies with divalproex sodium, carbamazepine, haloperidol versus trazodone versus placebo, risperidone, olanzapine, quetiapine, donepezil, xanomeline, tacrine, buspirone, and sertraline, at the very least. These data will undoubtedly have a major impact on how we care for our patients and lead to revisions of current practice guidelines.     

Cognitive function as an emerging treatment target for marijuana addiction.

Cannabis is the most widely used illicit substance in the world, and demand for effective treatment is increasing. However, abstinence rates following behavioral therapies have been modest, and there are no effective pharmacotherapies for the treatment of cannabis addiction. We propose a novel research agenda and a potential treatment strategy, based on observations that both acute and chronic exposure to cannabis are associated with dose-related cognitive impairments, most consistently in attention, working memory, verbal learning, and memory functions. These impairments are not completely reversible upon cessation of marijuana use, and moreover may interfere with the treatment of marijuana addiction. Therefore, targeting cognitive impairment associated with chronic marijuana use may be a promising novel strategy for the treatment of marijuana addiction. Preclinical studies suggest that medications enhancing the cholinergic transmission may attenuate cannabis-induced cognitive impairments, but these cognitive enhancing medications have not been examined in controlled human studies. Preliminary evidence from individuals addicted to other drugs suggests that computerized cognitive rehabilitation may also have utility to improve cognitive function in marijuana users. Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these treatments for marijuana addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The calcium channel blocker debate

What, finally can we conclude from the work to date regarding the use of CCB's? The large clinical trials here give a number of clear messages to the prescriber. Short-acting dihydropyridine CCB's are unproven as prophylactic agents in ischaemic heart disease. In patients with poor left ventricular function post-infarct, CCB's are associated with an unchanged or increased mortality. Use of medications in the treatment of hypertension should be with proven first-line therapeutic agents; beta-blockers, diuretics; and the long-acting dihydropyridine CCB's nifedipine GITS and nitrendipine. The final argument in the discussion over the safety or otherwise of calcium channel blockers will rest in the completion in the future of a number of prospective, randomised, place-controlled clinical drug trials. These trials are currently ongoing, and their results may not be available until after the year 2000.     

Recent developments in the pharmacotherapy of alcohol dependence.

The effectiveness of a treatment for alcohol dependence can be appropriately determined only after controlling for the usual clinical course of alcoholism, subgroups of alcohol-dependent individuals, and placebo effects. The results of appropriate treatment trials must also be interpreted in light of the side effects and costs, and there must be assurances that the overall improvement in functioning observed with the drug is significant enough to outweigh the liabilities. In addition, medications are almost always used in combination with education, counseling, and behavioral therapies, and the impact of these additional treatments must be considered. Viewed from this perspective, 3 medications are quite promising regarding their potential future impact in the alcohol field, including naltrexone, the medication with the most available data in the United States. There are additional data regarding buspirone and acamprosate. Intriguing results have also been generated regarding medications that affect serotonin and dopamine brain activity and with alcohol-sensitizing drugs such as disulfiram. However, none of these medications has been proven to be clinically effective in the routine treatment of the average alcoholic… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

When to start cholesterol-lowering therapy in patients with coronary heart disease. A statement for healthcare professionals from the American Heart Association Task Force on Risk Reduction

At present a large number of patients with atherosclerotic disease are not receiving aggressive cholesterol-lowering therapy. Consequently they are being deprived of a cost-effective, risk-reducing treatment. Every physician who treats patients with clinical atherosclerotic disease should become fully informed about the results of cholesterol-lowering trials in patients at high risk. All physicians who care for high-risk patients should take responsibility for cholesterol management, including primary care physicians and cardiovascular specialists. Highly effective and generally safe drugs for cholesterol lowering are available. The benefits of therapy for reducing recurrent CHD and prolonging life are considerable. There is no justification for unduly delaying institution of therapy for the majority of patients. The many advantages of nonpharmaceutical therapy call for its use in almost all patients, but drug treatment should not be postponed if the target for LDL cholesterol lowering (< or = 100 mg/dL) is unlikely to be achieved in the near term by a nonpharmaceutical approach alone. The view that patients with CHD or other forms of atherosclerotic disease do not receive substantial clinical benefits from aggressive cholesterol-lowering therapy is no longer warranted. Intensive cholesterol reduction, initiated immediately, has the potential to significantly reduce both morbidity and mortality. Cholesterol-lowering therapy thus should become a routine part of clinical management to reduce risk of future coronary events and to prolong life in patients with CHD or other forms of atherosclerotic disease.     

Medical treatment of Alzheimer's disease

OBJECTIVE: To review the drugs commercially available at present and in the near future in relation to the evolution of Alzheimer disease, bearing in mind the possible psychiatric disorders which may be associated with the disease. DEVELOPMENT: The therapeutic approach is planned according to the different phases of the disease. In the preclinical phase, anti-inflammatory drugs and estrogens in post-menopausal women have been effective. In the initial phase current recognition therapy is directed basically towards correcting the break-down of acetylcholine (tacrine, donepezil, SB202026, SDZ ENA 713). For depressive symptoms serotonin levels are corrected using selective inhibitors of serotonin uptake. CONCLUSIONS: Drug treatment should be considered with the association of drugs which activate the malfunctioning circuits and/or pathways. It would also be useful to design clinical studies using pharmacological combinations of cholinergic agonists, estrogens, anti-inflammatory drugs, seligiline and/or new anti-cholinesterase drugs amongst others.     

