Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome

Introduction: Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or – the most feared and life-threatening symptom – aortic root dissection are the most common manifestations. Therapeutic strategies, such as prophylactic aortic root surgery and pharmacological therapy, focus on the prevention of aortic dissection. Currently, the standard medicinal treatments targeting aortic dilatation and dissection consist of agents generally used to lower blood pressure and/or the inotropic state of the heart. By these means, the cyclic repetitive forces exerted on the aortic wall are diminished and thus the onset of aortic dilatation is potentially prevented. Although these pharmacological agents may offer some benefit in reduction of aortic aneurysm expansion rate, they do not target the underlying cause of the progressive aortic degradation.

Areas covered: This review discusses the effectiveness of frequently prescribed medications used to prevent and delay aortic complications in Marfan syndrome. New insights on the biochemical pathways leading to aortic disease are also discussed to highlight new targets for pharmacological therapy.

Expert opinion: Recent insights in the transforming growth factor beta signaling pathway and inflammatory mechanisms in a well-established mouse model of Marfan syndrome, have led to studies exploring new pharmacological treatment strategies with doxycycline, statins and angiotensin II receptor blockers. Pharmacological therapy is focused more on prevention than on delay of aortic wall pathology in Marfan syndrome. Of the new pharmacological treatment strategies targeting aortic pathology in Marfan syndrome, angiotensin receptor type 1 blockers are promising candidates, with several clinical trials currently ongoing.     

马方综合征主动脉根部瘤的手术时机和治疗对策

目的 总结马方综合征合并主动脉根部瘤的外科治疗经验,探讨手术时机和手术方法,总结疗效.方法 1995年2月至2009年8月手术治疗马方综合征主动脉根部瘤113例;其中合并主动脉夹层59例,DeBakey Ⅰ型主动脉夹层50例,DeBakeyⅡ型主动脉夹层9例;根部瘤合并中-重度主动脉瓣关闭不全81例,合并中-重度二尖瓣关闭不全9例,根部瘤直径平均(68±15) mm;术前心功能分级Ⅱ级70例,Ⅲ级32例,Ⅳ级11例.本组施行Bentall手术97例,Wheat手术6例,Cabrol手术6例,主动脉替换加升主动脉成形术4例.其中急诊手术40例,择期手术73例.同期施行二尖瓣成形术3例,二尖瓣替换术3例,冠状动脉搭桥术2例,全弓置换加术中支架象鼻术3例.结果 全组术后死亡3例,死亡率为2.6％. 102例随访3～157个月,平均(78±49)个月.晚期死亡5例,随访102例,心功能Ⅰ～Ⅱ级98例,Ⅲ级4例.结论 Bentall手术仍是治疗马方综合征主动脉根部瘤的首选方法,远期随访效果良好.对有家族史的患者避免形成主动脉夹层和主动脉破裂,根部直径≥4.5 cm推荐手术治疗.     

Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) affects about one-third of patients with IBS, which is observed in about 12% of people across five continents. The ultimate goal in this field is to identify the underlying cause of symptoms in order to individualize education of the patient, and to provide optimal treatment of this highly prevalent condition.

Areas covered: This review addresses the pharmacological treatments for IBS-D under three categories: drugs for IBS-D (i.e., the 5-HT₃ antagonist, alosetron); drugs approved for other indications that are used in IBS-D (e.g., opioid agonists; other 5-HT₃ antagonists; serotonergic psychoactive agents; bile acid binders; 5-ASA compounds; probiotics and non-absorbable antibiotics); as well as development of drugs that are likely to impact the management of IBS-D in the future (e.g., drug absorbents; TPH₁ inhibitors; mast cell stabilizers; centrally acting benzodiazepines). The final section addresses key findings: regulatory roadblocks; weaknesses in the current research in this field so far and opportunities to address unmet needs including restoration of normal intestinal barrier function or permeability, and suppression within the intestines of local immune activation that is thought to trigger abnormal motor, sensory and secretory functions in IBS-D.

Expert opinion: While symptomatic treatment of diarrhea is effective, there is a need for new treatments for the IBS-D complex. Greater understanding of the mechanisms in IBS-D has led to promising approaches to develop more efficacious therapies.     

Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease

Background: Allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin. However, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application. Objective: This review will provide an overview of the pathophysiology of GVHD and discuss the recent advances in GVHD management in both preclinical and clinical studies. Methods: An extensive literature search on PubMed from 1995 to 2008 was performed. Results/conclusion: There has been much progress in our understanding of GVHD and finding new means to control acute GVHD. While these approaches hold promise, as yet none has been able to replace the standard methods we may use routinely to decrease the incidence of the condition.     

Current and future treatment of Lyme disease

Lyme borreliosis, a tick-transmitted spirochetal disease, may begin with a characteristic expanding skin lesion at the site of the tick bite. Within several days to weeks, the infection can spread haematogenously to involve the heart, nervous system or the joints. After months to years, the spirochete may persist in these organs causing a chronic form of illness. All stages of this disease can be treatable with antimicrobial agents.     

Current and future treatment of Lyme disease

Lyme borreliosis, a tick-transmitted spirochetal disease, may begin with a characteristic expanding skin lesion at the site of the tick bite. Within several days to weeks, the infection can spread haematogenously to involve the heart, nervous system or the joints. After months to years, the spirochete may persist in these organs causing a chronic form of illness. All stages of this disease can be treatable with antimicrobial agents.     

Current and future pharmacological intervention for diabetic retinopathy

Diabetic retinopathy (DR) is a potentially visually devastating complication of chronic hyperglycaemia. Prospective, randomised clinical trials have delineated the standard prevention protocols, including intensive glycaemic, blood pressure, and lipid control, and laser photocoagulation treatment for neovascularisation and clinically significant macular oedema. However, despite these interventions, vision loss from DR still occurs at an alarming rate. Researchers have directed their efforts towards better understanding the specific biological and chemical changes occurring in DR to develop more targeted pharmacological prevention and treatment strategies. This review of diabetic retinopathy will primarily detail the therapies in development at present, including aldose reductase inhibitors, advanced glycosylation end product inhibitors, antioxidants, supplemental oxygen, growth factor modulators including vascular endothelial growth factor inhibitors and protein kinase C inhibitors, extracellular matrix modifiers including corticosteroids, and vitreous modulators. The experimental therapies alter several different pathways that lead to DR. Future research will further delineate these pathways, and therapy is likely to involve arresting several different promoters of DR.     

Current and future pharmacological intervention for diabetic retinopathy

Diabetic retinopathy (DR) is a potentially visually devastating complication of chronic hyperglycaemia. Prospective, randomised clinical trials have delineated the standard prevention protocols, including intensive glycaemic, blood pressure, and lipid control, and laser photocoagulation treatment for neovascularisation and clinically significant macular oedema. However, despite these interventions, vision loss from DR still occurs at an alarming rate. Researchers have directed their efforts towards better understanding the specific biological and chemical changes occurring in DR to develop more targeted pharmacological prevention and treatment strategies. This review of diabetic retinopathy will primarily detail the therapies in development at present, including aldose reductase inhibitors, advanced glycosylation end product inhibitors, antioxidants, supplemental oxygen, growth factor modulators including vascular endothelial growth factor inhibitors and protein kinase C inhibitors, extracellular matrix modifiers including corticosteroids, and vitreous modulators. The experimental therapies alter several different pathways that lead to DR. Future research will further delineate these pathways, and therapy is likely to involve arresting several different promoters of DR.     

Current and future immunosuppressive strategies in renal transplantation

The past decade has witnessed the introduction of several new immunosuppressive agents. The availability of these new pharmacologic offerings has not diminished the challenge of achieving a balance of adequate graft protection while minimizing the consequences of excessive immunosuppression. For renal transplant recipients, maintenance immunosuppression generally consists of a calcineurin inhibitor in combination with an antiproliferative agent and a corticosteroid; more recently, mammalian target of rapamycin inhibitors have been used. Excellent results have been achieved at many transplant centers with combinations of these agents in a variety of protocols. Regimens designed to limit or eliminate calcineurin inhibitor and/or corticosteroid therapy are actively being pursued in the transplant community. Allograft tolerance and xenotransplantation are being studied, and the knowledge gained from the effort may help in the development of innovative strategies and new immunosuppressive agents.     

Progress with novel pharmacological strategies for gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis.In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.     

