Development Of Tachyphylaxis Research Articles

Rhinitis medicamentosa

One type of non-allergic non-infectious rhinitis is represented by a heterogeneous group of rhinitis medicamentosa, which can be divided into several pathogenetic types. The most common rebound nasal congestion associated with the use of topical decongestants. Excessive use of intranasal decongestants leads to a decrease in the number of alpha-adrenoreceptors on the surface of cell membranes and uncoupling their connection with the G-protein and the development of tachyphylaxis. To prevent the development of rebound nasal congestion caused by topical decongestants, it is important to limit the frequency of their use. In most cases, the duration of the use of vasoconstrictor drugs should be limited to 5-7 days, according to Patient information leaflets for the drugs. However, in patients who have had a history of episodes of rebound nasal congestion, which develops including the previously indicated periods, the duration of decongestant therapy should be limited to 3 days. Rhinitis associated with local inflammation is caused by the intake of acetylsalicylic acid (ASA) or other non-steroidal anti-inflammatory drugs. Currently, the so-called "aspirin triad" is well known - a combination of bronchial asthma, rhinosinusitis (often polyposis) and intolerance to ASA. Neurogenic rhinitis develops due to the use of drugs that violate vascular tone, for example, antihypertensive drugs or type 5 phosphodiesterase inhibitors. Drug-induced rhinitis has a significant impact on the patient's quality of life: nasal congestion, rhinorrhea, secondary night apnea, insomnia as a result of nasal breathing disturbances, headaches, irritability, weakness after sleepless nights disturb patients to a large extent. Timely diagnosis and withdrawal of a provocative drug, the use of topical corticosteroids in case of severe rhinitis are the basis of the treatment of rhinitis medicamentosa. In severe cases, there is a need, including surgical treatment, such as, for example, submucosal laser destruction of the lower nasal concha.

Oral Ondansetron Offers Effective Antidiarrheal Activity for Carcinoid Syndrome Refractory to Somatostatin Analogs.

Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome. We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit. A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months). Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit. Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders.

Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes: A review.

A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) <7.0% (53 mmol/mol) and, furthermore, an increasing number of patients with type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy, which is associated with well-described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long-acting GLP-1RAs, but the risk-benefit ratio emerging from studies evaluating the effect of long-acting GLP-1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might be attributable to a lack of glucagonostatic effect of these long-acting GLP-1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP-1-induced retardation of gastric emptying. In contrast, the short-acting GLP-1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short-acting GLP-1RAs are all derived from small open-label trials and should thus be interpreted with caution. In the present paper we review the potential role of GLP-1RAs, in particular short-acting GLP-1RAs, as add-on to insulin in the treatment of type 1 diabetes.

Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure)

ObjectivesThis study determined whether there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration in patients with preclinical diastolic dysfunction (PDD). BackgroundPDD is characterized by normal systolic function and moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. MethodsA double-blinded, placebo-controlled proof-of-concept study was conducted to compare 12 weeks of twice daily subcutaneous BNP, 10 μg/kg (n = 24), versus placebo (n = 12) in PDD. Subjects underwent 2 study visits, at baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. ResultsAmong those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP, as measured by a decrease in the Doppler E/e′ ratio (where E is early mitral inflow velocity and e′ is mitral annulus early diastolic motion) (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks, there was statistically significantly greater sodium excretion, urine flow, and urinary cyclic guanosine monophosphate excretion to AVL (all p < 0.001), as well as a trend toward greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. ConclusionsIn subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP. (Human Brain Natriuretic Peptide [BNP] [or Nesiritide] to Help Heart, Kidney and Humoral Function; NCT00405548)

69-Year-Old Woman With Confusion and Fatigue

Resident in Internal Medicine, Mayo School of Graduate Medical Education, Rochester, MN (H.M.K.); Advisor to resident and Consultant in Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN (A.E.K.). A 69-year-old woman presented to her primary care physicianwith a 4-day history of fatigue and dizziness. She was 45 minutes late for her appointment because she had trouble driving to the office. She reported no motor or sensory deficits but had difficulty with coordination. Review of systems was positive for dysuria and urinary frequency. She did not have fever, chills, weight or appetite changes, respiratory, cardiac, or gastrointestinal symptoms, or recent head trauma. The patient’s medical history was remarkable for hypertension, hyperlipidemia, type 2 diabetes mellitus, osteoporosis, and gastroesophageal reflux disease. Medications included metoprolol tartrate, lisinopril with hydrochlorothiazide, lovastatin, cholecalciferol, and as-needed calcium carbonate. She had smoked half a pack of cigarettes per day for 40 years but had quit smoking 6 years previously. She didnot use alcohol or illicit drugs. On examination, the patient was afebrile with a blood pressure of 104/67 mm Hg, heart rate of 76 beats/min, respiratory rate of 17 breaths/min, oxygen saturation of 94% while breathing room air, and body mass index (calculated as weight in kilograms divided by height inmeters squared) of 39 kg/m. Shewas alert and oriented to person, place, and time. Her speech was dysarthric, and she had difficulty following simple commands. Her coordination was impaired with symmetric dysmetria on finger-to-nose testing, heel-kneeshin testing, and rapid alternating movements. Cranial nerves II through XII were intact. Results of motor and sensory examinations were within normal limits. Reflexes were symmetric. Lymph node, thyroid, cardiac, respiratory, gastrointestinal, musculoskeletal, and skin examinations identified no abnormalities.

