Pharmacological Modalities Research Articles

Update on cutaneous laser therapy: recent medical advances of laser light and skin interactions

The introduction of the theory of selective photothermolysis has brought to medicine an entirely new therapeutic modality for treating cutaneous disorders. With ongoing research into existing therapies, cutaneous laser medicine is experiencing an expansion in application and safety profiles for many existing technologies. Additional trials and reports have also deepened our understanding and broadened our use for many existing cutaneous laser applications, such as for the treatment of pigment disorders, scarring, vascular disorders and noninvasive removal of fat. Recent data has demonstrated a valuable role of combined pharmacologic and laser modalities for the treatment of vascular malformations. This article will review recent developments of cutaneous laser science and technologies over the last several years, including such innovations as fractional photothermolysis and cryolipolysis.

Recommendations of the OARSI FDA Osteoarthritis Devices Working Group

Osteoarthritis (OA) is the most common type of arthritis and a major cause of chronic musculoskeletal pain and functional disability. While both pharmacologic and non-pharmacologic modalities are recommended in the management of OA, when patients with hip or knee OA do not obtain adequate pain relief and/or functional improvement, joint replacement surgery or other surgical interventions should be considered. Total joint arthroplasties are reliable and cost-effective treatments for patients with significant OA of the hip and knee. Evidence from cohort and observational studies has confirmed substantial improvements in pain relief with cumulative revision rates at 10 years following total hip (THA) and total knee arthroplasties (TKA) at 7% and 10%, respectively. Joint replacements have been used in most every synovial joint, although results for joints other than hip and knee replacement have not been as successful. The evolution of new device designs and surgical techniques highlights the need to better understand the risk to benefit ratio for different joint replacements and to identify the appropriate methodology for evaluating the efficacy and optimal outcomes of these new devices, designed to treat OA joints.

Have the metabolic support pendulums in the intensive care unit stopped swinging?

Have the metabolic support pendulums in the intensive care unit stopped swinging?

Burns: where are we standing with propranolol, oxandrolone, recombinant human growth hormone, and the new incretin analogs?

The hypermetabolic response in critically ill patients is characterized by hyperdynamic circulatory, physiologic, catabolic and immune system responses. Failure to satisfy overwhelming energy and protein requirements after, and during critical illness, results in multiorgan dysfunction, increased susceptibility to infection, and death. Attenuation of the hypermetabolic response by various pharmacologic modalities is emerging as an essential component of the management of severe burn patients. This review focuses on the more recent advances in therapeutic strategies to attenuate the hypermetabolic response and its associated insulin resistance postburn. At present, beta-adrenergic blockade with propranolol represents probably the most efficacious anticatabolic therapy in the treatment of burns. Other pharmacological strategies include growth hormone, insulin-like growth factor, oxandrolone and intensive insulin therapy. Novel approaches to the management of critical illness by judicious glucose control and the use of pharmacologic modulators to the hypercatabolic response to critical illness have emerged. Investigation of alternative strategies, including the use of metformin, glucagon-like-peptide-1 and the PPAR-γ agonists are under current investigation.

Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer

Triple-negative breast cancers, which represent 10–20% of all mammary tumours, are characterised by the aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer development. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed. Here we examined if the leptin (obesity hormone) receptor is a viable target for the treatment of this cancer subtype. In human triple-negative breast cancer tissues, the leptin receptor was expressed in 92% (64/69) and leptin in 86% (59/69) of cases. In a model triple-negative breast cancer cell line MDA-MB-231, the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation at 50pM concentration. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously significantly extended the average survival time from 15.4days (untreated controls) to 24 and 28.1days at 0.1 and 1mg/kg/day doses, respectively. In parallel, conventional treatment with 1mg/kg/day intraperitoneal cisplatin prolonged the average survival time to 18.6days, while administration of 20mg/kg/day oral Tamoxifen (negative control) had no significant survival effects relative to controls. In normal CD-1 mice, Allo-aca produced no systemic toxicity up to the highest studied subcutaneous bolus dose of 50mg/kg, while, as expected, it induced a modest 6–10% body weight increase. Our results indicate that leptin receptor antagonists could become attractive options for triple-negative breast cancer treatment, especially in the obese patient population.

