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PubMed2000

Therapeutic developments in multiple sclerosis.

Recently there have been considerable advances made in the treatment of multiple sclerosis. For the first time since its initial clinical description in the 1800s, there are now available several medications which unequivocally exert favourable clinical effects through the lowering of the biological activity of the human illness. The therapeutic efficacy of IFN-beta preparations seems particularly well established in this regard on the basis of five large, independent, trials of this agent. These trials have demonstrated remarkably consistent reductions in both attack rates and disability levels using a combination of clinical and magnetic resonance imaging outcome measures. The therapeutic benefit of glatiramer acetate also has been well established, although there is less available data on this agent than there is for interferon. It is important to recognise, however, that, although these agents represent an important first step in the management of patients with multiple sclerosis, they are only partial therapies. In order to actually cure the illness or even to substantially improve patient outcome we need considerably better agents than we have currently. Nevertheless, it is likely that, with improved knowledge of the role that interferon beta plays in the pathogenesis of multiple sclerosis and with better understanding of the mechanism by which glatiramer acetate exerts its therapeutic effect, greatly improved therapeutic agents will be available in the future. In addition, it seems likely that, in the future (by analogy to the experience in oncology), we will begin utilising combinations of therapies in order to better control the biological activity of this debilitating disease. Such combination therapy will almost certainly include combinations of partially effective agents as well as combinations of these agents with other medications (e.g., the immunosuppressive drugs) which, by themselves, have only been demonstrated to exert marginal clinical benefits on the course of illness. Moreover, it also seems likely that, increasingly, therapeutic strategies that enhance or promote myelin repair will become a major focus of clinical research in this area.

Clinical Trials as Topic↗

PubMed2002

Death-associated protein kinase as a potential therapeutic target.

Death associated protein kinase (DAPK) is a calmodulin (CaM)-regulated serine/threonine protein kinase implicated in diverse apoptosis pathways, including those involved in neuronal cell death and tumour suppression. The requirement of DAPK catalytic activity for its proposed cell functions and the validation of protein kinases as therapeutic targets demand that DAPK be examined as a potential therapeutic target in human disease. The relevant placement of DAPK activity in apoptosis pathways is at an early stage of investigation, making its study as a therapeutic target tenuous. However, the current body of knowledge raises the possibility of DAPK as a therapeutic target for diseases characterised by rapid neurodegeneration, such as stroke or traumatic brain injury. The unmet need in these diseases is for an acute treatment schedule that might reduce neuronal loss. Bioavailable inhibitors of DAPK catalytic activity that target the central nervous system have a potential to fill this need. The development of such DAPK inhibitors is now feasible based on the recent emergence of enabling technology and knowledge. These include a quantitative and selective enzyme assay, a high resolution structure of the active catalytic domain and discovery of cell-permeable, low molecular weight inhibitors of CaM kinases that cross the blood-brain barrier. DAPK as a potential therapeutic target for cancer is less attractive due to the incomplete state of knowledge about DAPK and inherent limitations in drug development for the discovery of specific activators of genes downregulated by promoter hypermethylation. This article provides a brief summary of relevant research and the rationale that is at the foundation of this opinion.

Animals↗

PubMed2006

Self-efficacy, therapeutic alliance, and alcohol-use disorder treatment outcomes.

OBJECTIVE: High abstinence self-efficacy reliably predicts better treatment outcomes for patients with alcohol use disorders, but little is known about aspects of treatment that may be particularly beneficial for patients who enter treatment with low self-efficacy. This study examines whether the relationship between self-efficacy and treatment outcomes is influenced by the quality of the therapeutic alliance in Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity), a multisite clinical trial of three treatments for alcohol use disorders. METHOD: Information on 785 patients in the outpatient sample of Project MATCH was used to test for an interaction between baseline self-efficacy and therapeutic alliance in relation to 1-year alcohol use outcomes. RESULTS: A significant interaction was found between self-efficacy and the therapists' perception of the therapeutic alliance predicting I1year drinking outcomes. Patients with low self-efficacy who established a strong treatment alliance, as judged by the therapist, experienced I1year outcomes that were superior to those of patients with low self-efficacy with poorer treatment alliance and comparable with those of patients with high self-efficacy. Therapeutic alliance was not strongly related to the outcomes of patients with high baseline self-efficacy. CONCLUSIONS: In patients who are treated for alcohol-use disorders, a positive therapeutic alliance may counteract the negative impact of a low baseline self-efficacy. Potential reasons why the therapist's perception of the alliance may be particularly important for patients with low self-efficacy are discussed.