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor.

Rapid response to intravitreal aflibercept in neovascular age-related macular degeneration after development of tachyphylaxis to bevacizumab and ranibizumab

This article reports a rapid response of intravitreal aflibercept for the treatment of a case of neovascular age-related macular degeneration that developed tachyphylaxis to bevacizumab and ranibizumab. An 80-year-old man with neovascular age-related macular degeneration became unresponsive to monthly treatment with bevacizumab or ranibizumab after initial responsiveness, to as-needed treatment with these antivascular endothelial growth factor drugs for 49 months. Subretinal fluid and pigment epithelial detachment had sustained in spite of 14 bevacizumab and seven ranibizumab injections prior to intravitreal aflibercept treatment. After only one injection of intravitreal aflibercept, a marked improvement was seen within 1 week. Complete drying of subretinal fluid and marked subsidence of pigment epithelial detachment were noted 4 weeks after the first aflibercept injection and sustained for three consecutive monthly injections. This case reveals that shifting to aflibercept may be an effective alternative treatment for neovascular age-related macular degeneration that becomes tachyphylactic to bevacizumab or ranibizumab.

Histamine2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing.

Histamine2-receptor antagonists (H2RAs) are available over-the-counter (OTC) for the treatment and prevention of heartburn, but more than occasional, single-dose use can lead to rapid development of tachyphylaxis. The aim of this review is to assess the published evidence regarding the development of tachyphylaxis with repeat usage of H2RAs. PubMed and SCOPUS were searched across all years to identify clinical studies that examined the development of tachyphylaxis with repeated dosing of H2RAs. Although a single (first) dose of an H2RA can be effective for controlling gastric acid and preventing or relieving food-related heartburn, numerous studies confirm that tachyphylaxis, also known as tolerance, is consistently detected at the first time point assessed after the first dose, including the second day and/or second dose. Even if symptom relief is achieved with an H2RA, it may be due to desensitization of the esophagus to acid exposure, potentially providing symptom relief without significantly decreasing esophageal acid exposure. When recommending OTC drugs for treatment of frequent heartburn, clinicians should be aware of the potential for rapid development of tachyphylaxis in patients who use H2RAs for 2 or more consecutive days. Even if symptom relief is achieved, it may be due to desensitization of the esophagus to acid by the H2RA, potentially providing symptom relief without significantly decreasing esophageal acid exposure. Other strategies, such as an OTC proton pump inhibitor, may be needed to optimize management of frequent heartburn.

Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab

AimTo determine whether tachyphylaxis occurs during treatment with ranibizumab (Lucentis, Genentech, Inc., South San Francisco, California, USA) for exudative age-related macular degeneration (AMD).DesignRetrospective review of cases.ParticipantsThe treatment results of 1076...

Amphetamine tachyphylaxis in the pithed guinea-pig.

A single dose of (+)-amphetamine (8 mg kg-1, i.p.) administered 4 h before experimentation, reduced the pressor and positive chronotropic effects elicited by this drug (0-6 mg kg-1, i.v.) and augmented the rate of the development of tachyphylaxis to these responses in the pithed guinea-pig preparation. Amphetamine pretreatment reduced the pressor and positive chronotropic effects of phenylephrine (0-1 mg kg-1, i.v.) and the positive chronotropic effects of angiotensin (30 mug kg-1, i.v.). The rate of the development of tachyphylaxis to the cardiovascular responses elicited by phenylephrine and angiotensin was augmented by amphetamine pretreatment. The results suggest that an indirect mechanism (noradrenaline) may in part mediate the cardiovascular effects of these 3 drugs and/or that amphetamine may act as a competitive antagonist at adrenoceptor sites.

Forskolin reverses tachyphylaxis to the bronchodilator effects of salbutamol: an in-vitro study on isolated guinea-pig trachea.