Review article: the functional abdominal pain syndrome

Functional abdominal pain syndrome (FAPS) is a debilitating disorder with constant or nearly constant abdominal pain, present for at least 6 months and loss of daily functioning. To review the epidemiology, pathophysiology and treatment of FAPS. A literature review using the keywords: functional abdominal pain, chronic abdominal pain, irritable bowel syndrome and functional gastrointestinal disorders. No epidemiological studies have focused specifically on FAPS. Estimates of prevalence range from 0.5% to 1.7% and tend to show a female predominance. FAPS pathophysiology appears unique in that the pain is caused primarily by amplified central perception of normal visceral input, rather than by enhanced peripheral stimulation from abdominal viscera. The diagnosis of FAPS is symptom-based in accordance with the Rome III diagnostic criteria. These criteria are geared to identify patients with severe symptoms as they require constant or nearly constant abdominal pain with loss of daily function and are differentiated from IBS based on their non-association with changes in bowel habit, eating or other gut-related events. As cure is not feasible, the aims of treatment are reduced suffering and improved quality of life. Treatment is based on a biopsychosocial approach with a therapeutic patient-physician partnership at its base. Therapeutic options include central nonpharmacological and pharmacological modalities and peripheral modalities. These can be combined to produce an augmentation effect. Although few studies have assessed functional abdominal pain syndrome or its treatment specifically, the treatment strategies outlined in this paper appear to be effective.

Commentary on an article by Noriyuki Ishiyama, MD, et al.: “Reduction of Peritendinous Adhesions by Hydrogel Containing Biocompatible Phospholipid Polymer MPC for Tendon Repair”

Peritendinous adhesions that form after the repair of lacerated digital flexor tendons cause stiffness and functional impairment. In the healing process, tendon regeneration and scarring are, probably, the two sides of the same coin. Surgeons, physical therapists, and basic scientists have explored new surgical and rehabilitation methods, pharmacological modalities, and nonpharmacological modalities (including ultrasound and pulsed electromagnetic field stimulation) to allow unrestricted gliding of the digital tendons. Pharmacological adjuvants fall into two main categories, namely, drugs (e.g., nonsteroidal anti-inflammatory drugs, hyaluronic acid, and 5-fluorouracil) and barriers1,2. The authors explored a novel management modality …

Apnea of prematurity: pathogenesis and management strategies

Apnea of prematurity (AOP) is a significant clinical problem manifested by an unstable respiratory rhythm reflecting the immaturity of respiratory control systems. This review will address the pathogenesis of and treatment strategies for AOP. Although the neuronal mechanisms leading to apnea are still not well understood, recent decades have provided better insight into the generation of the respiratory rhythm and its modulation in the neonate. Ventilatory responses to hypoxia and hypercarbia are impaired and inhibitory reflexes are exaggerated in the neonate. These unique vulnerabilities predispose the neonate to the development of apnea. Treatment strategies attempt to stabilize the respiratory rhythm. Caffeine remains the primary pharmacological treatment modality and is presumed to work through blockade of adenosine receptors A(1) and A(2). Recent evidences suggest that A(2A) receptors may have a greater role than previously thought. AOP typically resolves with maturation suggesting increased myelination of the brainstem.