Adolescent↗

PubMed2003

Preventative and therapeutic vaccines for cervical cancer.

"High-risk" genotypes of the human papillomavirus (HPV), most commonly HPV genotype 16, are the primary etiologic agents of cervical cancer. Indeed HPV DNA is detected in 99% of cervical carcinomas. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by the induction of the appropriate viral-antigen-specific immune responses. Transmission of papillomavirus may be prevented by the generation of antibodies to capsid proteins L1 and L2 that neutralize viral infection. HPV L1 virus-like particles (VLPs) show great promise as prophylactic HPV vaccines in ongoing clinical trials but L2-based preventative vaccines have yet to be tested in patients. Since the capsid proteins are not expressed at detectable levels by infected basal keratinocytes or in HPV-transformed cells, therapeutic vaccines generally target the nonstructural early viral antigens. Two HPV oncogenic proteins, E6 and E7, are critical to the induction and maintenance of cellular transformation and are co-expressed in the majority of HPV-containing carcinomas. Although other early viral antigens show promise for vaccination against papillomas, therapeutic vaccines targeting E6 and E7 may provide the best opportunity to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 are administered in live vectors, as peptides or proteins, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should this new generation of HPV preventative and therapeutic vaccines function in patients as demonstrated in animal models, oncogenic HPV infection and its associated malignancies could be controlled by vaccination. Importantly, recent advances in HPV detection and continued improvements in screening further enhance our opportunities to systematically eradicate HPV-associated malignancy.

Animals↗

PubMed2002

Assessment of therapeutic response of Plasmodium vivax and Plasmodium falciparum to chloroquine in a Malaria transmission free area in Colombia.

In order to determine the frequency of therapeutic failures to chloroquine (CQ) in patients with malaria due to either Plasmodium falciparum or P. vivax, and to explore the usefulness of a malaria-free city as a sentinel site to monitor the emergence of drug resistance, 53 patients (44 infected with P. vivax and 9 with P. falciparum) were evaluated at the Laboratory of Parasitology, Universidad del Valle in Cali, Colombia. Patients received 25 mg/kg of CQ divided in three doses over 48 h; they were followed during 28 days according to WHO/PAHO protocols. While therapeutic failures to CQ in the P. vivax group were not detected, the proportion of therapeutic failures in the P. falciparum group was high (78%) and consistent with the reports from endemic areas in Colombia. The diverse origin of cases presenting therapeutic failure confirmed that P. falciparum resistant to CQ is widespread in Colombia, and further supports the change in the national antimalarial drug scheme. Monitoring of drug resistance in malaria free areas would be useful to identify sites requiring efficacy evaluation, and in some situations could be the most appropriate alternative to collect information from endemic areas where therapeutic efficacy studies are not feasible.

Adolescent↗

PubMed2003

The early impact of therapeutic alliance in brief psychodynamic psychotherapy.

INTRODUCTION: Therapeutic alliance is a key component of the psychotherapeutic process. This study estimated the impact of the therapeutic alliance as measured by CALPAS-P in an individual brief psychodynamic psychotherapy program. METHODS: To study the impact of the therapeutic alliance patients in psychotherapy answered to the CALPAS-P at the first and third session and to the Self-report Questionnaire (SRQ-20), to the Beck Depression Inventory (BDI) and to the Hamilton Anxiety Scale at the beginning and at the end of psychotherapy. RESULTS: The study of the impact of the therapeutic alliance in brief psychodynamic psychotherapy showed that higher TUI scores in the first session were significantly associated to the improvement on the BDI. Patients with best scores in the working alliance, measured at the third PWC session had also significant symptomatic changes. DISCUSSION: The study of the impact of the therapeutic alliance in brief psychotherapy indicated that patients who perceived that their therapists had the best capability to understand and to be involved in their issues had best results in reducing depressive symptoms and patients with higher capability to form the working alliance reached the best psychotherapy outcomes.

