Treatment of inflammatory bowel disease in the elderly: an update

Inflammatory bowel disease (IBD) is most common in young adults, but it can also present in the elderly. Furthermore, with the aging of the population, the number of elderly patients with IBD is expected to grow. Other conditions, such as diverticulitis and ischaemic colitis, may be more common in the elderly and need to be considered in the differential diagnosis. Management of elderly patients with IBD follows the same principles as in younger patients, with a few exceptions. For patients with mild-to-moderate colitis, a 5-aminosalicylate drug is often used (sulfasalazine, olsalazine, mesalazine, balsalazide). Topical therapy may be sufficient for those with distal colitis, whereas an oral preparation is used for more extensive disease. In those with more severe or refractory symptoms, corticosteroids are used, although the elderly appear to be at increased risk for corticosteroid-associated complications. For patients with corticosteroid-dependent or corticosteroid-refractory disease, immunosuppression with azathioprine or mercaptopurine may help avoid surgery. In patients with Crohn's disease, a similar approach is followed, with the additional consideration that the formulation of drug used must ensure delivery of drug to the site of inflammation. In fistulising Crohn's disease, antibacterials, immunosuppressive drugs, infliximab and surgery are often used in combination. Controlled trials and clinical experience have shown that infliximab is a significant addition to the therapeutic armamentarium for patients with Crohn's disease.     

Peyronie's disease: an update of the medical management

Peyronie's disease (PD) is characterised by penile plaque formation, pain, penile deformity and erectile dysfunction. It is a fibrotic disorder of the tunica albuginea with a poorly understood aetiology and epidemiology. PD may be classified into inflammatory (acute) and chronic stages. Medical treatment is usually instigated during the inflammatory phase of the disease. A review of the literature reveals a wide range of oral, intralesional and alternative therapies that are discussed in relation to established pathophysiological mechanisms of the disease. The advantages and disadvantages of each treatment are summarised. This review also discusses the ongoing therapeutic dilemmas of PD and suggests a treatment strategy based on an analysis of the urological literature.     

Clonazepam in the treatment of psychiatric disorders: an update

An updated overview over the past decade is provided with respect to the use of clonazepam in a variety of psychiatric disorders. The efficacy of clonazepam monotherapy for the short-term treatment of panic disorder (PD) was fully established in two large pivotal multicentre studies in the late 1990s in a total of >800 patients. Other studies support a role for clonazepam, in association with selective serotonin reuptake inhibitors (SSRIs), to accelerate treatment response in PD. Although some longitudinal data suggest an ability to maintain improvement without tolerance for up to 3 years, long-term controlled studies of clonazepam in PD are lacking. Studies have shown that clonazepam can also block CO2-induced panic and improve certain aspects of quality of life in PD. Clonazepam has shown some efficacy in social phobia; however, because this evidence is based on few studies, further studies are warranted before definitive conclusions can be drawn. Finally, evidence for the use of clonazepam in acute mania and as augmentation therapy with SSRIs to accelerate response in depression is examined. The long half-life and higher potency of clonazepam may allow easier discontinuation with fewer withdrawal symptoms compared to other benzodiazepines and studies using a slow clonazepam taper appear promising.     

Risperidone long-acting injection and Huntington's disease: case series with significant psychiatric and behavioural symptoms

There is currently no known disease-altering treatment for Huntington's disease (HD). Successful symptomatic treatment often involves antipsychotic medication, including risperidone, yet the evidence base is limited to case reports. Although noncompliance to oral antipsychotic drugs can be a practical problem, especially when significant psychiatric manifestations of HD are present, the effect of depot antipsychotic medication in HD remains largely unknown. A period of nondrug compliance to oral risperidone in five patients with HD, and significant psychiatric and behavioural symptoms, after appearing to show symptomatic improvement, suggested a possible role for risperidone long-acting injection. The patients gave informed consent before receiving a fortnightly injection at a dose of 25 mg. At the end of 2-15 months (mean 1 year) they appeared to show an unexpected sustained symptomatic improvement (chorea, functioning and insight). In conclusion, this case series suggests risperidone long-acting injection may be a viable symptomatic treatment strategy in similar HD patients. If replicated, these findings have the potential to offer an effective strategy to manage some of the most difficult patients with HD to achieve symptomatic relief.     