Recent Advances in the Pathogenesis and Treatment of Osteoarthritis

671 Aging Health (2010) 6(6), 671–674 10.2217/AHE.10.72 © 2010 Future Medicine Ltd The opening ceremony featured several keynote speakers: the famous epidemiologist Weiya Zhang from the University of Nottingham (UK) and the world-class researcher Anthony Robin Poole from the McGill University of Montreal (Canada). Zhang’s lecture was entitled ‘Metaepidemiology: building the bridge from research evidence to clinical practice’, whereas Poole presented a lecture titled ‘Cartilage: inside out’. These lectures were preceded by the awards ceremony. Each year, the OARSI gives out a basic science and a clinical research award. This year, the winners were Felix Eckstein (clinical award) and Martin Lotz (basic research award). Eckstein, born 1964 in Freiburg, Germany, studied Medicine in Freiburg and Heidelberg, where he graduated in 1991. In 1991, he joined the research group led by Reinhard Putz at the Institute of Anatomy at the Ludwig Maximilians University (LMU), Munich, Germany, to work on joint morphology and mechanics. In 2004, Eckstein became Professor of Anatomy and Director of the Institute of Anatomy and Musculoskeletal Research at the Paracelsus Private Medical University (PMU) in Salzburg, Austria. The research by Eckstein’s team focuses on the integration of imaging methods for understanding the morphology, function and disease of musculoskeletal tissues, in particular OA and osteoporosis. Lotz is currently head of the Division of Arthritis Research at Scripps Research Institute (La Jolla, CA, USA). He received his award for his work on chondrocyte differentiation, apoptosis and OA. His studies on human joint aging in vitro and in animal models led to the identification of cell death as an important event in the pathogenesis of aging-related and post-traumatic OA. He also found that inhibitors of cell death were effective in reducing cartilage damage in vitro and in vivo; some of these inhibitors are currently being developed as treatments to address inflammation after joint injury and to prevent the development of OA. The Osteoarthritis Research Society International (OARSI) is the premier i nternational organization for scientists and healthcare professionals focused on the prevention and treatment of osteoarthritis (OA) through the promotion and presentation of research, education and the worldwide dissemination of new knowledge. The mission of the OARSI is to provide quality educational opportunities and disseminate research on OA throughout the world. In order to accomplish this goal, OARSI sponsors yearly conferences and workshops, a superb academic journal, Osteoarthritis and Cartilage, a newsletter covering society business as well as medical and research developments and important committees, such as the Osteoarthritis Clinical Trials Design Task Force. The 2010 OARSI World Congress, ‘Osteoarthritis: Start a New Decade’, was a great opportunity for the OARSI to assess the events of the last decade and to draw up the goals of the following one. More than 1000 of the world’s leading scientists, clinicians and o thers interested in OA convened in Brussels for this event featuring the latest research and c linical updates in OA. The program was chaired by Yves Henrotin and Amanda Fosang, with the participation of the previous president, Francis Berenbaum. This year’s program covered the most topical issues related to cartilage and OA, including the mechanisms of cartilage degradation, nonpharmacological and pharmacological modalities, obesity, angiogenesis, animal models, mechanobiology, imaging, biomarkers, epidemiology, genetics, spine OA, dietary and surgery. A debate session co-chaired by Matthew Warman (Children’s Hospital, Boston, MA, USA) and T Spector (King’s College London, UK) dedicated to genome-wide association studies. A precongress workshop was organized to inform the attendees of the evolving evidence and changes in the OARSI recommendations for the m anagement of knee and hip OA. CONFERENCE SCENE

Beginning the Treatment of Musculoskeletal Pain

The selection of appropriate therapy for the management of musculoskeletal pain requires understanding the general principles of pain management and recognizing the importance of using both nonpharmacologic and pharmacologic modalities. Aspects to consider include the type of pain, its intensity and duration, presence of comorbidities and/or use of concomitant medications, patient age, likelihood of adverse effects, psychosocial factors, past pain treatments, patient preferences, and costs.

Osteoarthritis: etiology, epidemiology, impact on the individual and society and the main principles of management

Etiology, epidemiology, and impact of osteoarthritis on an individual, society, and nation and the main principles of management of this disease are reviewed in the article. Treatment should be tailored to the needs of an individual patient. Physicians should be familiar with pharmacologic and nonpharmacologic treatment modalities to maximize effective utilization and a thorough understanding of short- and long-term complications and costs. Severity of osteoarthritis should be taken into physician's and patient's consideration while applying an appropriate treatment. A stepwise management of osteoarthritis has to be taken into account. As effective interventions remain underused, state arthritis programs, including osteoarthritis programs, have to be developed to build an appropriate scientific base in public health, observe burden and impact, assess and disseminate evidence-based interventions, and work to reduce and delay disability, and improve quality of life among people with arthritis. Adequate studies on the costs of osteoarthritis are urgently required so that cogent arguments can be made to governments to appropriately fund prevention and treatment programs for this condition. Its recognition as a major cause of disability, particularly in the aging population, should increase community focus on this important condition. Osteoarthritis as a pathogenic process and its impact on an individual and society should be taken into special consideration by health providers and officers developing the national health policy in Lithuania, because there is a lack of information related to the prevalence of osteoarthritis, risk factors, also osteoarthritis-associated disability, and costs of the management of this disease among Lithuanian inhabitants.

The burden of osteoarthritis:the societal and the patient perspective

Osteoarthritis (OA) is a highly prevalent disease affecting mainly knees, hips and hands. It has potentially devastating effects on health-related quality of life and will represent an increasing economic burden in the future. Moreover, pain and physical disability brought about by OA also affect social functioning and mental health, further diminishing the patient’s quality of life. The burden of OA is therefore considerable, both from a societal and individual patient perspective. OA is a multifactorial disease with age being the major risk factor. As a consequence of aging populations in western and developing countries, OA will contribute to an increase of health-related burden for individuals as well as for the society. Both pharmacological and nonpharmacological treatment modalities are important, but the choice of therapy in individual patients must take into account evidence for effectiveness and individual factors.