Adult↗

PubMed2006

Therapeutic levels of intravenous procainamide in neonates: a retrospective assessment.

STUDY OBJECTIVES: To evaluate dosing and pharmacokinetic parameters of intravenous continuous-infusion procainamide in neonates, and to identify dosage regimens and factors leading to therapeutic procainamide levels and minimal adverse events. DESIGN: Retrospective, observational study. SETTING: Pediatric hospital. PATIENTS: . Twenty-one patients (seven preterm, 14 full term) younger than 30 days who received continuous-infusion procainamide therapy for more than 15 hours or had two consecutive therapeutic procainamide levels obtained while receiving therapy between June 1, 2002, and December 31, 2005. MEASUREMENTS AND MAIN RESULTS: Data on demographics, dosing, drug levels, and adverse effects were collected. Doses that achieved therapeutic levels were documented, and procainamide clearance was calculated and evaluated with regard to renal function and gestational age in patients who were at steady state. Mean clearance and mean N-acetylprocainamide (NAPA):procainamide ratios were compared between preterm and term neonates. No patients experienced hemodynamic instability or other adverse effects due to procainamide. Procainamide was given as a mean +/- SD 9.6 +/- 1.5-mg/kg bolus in 20 of 21 patients before continuous infusion. The mean +/- SD dose at which two therapeutic levels were achieved was 37.56 +/- 13.52 microg/kg/minute. Procainamide clearance was 6.36 +/- 8.85 ml/kg/minute and correlated with creatinine clearance (r=0.78, p<0.00001) and age at day of sampling (r=0.49, p<0.00001). The NAPA:procainamide ratio at steady state was 0.84 +/- 0.53; two patients were determined to be fast acetylators (ratio > 1). Preterm infants had lower mean clearance rates (p<0.001) but higher NAPA:procainamide ratios (p<0.01) than those of term infants. Five patients experienced seven supratherapeutic levels while receiving therapy; four of these patients were preterm, and all had creatinine clearances less than 30 ml/minute/1.73 m(2). Three patients had four pairs of levels obtained after discontinuation of procainamide, and elimination rate constant and half-life were calculated. CONCLUSION: Procainamide can be safely used in neonates, with no short-term adverse effects. The dosage regimen for intravenous procainamide required to achieve therapeutic levels in neonates is similar to that of older infants and children. Doses may need to be reduced in premature infants and in those with renal dysfunction.

Acecainide↗

PubMed2006

Effect of a therapeutic maximum allowable cost (MAC) program on the cost and utilization of proton pump inhibitors in an employer-sponsored drug plan in Canada.