The objective of this study was to assess the relaxant responses of salbutamol, a beta2 agonist, and forskolin, an activator of adenylate cyclase, and the possible role of forskolin in reversing tachyphylaxis to salbutamol. The in-vitro bronchodilator effects of salbutamol and forskolin (10(-9)-10(-5) M) were tested on isolated guinea-pig tracheal rings precontracted with carbachol (10(-7) M). Both salbutamol and forskolin elicited concentration-dependent relaxation. Potency (EC50; the dose resulting in 50% relaxation) was determined from cumulative concentration-response curves. Salbutamol was more potent than forskolin in relaxing the tracheal preparations (-log molar EC50 7.68+/-0.14 and 6.3+/-0.17, respectively). Reproducible relaxant responses to salbutamol could be elicited after 24 h incubation in Krebs solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by incubation (24h) of the preparations in Krebs solution containing salbutamol (10(-6) 3x10(-6) or 10(-5) M). This pretreatment of the tissues resulted in a significant reduction in the potency of salbutamol. The potency of salbutamol was reduced to 6.85+/-0.2, 6.8+/-0.1 and 5.9+/-0.27 after 24h incubation with salbutamol 10(-6), 3x10(-6) or 10(-5) M, respectively. The potency of salbutamol was increased from 7.35+/-0.2 to 7.76+/-0.28 by addition of forskolin (3x10(-7) M) under control conditions. Moreover, forskolin (3x10(-7) M) reversed the development of tachyphylaxis to salbutamol-induced relaxation in tissues pretreated with salbutamol. The potency of salbutamol was increased to 7.29+/-0.41, 7.37+/-0.17 and 7.23+/-0.35 after the addition of forskolin (3x10(-7) M) to preparations pre-incubated (24h) with salbutamol 10(-6), 3x10(-6) or 10(-5) M respectively. These results show that in guinea-pig tracheal ring preparations, forskolin shares with salbutamol the ability to relax airway smooth muscle and produces an apparent reversal of tachyphylaxis to the bronchodilator effects of salbutamol, particularly in the low concentration range. This effect could provide an alternative therapy for long term use, particularly with high doses of beta2 agonists in bronchial asthma.

Repeated administration of ET B receptor agonist, IRL-1620, produces tachyphylaxis only to its hypotensive effect

IRL-1620, a highly selective ET B receptor agonist, is presently in a phase I clinical trial ( NCT00613691) in the United States for patients with recurrent or progressive carcinoma. The effect of acute repeated administration of IRL-1620 on the development of tachyphylaxis to changes in blood pressure, heart rate and blood flow (renal and cerebral) has not been studied. The present studies were conducted in urethane anesthetized rats to determine the cardiovascular effects of acute repeated intravenous administration of IRL-1620. In order to determine the tachyphylactic effect, each dose of IRL-1620 was administered at 0, 60, and 120 min. It was found that IRL-1620 did not significantly affect heart rate. IRL-1620 produced a transient fall in blood pressure. A fall in mean arterial pressure (MAP) of 35.47% with 1.6 μg/kg, 38.87% with 5.0 μg/kg and 28.04% with 15.0 μg/kg dose of IRL-1620 was observed. Repeated administration of a low dose (1.6 μg/kg, i.v.) of IRL-1620 produced a fall in MAP but no tachyphylaxis was observed. However, repeated administration of IRL-1620 (5.0 μg/kg, i.v.) produced a fall in MAP of 40.12%, 29.15%, and 21.61% with the first, second and third injections, respectively. IRL-1620 produced a consistent decrease in renal blood flow and increase in cerebral blood flow without any evidence of tachyphylaxis. Pretreatment with ET A antagonist BMS187824 (5 mg/kg, i.v.), followed by three doses of 5 μg/kg IRL-1620 at 60 min intervals eliminated the development of tachyphylaxis to the transient hypotension, confirming the involvement of the ET A receptor in tachyphylactic development. The findings indicate development of tachyphylaxis to IRL-1620 only to the fall in blood pressure when given repeatedly at mid-high doses, while the decrease in renal and increase in cerebral blood flow were not affected with regards to tachyphylactic development.

TACHYPHYLAXIS AFTER INTRAVITREAL BEVACIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION

To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD). We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28 +/- 7 days after administration in an eye that had previously demonstrated a therapeutic response in the same time interval. Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with IVB. High-dose IVB (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen after an episode of unilateral postinjection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31-128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5-10 treatments). Tachyphylaxis can occur after long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.