Propranolol in the management of periorbital infantile haemangioma

Infantile haemangiomas are the commonest tumours of the orbit in children. Treatment is usually expectant, unless they are visually threatening. Although steroids, other pharmacological and surgical treatment modalities have their place, there are risks involved. A previous case series reported the successful use of propranolol for infantile haemangioma. The safety and efficacy of propranolol in the treatment of periorbital haemangioma was reviewed in a serious of our patients. We performed a retrospective review of patients seen by two ophthalmologists (TJS and GAG), collecting data on colour, size of lesion, duration of treatment and side-effects of treatment. Our main outcome measures were colour and size of infantile haemangioma before and after treatment, the change in astigmatism of our patients and the incidence of complications from propranolol. We reviewed 10 patients with infantile haemangioma. They were treated with propranolol oral syrup 2 mg/kg/day in divided doses for a mean duration of 32.8 (range 12-42) weeks. All our patients had a reduction in colour and size of the lesions. The mean lesion size decreased from 756.7 to 543.2 mm(2) after treatment (P = 0.075). Five patients had significant astigmatism and 60% had successful reduction of astigmatism after treatment. None of our patients suffered significant side-effects of propranolol. Propranolol appears to be a safe and effective treatment in the management of infantile haemangioma.

Reduction of adhesion formation and promotion of wound healing after laminectomy by pharmacological inhibition of pro-inflammatory cytokines: an experimental study in the rat

In a previous experiment using TNF inhibition in the rat it was accidentally found that adhesion and scar formation was reduced compared to previous experience. Wound and bone healing also seemed enhanced. The present study was conducted to assess if this observation could be verified in a controlled setting using a standardized laminectomy in the rat. Five rats received doxycycline and five other rats received saline and served as control. Macroscopic blinded evaluation 1 week after the laminectomy revealed that adhesion and scar formation was less in doxycycline-treated animals than in control animals. Wound and bone healing was found to be better in doxycycline-treated animals. The mechanisms for the observed effects cannot be fully understood but the data indicate that further research may lead to opportunities to design pharmacological modalities to reduce adhesion and scar formation, maybe in combination with suitable barriers.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Vertebral augmentation techniques for the treatment of vertebral compression fractures: A review

Vertebral augmentation techniques have become enormously popular procedures in the United States and abroad for the treatment of painful vertebral compression fractures. This minimally invasive procedure avoids or mitigates the direct and indirect adverse effects of pharmacologic and conventional pain treatment modalities while providing pain relief and improved function in an expedited fashion. Vertebral augmentation procedures include percutaneous vertebroplasty, the injection of bone cement directly into a fractured vertebral body, and balloon kyphoplasty, in which an inflatable bone tamp is employed to create a cavity in the bone prior to cement injection. These procedures are performed on fractures of thoracolumbar vertebrae and the sacral vertebrae (sacroplasty). Until recently, the efficacy of vertebral augmentation procedures had been supported in numerous case reports, case series, and nonrandomized trials. Practitioners valued the procedures, and patients seemed to prefer the active intervention as opposed to medical therapy. However, the level of evidence of these early reports was fair to poor because of the lack of randomized, controlled trials. Recent prospective, randomized, and controlled trials have done little to confirm or deny the efficacy of the techniques. In general, they have found percutaneous vertebroplasty or balloon kyphoplasty either beneficial or not different compared with conservative therapy with regards to primary (pain and disability) and secondary outcome indexes (quality of life, analgesic usage, etc.). The direction of future studies should be directed at endpoints, such as short-term benefits, cost-effectiveness, and longer-term prognosis, and should include adequate sample sizes to allow stratification of patients according to history and physical findings.

Stress Fractures in Athletes

Stress fractures that occur in the young active population typically represent an overuse injury, and may lead to prolonged periods of restriction from play if they are not treated appropriately. Several risk factors have been identified and must be addressed when treating these patients. Low-risk stress fractures can be successfully treated with activity restriction and a stepwise return to sport. Several pharmacologic and nonoperative treatment modalities have been described. However, high-risk stress fractures are more difficult to treat because they may have an increased rate of delay and nonunion, and often require surgical stabilization. When treating an athlete with a stress fracture, the objective is a safe and quick return to sport; therefore, special considerations must be made in this population, particularly when dealing with the in-season athlete.