BACKGROUND: Therapeutic maximum allowable cost (MAC) is a managed care intervention that uses reference pricing in a therapeutic class or category of drugs or an indication (e.g., heartburn). Therapeutic MAC has not been studied in Canada or the United States. The proton pump inhibitor (PPI) rabeprazole was used as the reference drug in this therapeutic MAC program based on prices for PPIs in the province of Ontario. No PPI is available over the counter in Canada. OBJECTIVE: To evaluate the utilization and anticipated drug cost savings for PPIs in an employer-sponsored drug plan in Canada that implemented a therapeutic MAC program for PPIs. METHODS: An employer group with an average of 6,300 covered members, which adopted the MAC program for PPIs in June 2003, was compared with a comparison group comprising the book of business throughout Canada (approximately 5 million lives) without a PPI MAC program (non-MAC group). Pharmacy claims for PPIs were identified using the first 6 characters of the generic product identifier (GPI 492700) for a 36-month period from June 1, 2002, through May 31, 2005. The primary comparison was the year prior to the intervention (from June 1, 2002, through May 31, 2003) and the first full year following the intervention (June 1, 2004, through May 31, 2005). Drug utilization was evaluated by comparing the market share of each of the PPIs for the 2 time periods and by the days of PPI therapy per patient per year (PPPY) and days of therapy per prescription (Rx). Drug cost was defined as the cost of the drug (ingredient cost), including allowable provincial pharmacy markup but excluding pharmacy dispense fee. Cost savings were calculated from the allowed drug cost per claim, allowed cost per day, and allowed cost PPPY. RESULTS: (All amounts are in Canadian dollars.) The MAC intervention group experienced an 11.7% reduction in the average cost per day of PPI drug therapy, from 2.14 US dollars in the preperiod to 1.89 US dollars in the postperiod, compared with a 3.7% reduction in the comparison group (2.16 US dollars vs. 2.08 US dollars). Utilization dropped by 11.9% in the intervention group, from 166.7 days of PPI drug therapy PPPY to 146.9 days PPPY, compared with an increase of 7.9% in the comparison group, from 136.1 days to 146.8 days PPPY. The combined effect of the decrease in drug cost per day and utilization was a 22.1% reduction in allowed drug cost PPPY in the intervention (MAC) group (from 357 US dollars to 278 US dollars PPPY) versus a 4.1% increase in the comparison group (from 293 US dollars to 305 US dollars PPPY). CONCLUSION: A MAC program for PPIs for one employer in Canada was associated with savings for the drug plan sponsor of approximately 8% in actual drug cost per day of therapy compared with the comparison group. Total savings after consideration of utilization was approximately 26% for the intervention group versus the comparison group.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Number needed to treat: a descriptor for weighing therapeutic options.

PURPOSE: The utility and limitations of the number needed to treat (NNT) are described and compared with those of alternative descriptors of therapeutic yield. SUMMARY: Pharmacists, physicians, and patients are more likely to launch interventions based on relative measures of therapeutic yield. The NNT is a simple way to express the absolute therapeutic yield of an intervention. It is essential to take baseline risk and length of follow-up into account when calculating and interpreting absolute or relative measures of therapeutic yield. Patients may have difficulty understanding what the NNT tells them about the benefits and harms associated with an intervention, and confidence intervals for the NNT can be difficult to interpret. Relative measures of benefits are advantageous for comparing benefits across populations with different risks. The use of absolute measures to describe therapeutic options leads to more conservative decision-making and is potentially more useful. Among the absolute measures, the absolute risk reduction may be easier to understand than the NNT. These measures are most helpful when the best options are not clear or when patient input is needed. Personal digital assistants and Web-based tools can assist with calculations. CONCLUSION: The NNT is a useful measure but is influenced by numerous variables and may not be easily understood by patients.

Algorithms↗

PubMed1996

The use of therapeutic drug monitoring to optimise immunosuppressive therapy.

Most experience of the therapeutic drug monitoring of immunosuppressive agents has been acquired in the field of solid organ transplantation; however, agents such as cyclosporin (cyclosporin A) are being increasingly utilised for the management of autoimmune diseases. Cyclosporin is the most widely studied immunosuppressant, but in spite of this many controversies still exist as to the optimum strategy for monitoring this drug. Owing to its widely variable pharmacokinetics and metabolism, and the absence of a simple method to measure therapeutic effectiveness, many factors should be considered. In most circumstances, measuring whole blood through concentrations of cyclosporin with a specific assay methodology is warranted. In addition, knowledge of other factors that may alter the pharmacokinetics (such as liver function, concomitant food or medications, gastrointestinal status, and time since transplantation) should be taken into account so that therapy can be appropriately adjusted. Other methods of monitoring have been investigated, such as AUC (area under the concentration-time curve) monitoring and immunological monitoring. However, further refinement of these techniques and greater experience with their efficacy must be accumulated before their role in the monitoring of cyclosporin can be defined. Tacrolimus, like cyclosporin, shares many of the difficulties in monitoring for efficacy and toxicity due largely to the variable pharmacokinetics; similarly to cyclosporin, whole blood through concentration monitoring should be utilised in combination with knowledge of the factors that may affect the pharmacokinetics. Muromonab CD3 (OKT3) is a monoclonal antibody used for the treatment and prophylaxis of acute allograft rejection. Several immunological monitoring techniques have been investigated for this agent. Monitoring CD3+ levels can assist clinicians in determining therapeutic efficacy, while measuring antimuromonab CD3 antibody titres can help determine if xenosensitisation has occurred, causing therapeutic ineffectiveness. The clinical monitoring of azathioprine, one of the first immunosuppressive agents used in transplantation, has historically been limited to monitoring complete blood counts for bone marrow suppression. However, newer techniques measuring intracellular DNA nucleotides appear to be promising. The new immunosuppressants on the horizon include mycophenolate mofetil and rapamycin. The clinical experience with therapeutic drug monitoring of these 2 compounds is scant in the literature; however, both agents have demonstrated efficacy in preventing or treating allograft rejection while maintaining a relatively well tolerated toxicity profile in recent clinical trials. Routine monitoring does not appear to be warranted for immunosuppressive therapy in autoimmune diseases.