Inflammation in Parkinson's disease: an update

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.     

Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders. If more effective therapies than the ones currently available are not developed that either prevent AD or other neurodegenerative or block progression of the diseases in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Besides the neuropathologic hallmarks of the diseases, namely neurofibrillary tangles and AD neuritic plaques, the disease is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in basal forebrain. AD and other forms of dementia could be treated by the use of agents which restore the level of acetylcholine through inhibition of both two major forms of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the inhibition of AChE holds a key role not only to enhance cholinergic transmission in the brain but also to reduce the aggregation of beta-amyloid and the formation of the neurotoxic fibrils in AD. Following this view, in recent years, an increased interest has emerged directed to finding drugs able to inhibit both of these events. This review summarizes and highlights recent advances in current knowledge on natural products as cholinesterase inhibitors and how these compounds have also served as the starting points for semi-synthetic analogs with improved properties.     

Proteomics and cardiovascular disease: an update

Proteomics has unraveled important questions in the biology of cardiovascular disease and holds even greater promise for the development of novel diagnostic and prognostic biomarkers. This approach may establish early detection strategies, and monitor responses to therapies. Technological advances (most notably blue native polyacrylamide gel electrophoresis, electrospray ionization, matrix-assisted laser desorption/ionization (MALDI), analysis of MALDI-derived peptides in Time-of-Flight (TOF) analyzers, and multidimensional protein identification technology (MudPIT) and bioinformatics for data handling and interpretation allow a large-scale identification of peptide sequence and post-translational modifications. Moreover, combination of proteomic biomarkers with clinical phenotype, metabolite changes, and genetic haplotype information is promising for the physician assessment of individual cardiovascular risk profile.     

Paroxetine: an update of its use in psychiatric disorders in adults

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or =60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.     

Ulcerative proctitis: an update on the pharmacotherapy and management

Introduction: Ulcerative colitis (UC) presents as proctitis in approximately a quarter of the patients. It may progress into left-sided or extensive colitis in up to 50% of cases upon long-term follow-up.

Areas covered: Currently available data on ulcerative proctitis are summarized and critically reviewed. Extensive literature search (MEDLINE) was performed to identify relevant articles up to March 2014.

Expert opinion: The short-term goal of the treatment in UC is to induce remission, whereas long-term goals are to maintain remission and prevent disease progression. Topically administered 5-aminosalicylates (5-ASA) and corticosteroids are effective in the treatment of proctitis, although they seem to be underused in everyday practice. Locally administered 5-ASA preparations are more effective than oral compounds. The combination of topical and oral 5-ASA and steroids should be considered for escalation of treatment. Refractory patients should be re-evaluated to exclude for compliance failures, infections or proximal disease extent. True refractory or steroid-dependent patients may require immunomodulators or biological therapy. Alternative medicine can be used complementarily, while experimental approaches are reserved for patients failing conventional medication. Proctocolectomy may be the last resort of treatment. Upon long-term, 5-ASA maintenance treatment is indicated in all UC cases to prevent relapse and disease progression.     

Antipsychotic drug use in neurodegenerative disease in the elderly: problems and potential from a pharmacological perspective

The past decade has seen the introduction of several new antipsychotics for the treatment of schizophrenia. These drugs demonstrate substantially lower levels of extrapyramidal side effects (EPS) than the classical antipsychotics, as well as having (often poorly supported) claims of increased efficacy at ameliorating certain schizophrenic syndromes. Increasingly, these ‘atypical’ drugs are being used in the treatment of psychotic or related behavioural disturbances in patients with neurodegenerative disease. Thus, some newer antipsychotics are particularly valuable in ameliorating the L-dopa-induced psychosis in Parkinson’s disease, while behavioural problems in dementing disorders, such as those occurring in Alzheimer’s disease, are also frequently treated by antipsychotic drugs. The relationship between drug pharmacology and neurotransmitter pathology is essential to understanding the relative efficacy of individual antipsychotic drugs in treating the psychotic and behavioural disturbances of neurodegenerative disorders.     