Current and future strategies against cutaneous parasites

Pharmaceutical Research - Cutaneous parasites are identified by their specific cutaneous symptoms which are elicited based on the parasite’s interactions with the host. Standard...     

Current and emerging drug treatment strategies for peripheral arterial disease

ABSTRACT

Introduction

Peripheral artery disease (PAD) is a prevalent but underdiagnosed manifestation of atherosclerosis that has a worse prognosis than coronary artery disease. Patients with PAD are at heightened risk of both systemic cardiovascular adverse events and limb-related morbidity. There is insufficient awareness of its clinical manifestations, including intermittent claudication and critical limb ischemia and of its risk of adverse cardiovascular and limb outcomes.     

Current pharmacological approaches to the treatment of tendinopathy

ABSTRACT

Introduction

Tendinopathies are common in elite and recreational athletes: traditionally considered overuse injuries, they involve excessive tensile loading and subsequent breakdown of the loaded tendon. Many pharmacological treatments have been proposed for the management of tendinopathy, with no agreement regarding the overall best option available both for Achilles and patellar tendinopathy.     

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.     

Current strategies for the treatment of Alzheimer's disease and other tauopathies

The pathological hallmarks of Alzheimer's disease (AD) include abnormal intra- and extraneuronal tau and amyloid accumulation, respectively, accompanied by gliosis, oxidative stress and neuron loss. The discovery of mutations within the tau gene itself that cause clinical dementia (i.e., fronto-temporal dementia with Parkinsonism linked to chromosome 17 [FTDP17]) demonstrated that disruption of normal tau function independent of amyloidogenesis was sufficient to cause neuronal loss and clinical dementia. These studies demonstrate the need for therapeutics that either decrease the total pool of tau or selectively reduce aberrant forms of tau (i.e., hyperphosphorylated, misfolded etc.). To this point, therapeutic development for tauopathies, including AD, have primarily focused on either the phosphorylation of tau, as it is a downstream target for many kinases and signalling cascades, or inhibition of tau aggregation. Recent developments, however, suggest that pharmacological targeting of other mechanisms may hold therapeutic promise for the treatment of tauopathies.     

Variceal bleeding : pharmacological treatment and prophylactic strategies

Oesophageal varices and ascites may develop when the hepatic venous pressure gradient (HVPG) increases above 10 mmHg, and variceal bleeding may occur when the HVPG rises above 12 mmHg. Pharmacological therapy of portal hypertension may prevent bleeding by reducing the HVPG below 12 mmHg. Even if this threshold level is not reached, the risk of bleeding decreases markedly with reductions in HVPG that are >20% from baseline.Endoscopic therapy is a local treatment that prevents bleeding by obliterating the varices, and has no effect on the pathophysiological mechanisms that lead to portal hypertension and variceal rupture. When used together, both pharmacological and endoscopic therapies may have an additive effect, which has been demonstrated in different clinical settings. In acute oesophageal variceal bleeding, vasoactive drugs (either terlipressin or somatostatin) should be started as soon as possible (before diagnostic endoscopy) and maintained for 2-5 days. The efficacy of pharmacotherapy is improved with the addition of emergency endoscopic therapy. Adding endoscopic variceal ligation (EVL) improves the efficacy and safety achieved with the combination of emergency sclerotherapy and vasoactive drugs. Antibacterial prophylaxis should be an integral part of therapy in acute bleeding.To prevent rebleeding, both EVL and the combination of beta-adrenoceptor antagonists (beta-blockers) and isosorbide mononitrate (ISMN) may be a valid first-line choice. Adding beta-blockers improves the efficacy of EVL alone. Haemodynamic responders to beta-blockers with or without ISMN (i.e. those with a decrease in HVPG to <12 mmHg or by >20% of baseline) have a reduction in the risk of haemorrhage to below 10% of patients and, consequently, will not need further treatment, while rescue therapies should be provided to nonresponders. Transjugular intrahepatic portosystemic shunts are the recommended rescue therapy when EVL and/or beta-blockers with or without ISMN fail. beta-Blockers significantly reduce the risk of a first haemorrhage in patients with large varices and improve survival. Compared with beta-blockers, EVL reduces the risk of first bleeding without any differences in mortality and should be offered to patients with large varices who have contraindications or an intolerance to beta-blockers.