Autoimmune Diseases↗

PubMed2003

Therapeutic potential of cannabinoids in CNS disease.

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.

Analgesia↗

PubMed2006

Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics.

The delivery of therapeutic proteins by noninvasive routes of administration has been a challenging goal, hence current modes of delivery generally require injections. However, we have recently shown that a naturally occurring receptor, the neonatal Fc receptor (FcRn) can be utilized to carry aerosolized therapeutic proteins conjugated to a portion of its respective ligand (Fc domain of immunoglobulin G) across epithelial cells of the lung to effectively deliver biologically active molecules to the bloodstream. First-generation dimeric Fc fusion molecules were successfully transported by the pulmonary route and biologic activity was demonstrated in both non-human primates and human volunteers. Continuing efforts to improve transport efficiency have led to the development of an alternate configuration of Fc fusion proteins with improved characteristics. These second generation Fc fusion molecules are monomeric with respect to the therapeutic protein and dimeric with respect to the Fc region, and have been termed Fc fusion 'monomers'. Several different Fc fusion monomers have demonstrated improved transport efficiency, achieving high bioavailabilities for pulmonary delivery in non-human primates. While the traditional dimeric Fc fusion molecule generally increases the half-life compared with the unconjugated effector molecule, the monomer configuration has been shown to result in an even greater extension of the circulating half-life, which improves pharmacokinetic parameters for protein therapeutics, whether administered by pulmonary delivery or injection. Finally, many of the Fc monomer fusions have enhanced biologic activity compared with the dimeric configuration. Because of these many advantages, the monomer configuration promises to be an enabling advance to achieve clinically relevant, noninvasive delivery with potentially less frequent administration regimens for a broad range of protein therapeutics. In addition, molecules that are comprised of heterodimeric subunits or multi-subunit complexes can also be constructed as Fc fusions that result in a molecule with enhanced pharmacokinetics and greater bioactivity. Several examples of novel Fc fusion proteins, both monomer and heterodimer are described herein.

Animals↗

PubMed2003

Preterm labour: an overview of current and emerging therapeutics.

Preterm labour is a major cause of perinatal mortality and morbidity. However, during the past 40 years of clinical studies and despite the use of multiple therapeutic agents, the rate of preterm birth has not drastically declined. In 1991, it was estimated that in the US approximately 116,000 women admitted with acute episodes of preterm labour were treated each year with ritodrine, which is the first drug approved by the US FDA and still remains the standard therapy for treating preterm labour. Ritodrine (Yutopar( trade mark )) stimulates the beta(2)-adrenergic receptor throughout the body, causing an inhibitory action in different tissues that, among other side effects, also leads to an attenuation of uterine contractility. More recently, a new therapeutic agent, atosiban (Tractocile( trade mark )), a peptidic oxytocin receptor antagonist, has been introduced to the market. However, the use of the various pharmacological agents to treat preterm labour remains restricted, due to lack of uterine selectivity, low efficacy and potentially serious side effects for the mother or the foetus. Therefore, there is an urgent need to develop drugs with myometrial selectivity that would allow long-lasting inhibition of labour and prolong pregnancy up to a stage when good foetal maturation raises the chances of survival. One of the major obstacles hampering the development of new therapeutic agents is the marked inter-species difference in terms of preterm labour physiology, which complicates the preclinical evaluation of new candidate molecules in animal models of disease. In this review, the authors will provide a comprehensive update of past, current and new approaches for the management of preterm labour, including beta(2)-adrenergic agonists, calcium channel blockers, oxytocin antagonists, prostaglandin antagonists and other potential therapeutics. For each of the therapies used today, the review will cover the mechanism of action, benefit and adverse effects, and discuss the promise and potential benefits of new emerging therapeutic agents.