Antipsychotic drug use in neurodegenerative disease in the elderly: problems and potential from a pharmacological perspective

The past decade has seen the introduction of several new antipsychotics for the treatment of schizophrenia. These drugs demonstrate substantially lower levels of extrapyramidal side effects (EPS) than the classical antipsychotics, as well as having (often poorly supported) claims of increased efficacy at ameliorating certain schizophrenic syndromes. Increasingly, these 'atypical' drugs are being used in the treatment of psychotic or related behavioural disturbances in patients with neurodegenerative disease. Thus, some newer antipsychotics are particularly valuable in ameliorating the L-dopa-induced psychosis in Parkinson's disease, while behavioural problems in dementing disorders, such as those occurring in Alzheimer's disease, are also frequently treated by antipsychotic drugs. The relationship between drug pharmacology and neurotransmitter pathology is essential to understanding the relative efficacy of individual antipsychotic drugs in treating the psychotic and behavioural disturbances of neurodegenerative disorders.     

Chelation therapy in cardiovascular disease: an update

Introduction: The off-label use of chelation therapy (disodium edetate or EDTA) for prevention of cardiovascular disease (CVD) is widespread, despite the lack of convincing evidence for efficacy or approval from the Food and Drug Administration. After the publication of results from the National Institute of Health-sponsored Trial to Assess Chelation Therapy (TACT), a randomized controlled trial (RCT) in patients after myocardial infarction (MI), there is a renewed interest in clarifying the role of this treatment modality for patients with coronary artery disease.

Areas covered: This narrative review highlights the evidence from observational studies and RCT in assessing the effect of chelation therapy on cardiovascular outcomes and potential for adverse effects or harm.

Expert commentary: Although encouraging results were reported in TACT, the evidence is insufficient to recommend the routine use of chelation therapy even in the post-MI diabetic subgroup, which appeared to benefit. The ongoing TACT2 trial may clarify its use in post-MI diabetic patients. Unsubstantiated claims of chelation therapy as an effective treatment of atherosclerosis should be avoided and patients made aware of the inadequate evidence for efficacy and potential adverse effects, especially the harm that can occur if used as a substitute for proven therapies.     

Estrogen receptors and human disease: an update

A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561–570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states.     

Drug interactions in the management of HIV infection: an update

Improvement in the availability of antiretroviral (ARV) therapy continues to reduce HIV morbidity and mortality. With more treatment choices and better accessibility, the extent of medication use among patients with HIV/AIDS continues to grow. ARV drugs are particularly prone to drug interactions as a consequence of their metabolic and pharmacokinetic properties. The recognition and management of drug interactions in patients on ARVs is a constant challenge to medical providers. Staying abreast of drug interaction knowledge is complicated by the rate at which new information becomes available through in vivo investigation, case reports and pharmacokinetic studies. In addition, distinguishing the clinical significance of an interaction is difficult due to the large interpatient variability in pharmacokinetics exhibited by most ARV agents. This review provides an update to a previous review article published in 2005, and is intended to improve the reader's knowledge of drug interactions in the management of HIV infection.     

The treatment of chronic constipation in elderly people: an update

Constipation is a common problem in elderly persons, with prevalence ranging from 15% to 20% in the community-dwelling elderly population and up to 50% in some studies of nursing home residents. In these patients, constipation results from a combination of risk factors, such as reduced fibre and fluid intake, decreased physical activity resulting from chronic diseases and multiple medications. Despite the high prevalence of constipation, there is surprisingly little evidence available on which to base management decisions of this common condition.Increased fluid intake, regular physical activity and high fibre intake are usually proposed as first step nonpharmacological measures. However, adherence to these measures is limited and pharmacological treatment is frequently required. Data are too limited, especially in elderly persons, to formally recommend one class of laxatives over another or one agent over another within each class. However, bulk-forming and osmotic laxatives are usually recommended as first-line agents, even though data on their effectiveness are limited. The need to maintain good hydration is a limitation in the use of bulk-forming laxatives, in particular, in frail elderly patients. In these patients, polyethylene glycol, an osmotic agent, is an attractive alternative. In addition, it has been shown to relieve faecal impaction in frail patients with neurological disease. Its cost and potential danger in patients at high risk for aspiration is, however, a limitation. Stimulant laxatives are considered mainly as an intermittent treatment in patients who do not respond to bulk-forming or osmotic laxatives.Several promising compounds such as the new serotonin 5-HT4 receptor agonists (tegaserod, prucalopride) and neurotrophin-3 (NT3) have not been adequately tested in older individuals. They are not routinely used and their role in the management of constipation in these patients will be more precisely defined in the future. Other treatment options are available (acupuncture, biofeedback, botulinum toxin and surgery), but experience with these interventions in elderly patients is limited and their indications in this population remain to be clarified.Management of constipation in elderly persons depends largely on experience and beliefs. Several new compounds seem promising but will need to be specifically tested in this population before being recommended.     