Local immunoglobulin G antibodies in the stomach may contribute to immunity against Helicobacter infection in mice

The central nervous system consumes 20% of the cardiac output for normal function. The neurons are very sensitive to the effects of ischemia. Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular calcium (Ca2+) buildup, relative lack of inhibitory responses, generation of oxygen free radicals (especially during the reperfusion period) and several other destructive cascades. Medications that antagonize the effects of glutamate at post-synaptic receptors are either ineffective or have serious side-effects. Ca2+ entry blockers have shown disappointing results in clinical trials in patients with acute cerebral infarction. Data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 hours after the ischemic insult. Many such medications have few side-effects and are in clinical use for other indications. This review will summarize inhibitory mechanisms that may be important in cerebral ischemia, and provide experimental evidence for their potential efficacy.     

Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release

Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.     

Extinction in fear conditioning: effects on startle modulation and evaluative self-reports

gamma-Hydroxybutyric acid (GHB) is unfamiliar to many physicians in the United States but enjoys clinical use elsewhere for applications in resuscitation, anesthesia, and addiction therapy. Use within the United States is restricted to Food and Drug Administration-approved clinical trials for treatment of narcolepsy. Recently illicit use of GHB has emerged within the United States where it is distributed for purported euphoric and "fat-burning" metabolic effects. Clinical effects can be severe, progressing rapidly to respiratory arrest and death. We provide an updated comprehensive review of the literature with particular emphasis on toxicology, including GHB pharmacodynamics, clinical effects, and suggestions for overdose management. Recommended management of acute GHB intoxication includes prevention of aspiration, use of atropine for persistent symptomatic bradycardia, consideration of neostigmine as a reversal agent, and treatment for coingested substances. Emergency physicians are urged to become familiar with GHB because of its potential for severe morbidity as well as its potential use as a future resuscitative agent.     

Interaction of tacrine and velnacrine with neocortical synaptosomal membranes: relevance to Alzheimer's disease

The acridine-based, potential Alzheimer's disease therapeutic agents, tacrine and velnacrine, were incubated with rat or gerbil neocortical synaptosomal membranes. Electron paramagnetic resonance employing a protein-specific spin label was used to monitor this interaction. Analogous to their effects in erythrocyte membranes [Butterfield and Rangachari (1992) Biochem. Biophys. Res. Commun. 185: 596-603], in the present studies both agents decreased segmental motion of spin labeled synaptosomal membrane proteins, consistent with increased cytoskeletal protein-protein interactions (0.001 < P < 0.005), and tacrine was more potent than velnacrine. These results are discussed with possible relevance to molecular actions of the agents and molecular alterations in Alzheimer's disease.     

Use of platelet glycoprotein IIb/IIIa receptor inhibitors in acute coronary syndrome and coronary intervention

New strategies in the treatment of acute coronary syndromes have focused on the potential for blocking platelet aggregation through the use of platelet surface membrane glycoprotein (GP) IIb/IIIa receptor inhibitors. The benefits of GPIIb/IIIa inhibition in preventing ischemic complications of interventional treatment have been well defined in patients with unstable angina. In the future, major therapeutic applications for this class of agents may include the stabilization of patients with unstable angina and potentially as single medical therapy, as several recently completed trials have suggested. This article attempts to review recently published clinical trials regarding the use of GPIIb/IIIa receptor inhibitors, and clarify current problems in the use of this agent and directions for future investigation.     

Ethical concerns in the use of palliative drug treatment for Alzheimer's Disease

The cases of 3 patients with Alzheimer's disease (AD) who had varied outcomes from treatment with tacrine or other palliative drugs illustrate the need to consider the benefits of such agents for each case on an individual basis. In the absence of a cure, the most important factor in the care of AD patients may be the physician's attitude that irreversibility does not imply untreatability.     

Differences in the management of inflammatory bowel disease in children and adolescents compared to adults

Managing IBD in children and adolescents requires attention to issues unique to these age groups. The spectrum of presenting signs and symptoms is broad and often, subtle. Physician awareness of intestinal and extra-intestinal features prompts earlier diagnosis and intervention. The focus of treatment is not limited to intestinal symptoms, but also involves assessing weight and height gains, sexual maturation, extra-intestinal manifestations and psychosocial well-being. Differences in selecting drugs for pediatric versus adult patients are based on: 1. lack of prospective trials establishing effective doses for different ages; 2. inability to swallow capsules; 3. importance of nutrition in promoting growth; 4. paucity of data regarding the long-term safety of medications; 5. untoward cosmetic effects of corticosteroids, and 6. the need to develop coping mechanisms for a chronic illness. While sulfasalazine and mesalamine are useful in mild disease, corticosteroids are necessary for moderate and severe disease. Metronidazole and ciprofloxacin are effective in perianal CD. Elemental and polymeric formulas induce and maintain remission in active CD and reverse growth failure. Immunomodulatory agents (azathioprine and 6-mercaptopurine) enable physicians to reduce steroids and hospitalization. In practice, combination therapy is recommended to control symptoms and limit drug-induced side effects.