Adrenergic beta-Agonists↗

PubMed2005

Improving cancer therapeutics by molecular profiling.

The individualized medicine aims to identify the molecular basis of the individual's response to different therapeutic treatments. Individualized medicine is very relevant for human diseases such as cancer and it has become a major task to accomplish more efficient and specific therapeutics. An individualized response to treatment could underline therapeutic success or failure and, even more, could support the rationale for good or bad prognosis. The use of up to date genomic approaches is changing the way we understand modern medicine in terms of drug efficacy, toxicity and diagnosis. Results from genetic polymorphism studies, gene expression profiling and epigenetics illustrate how pharmacogenomic testing will contribute to the goal of individualized medicine. Antineoplastic drugs are designed to block the anomalous activity of specific molecules (therapeutic targets) that regulate cellular processes such as cell cycle. Understanding the relationship between molecular changes in therapeutic targets and enhanced antitumoral response or chemotherapeutic resistance is crucial to establish the clinical relevance of genomic approaches. The goal of this review is to discuss the basic and the clinical significance of genomic research on drug targets and its impact on the early diagnosis and treatment of cancer. We will also assess how these methodologies could contribute to individualized medicine in oncology. A special focus will be put on oncogenes and tumor suppressor genes. Aspects such as drug efficacy, side effects and the diagnostic value of antineoplastic pharmacogenomic research will be also considered.

Antineoplastic Agents↗

PubMed2002

Short-term effect of therapeutic shoeing on severity of lameness in horses with chronic laminitis.

OBJECTIVE: To evaluate the short-term effects of 4 therapeutic shoeing systems on lameness and voluntary limb-load distribution in horses with chronic laminitis. ANIMALS: 10 horses with chronic laminitis. PROCEDURES: A clinical trial was conducted that used a concurrent control, crossover design to evaluate the relative effectiveness of a standard flat shoe, fullered egg-bar shoe, heart-bar shoe, and modified equine digital support system to alleviate chronic lameness in horses. Therapeutic success was assessed during a 7-day period by use of subjective (Obel grade and clinical score) and objective (force-plate data) evaluations. RESULTS: Comparison of pretreatment and intertreatment control data indicated that disease status of the horses did not change during the course of the study. None of the therapeutic shoeing treatments used resulted in a significant change in severity of lameness. CONCLUSIONS AND CLINICAL RELEVANCE: Results were interpreted to imply that substantial clinical improvement should not be expected during the first 7 days after therapeutic shoeing for the specific shoes tested in this study. On the basis of our results, we hypothesize that when used as the lone indicator of therapeutic success, severity of lameness may not be a valid indicator.

Animals↗

PubMed2006

Stress-related behaviors among horses used in a therapeutic riding program.

OBJECTIVE: To determine whether therapeutic riding resulted in higher levels of stress or frustration for horses than did recreational riding and whether therapeutic riding with at-risk individuals was more stressful for the horses than was therapeutic riding with individuals with physical or emotional handicaps. DESIGN: Observational study. ANIMALS: 14 horses in a therapeutic riding program. PROCEDURE: An ethogram of equine behaviors was created, and horses were observed while ridden by 5 groups of riders (recreational riders, physically handicapped riders, psychologically handicapped riders, at risk children, and special education children). Number of stress-related behaviors (ears pinned back, head raised, head turned, head tossed, head shaken, head down, and defecation) was compared among groups. RESULTS: No significant differences in mean number of stress-related behaviors were found when horses were ridden by recreational riders, physically handicapped riders, psychologically handicapped riders, or special education children. However, mean number of stress-related behaviors was significantly higher when horses were ridden by the at-risk children. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that for horses in a therapeutic riding program, being ridden by physically or psychologically handicapped individuals is no more stressful for the horses than is being ridden in the same setting by recreational riders. However, at-risk children caused more stress to the horses, suggesting that the time horses are ridden by at-risk children should be limited both daily and weekly.