Primary prevention of venous thromboembolism in medical and surgical oncology patients

Recent data suggest that patients with a malignancy have a seven-fold increased risk for venous thromboembolism (VTE) compared with those without cancer, suggesting that these patients may benefit from thromboprophylaxis. Mechanisms for the prevention of thromboembolism can be divided into two broad categories: mechanical and pharmacological. Although generally used in combination with pharmacotherapy, little evidence exists for the efficacy of mechanical modalities either in the broader population of patients at risk for VTE or for patients with cancer specifically. A recent study using graduated compression stockings (GCS) for thromboprophylaxis showed no support for the use of stockings in acute stroke patients. Established pharmacological modalities, including warfarin, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the factor Xa inhibitor fondaparinux, have been shown to reduce risk for VTE in general medical and surgical populations. In medical cancer patients, only limited data are available for the efficacy of thromboprophylaxis. In contrast, considerable evidence indicates that thromboprophylaxis is warranted in patients undergoing cancer surgery. The most recent evidence suggests that catheter-related thrombosis is not prevented by current pharmacological modalities. On 22 May 2009, a group of clinicians based in the United Kingdom (UK) met in London, UK, to evaluate recent data on cancer thrombosis. This article (the second of four) briefly reviews key data on the prevention of VTE in medical and surgical oncology patients, providing context for a brief transcript of the surrounding discussion and a consensus statement, developed by meeting attendees, on the implications of this information for UK clinical practice.

Role of bracing in the management of knee osteoarthritis

Recommendations for nonpharmacological treatment for knee osteoarthritis are based mainly on modifying the symptomatic loading joint compartment. Braces are one of the modalities used to modify joint loading. Knee osteoarthritis braces consist of rest orthoses, knee sleeves, and unloading-knee braces. This review examines the most recent publications regarding the various bracing modalities proposed for different knee osteoarthritis compartments. The effectiveness of rest orthoses for lower-limb osteoarthritis has not been studied in clinical trials. Knee sleeves are elastic nonadhesive orthoses associated with various devices aimed at patellar or femoro-tibial stabilization. They may decrease knee pain. Unloading-knee braces are functional devices composed of external stems, hinges, and straps. Several recent biomechanical studies have established the effectiveness of modifying loading with unloading-knee braces. Such braces may decrease knee pain, and improve knee function. Braces are recommended for treating knee osteoarthritis. The different bracing modalities that are available must be adapted to the symptomatic knee osteoarthritis compartment. This nonpharmacological approach must be added to the other nonpharmacological, and pharmacological modalities to decrease pain and improve function and thereby increase the quality of life of osteoarthritis patients. The structural effect of bracing has not yet been evaluated. High-quality clinical trials of the addition of various treatment modalities for knee osteoarthritis are still necessary.

Anesthesia and analgesia for cancer-related amputation

Cancer-related amputations, although more and more infrequent, are responsible for a considerable amount of chronic pain that is often resistant to standard therapies and interventions. Cancer patients are particularly at risk of developing the common pain syndromes of phantom limb pain (PLP) and persistent stump pain, secondary to their underlying disease and side effects of the their treatment. A significant number of anesthetic and pharmacologic therapies have been trialed to eliminate these chronic pain conditions. Many techniques, including preemptive epidural analgesia and perineural blockade, have shown promise in eliminating the development of these conditions, but none has been definitively proven superior. Despite the interventions and multiple medications, this group of symptoms remains resistant and continues to drive the search for a panacea. This article reviews studies examining the effect of reducing PLP and persistent stump pain when specific regional anesthesia techniques, such as epidural anesthesia and perineural blocks, are used both preemptively and continued postoperatively. This article also reviews selected trials of pharmacologic therapies for the treatment of chronic postamputation pain in the cancer patient, such as opioids, select N-methyl d-aspartate antagonists, calcitonin, antidepressants, β-blockers, anticonvulsants, and botulinum toxin. Other therapies, such as mirror treatment, use for the alleviation of PLP, are covered as well. The selected key studies reviewed in this article reveal many promising techniques and pharmacologic modalities in the treatment of postamputation cancer pain, yet none has been reliably proven to completely block PLP or persistent stump pain once and for all. Though there have been no dramatic breakthroughs, it is evident that continued research, specifically for cancer patients, is more urgent than ever.