Pharmacokinetic optimisation in the treatment of Parkinson's disease : an update

Pharmacotherapy for Parkinson's disease is focused on dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists. The elimination half-life (t(1/2)) of levodopa from plasma (in combination with a decarboxylase inhibitor) of about 1.5 hours becomes more influential as the disease progresses. The long-duration of response to levodopa, which is evident in early Parkinson's disease, diminishes and after a few years of treatment motor performance is closely correlated to the fluctuating plasma concentrations of levodopa. Absorption of levodopa in the proximal small intestine depends on gastric emptying, which is erratic and may be slowed in Parkinson's disease. The effects of levodopa on motor function are dependent on gastric emptying in patients in the advanced stages of disease.The current treatment concept is continuous dopaminergic stimulation (CDS). Sustained-release formulations of levodopa may provide more stable plasma concentrations. Oral liquid formulations shorten the time to reach peak concentration and onset of effect but do not affect plasma levodopa variability. The t(1/2) of levodopa can be prolonged by adding a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), which may reduce fluctuations in plasma concentrations, although both peak and trough concentrations are increased with frequent administration. Intravenous and enteral (duodenal/jejunal) infusions of levodopa yield stable plasma levodopa concentrations and motor performance. Enteral infusion is feasible on a long-term basis in patients with severe fluctuations.Among the dopamine receptor agonists the ergot derivatives bromocriptine, cabergoline, dihydroergocryptine and pergolide, and the non-ergot derivatives piribedil, pramipexole and ropinirole, have longer t(1/2) compared with levodopa. Thus, they stimulate dopamine receptors in a less pulsatile manner, yet pharmacokinetic studies of repeated doses of dopamine receptor agonists are few. Optimisation of these drugs is often performed with standardised titration schedules. Apomorphine and lisuride have short t(1/2) and are suitable for subcutaneous infusion, with results similar to those of levodopa infusion. Transdermal administration of dopamine receptor agonists such as rotigotine might be an alternative in the future. In general, initial dopamine receptor agonist monotherapy is associated with poorer motor performance and lower incidence of motor complications compared with levodopa.Buccal administration of the monoamine oxidase-B inhibitor selegiline (deprenyl) provides better absorption and less formation of metabolites compared with standard tablets.To conclude, several new drugs, formulations and routes of administration have been introduced in the treatment of Parkinson's disease during the last decade, mainly with CDS as the aim. CDS can be approached by optimising the use of dopaminergic drugs based on pharmacokinetic data.     

Oxcarbazepine: an update of its efficacy in the management of epilepsy

Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a 10-keto analogue of carbamazepine with anticonvulsant activity. In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective as phenytoin and vaiproic acid at reducing generalised tonic-clonic and partial seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. The most commonly reported adverse events associated with oxcarbazepine monotherapy and/or adjunctive therapy in adults and/or children are somnolence, dizziness, headache, nausea and vomiting. Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults and children) and valproic acid (in adults), and although 75 to 90% of adult patients in 5 recent monotherapy studies reported adverse events while receiving oxcarbazepine, <8% withdrew from treatment because of them. Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of patients treated with oxcarbazepine. Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. Although oxcarbazepine does have a clinically significant interaction with some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for interactions than older antiepileptic drugs (AEDs) because its major metabolic pathway is mediated by noninducible enzymes. CONCLUSION: Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults and children. Furthermore, it is also effective as adjunctive therapy in the treatment of refractory partial seizures in both age groups. In addition, the drug is tolerated better than the older, established AEDs, and has a lower potential for drug interactions. These attributes make oxcarbazepine an effective component in the initial treatment of newly diagnosed partial and generalised tonic-clonic seizures, and also as an adjunct for medically intractable partial seizures in both adults and children.     

Rizatriptan: an update of its use in the management of migraine

Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2 to 4%). CONCLUSION: Rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest rizatriptan should be considered as a first-line treatment option in the management of migraine.