Adult↗

PubMed2005

Colorectal liver metastasis: towards the integration of conventional and molecularly targeted therapeutic approaches.

Radical surgery currently represents the only treatment with curative potential for patients with colorectal cancer (CRC) liver metastases. Unfortunately, only a minority of cases is eligible for hepatic resection and many patients still develop recurrent disease, which underscores the need for more effective adjuvant treatments. In case of unresectable disease, locoregional therapeutic strategies can obtain significant tumor regression/local disease control rates, but there is no definitive evidence of their effect on patients' survival. In regards to systemic chemotherapy, the conduction of randomized controlled trials has led to a substantial progress in terms of both tumor response and survival rates. Despite these results, most patients ultimately die of their disease due to hepatic and/or extra-hepatic cancer progression. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with metastatic CRC. The elucidation of CRC biology is paving the way to the development of molecularly targeted strategies, and results from controlled clinical trials have already demonstrated that some agents targeting tumor-specific molecules can significantly improve the therapeutic efficacy of conventional antineoplastic drugs. The dissection of the molecular mechanisms of CRC metastatization and tumor/host interactions will not only accelerate the development of more effective and less toxic anticancer strategies but also will allow for the personalization of the therapeutic regimen according to the molecular features of individual patients and their tumors. Only the broader clinical implementation of these novel molecular oncology findings and the optimal integration of conventional and molecularly targeted therapeutic approaches will enable clinicians to provide patients with a better chance of cure.

Antineoplastic Agents↗

PubMed2002

From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementia.

Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) may protect against Alzheimer's disease (AD). However, therapeutic studies with NSAIDs, including cyclooxygenase (COX) inhibitors and steroids have not supported such epidemiological evidence. The apparent inconsistency may be due to the fact that the epidemiological evidence is based on studies examining AD before clinical manifestations are apparent, while therapeutic studies have been carried out on people with illnesses severe enough to exceed the clinical detection threshold. Thus, it is conceivable that therapeutic strategies administered during early AD dementia or moderate dementia may not be optimally effective. Alternatively, the influence of inflammatory activity in the brain for cases at high risk to develop AD, e.g., mild cognitive impairment (MCI) cases, as a potential target of anti-inflammatory drugs in clinical studies maybe more suitable to be studied. The primary action of NSAIDs is inhibition of the COX enzymes. COX enzymes exist in an inducible form COX-2, that has been found to be elevated in the AD brain, and a constitutive form COX-1. Both COX-1 and COX-2 are known to be involved in numerous inflammatory activities as well as normal neuronal functions. In vitro, it has been demonstrated that non-selective inhibitors of COX can preferentially decrease the levels of the highly amyloidogenic amyloid-beta (Abeta)(1-42)peptide. Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Abeta plaque deposits in the brains of these animals can be significantly reduced by treatment with the non-selective COX inhibitor ibuprofen. These studies and epidemiological data strongly support a therapeutic potential for NSAIDs in the treatment of AD. Upon this premise, industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of AD. However, given the large number of candidate anti-inflammatory drugs and their widely divergent activities, it is essential to optimize drug selection and study design. A better understanding of the influence of inflammatory activity in AD, and identification of the specific mechanisms which play an early role in the disease's progression will greatly improve the likelihood of success in efforts to find an effective anti-inflammatory treatment strategy. We would like to discuss recent developments reinforcing anti-inflammatory drugs as therapeutic in the treatment of AD amyloidosis, and the relevance of understanding the role of COX and other inflammatory mediators in AD neuropathology and the clinical progression of AD dementia. These discussions may provide important criterion for the design of clinical trials of anti-inflammatory drugs in AD.

Alzheimer Disease↗