Peroxynitrite is a potent vasodilator agent in the pulmonary vascular bed of the rat

It has been reported that the vasodilator effects of peroxynitrite (PN) are tachyphylaxic; however, responses have not been determined in the pulmonary vascular bed of the rat. In the present study iv injections of PN (1, 3 and 10 mmol) decreased pulmonary and systemic arterial pressure. Responses to PN could be repeated without the development of tachyphylaxis. The decreases in pulmonary arterial (PA) pressure in response to PN were modest under baseline conditions but were greatly enhanced when baseline PA pressure was increased with U‐46619. Also, the iv injections of PN decreased PA pressure when baseline tone was increased by ventilatory hypoxia or administration of the eNOS inhibitor L‐NAME. Sodium nitroprusside and PN produced similar vasodilator responses in the pulmonary and systemic vascular beds. The repeated administration of PN did not alter responses to both vasoconstrictor and vasodilator agents, and did not impair endothelium dependent responses. The results of the present study show that PN has potent pulmonary vasodilator activity in the rat and is consistent with the hypothesis that PN is converted into a substance that has NO‐donor like activity and that the beneficial effects of PN may be derived in part from the inactivation of superoxide anion and the activation of soluble guanylate cyclase.

Novel Therapies for Cyclic GMP Control of Vascular Smooth Muscle Growth

Cyclic GMP, guanosine 3',5'-cyclic monophosphate, is a critical and multifunctional second-messenger molecule that mediates diverse physiological and pathophysiological functions in cardiac and vascular tissues. Synthesized through nitric oxide, carbon monoxide, and/or natriuretic peptide-mediated guanylate cyclase stimulation and guanosine triphosphate dephosphorylation, cyclic GMP is capable of stimulating a cascade of serine/threonine kinase events, including signaling through cyclic GMP- and/or cyclic AMP-dependent protein kinases, eliciting protein kinase-independent actions such as modulation of ion channels or transporters, or undergoing hydrolytic degradation through actions of cyclic GMP-regulated phosphodiesterases. Substrates, enzymes, cofactors, and associated variables in this multifaceted system have historically been targets of vital pharmacotherapies with perhaps most common the use of vascular smooth muscle-targeting organonitrates in cardiac patients and phosphodiesterase inhibitors in individuals with erectile dysfunction. Accumulating basic science and clinical evidence, however, suggests that cyclic GMP signaling is compromised under conditions of disease or elevated physiological stresses. Moreover, nitric oxide can stimulate an array of cytotoxic effects and nitric oxide-based therapies can be limited by diminished bioactivity and the development of tachyphylaxis or tolerance after prolonged use. Consequently, an emerging area for clinical drug development and therapeutic drug evaluation for conditions of cardiovascular adversity has focused on identification of cyclic GMP signaling pathways that act under oxidized or nitric oxide-unresponsive conditions and/or that operate irrespective of nitric oxide-induced complications. The aim of this therapeutic review is to describe novel, nitric oxide-alternate avenues for cyclic GMP signaling in vascular smooth muscle growth with particular emphasis on pharmacotherapeutics of recently characterized cyclic GMP-specific approaches.

Asthma and the elite athlete: Summary of the International Olympic Committee's Consensus Conference, Lausanne, Switzerland, January 22-24, 2008

Respiratory symptoms cannot be relied on to make a diagnosis of asthma and/or airways hyperresponsiveness (AHR) in elite athletes. For this reason, the diagnosis should be confirmed with bronchial provocation tests. Asthma management in elite athletes should follow established treatment guidelines (eg, Global Initiative for Asthma) and should include education, an individually tailored treatment plan, minimization of aggravating environmental factors, and appropriate drug therapy that must meet the requirements of the World Anti-Doping Agency. Asthma control can usually be achieved with inhaled corticosteroids and inhaled beta(2)-agonists to minimize exercise-induced bronchoconstriction and to treat intermittent symptoms. The rapid development of tachyphylaxis to beta(2)-agonists after regular daily use poses a dilemma for athletes. Long-term intense endurance training, particularly in unfavorable environmental conditions, appears to be associated with an increased risk of developing asthma and AHR in elite athletes. Globally, the prevalence of asthma, exercise-induced bronchoconstriction, and AHR in Olympic athletes reflects the known prevalence of asthma symptoms in each country. The policy of requiring Olympic athletes to demonstrate the presence of asthma, exercise-induced bronchoconstriction, or AHR to be approved to inhale beta(2)-agonists will continue.

Naloxone Increases the Anorexic Effect of MTII in OLETF Rats

Background: Leptin, an adipocyte-derived hormone, inhibits obesity in lean subjects, but is not widely used because of leptin resistance. Thus, circumventing the arcuate nucleus of the hypothalamus, the site responsible for leptin resistance, has been evaluated for treatment of obesity. However, chronic treatment of melanotan II (MTII), a synthetic agonist of the melanocortin 3/4 receptor, induces tachyphylaxis. Here, we evaluated whether naloxone, a non-specific agouti-related peptide (AgRP) antagonist, increases the anorexic effect of MTII in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods: We measured food intake following intracerebroventricular (i.c.v.) infusion of MTII and/or naloxone in OLETF rats. Sprague-Dawley rats were used as a normal control group. Results: The anorexic effect of i.c.v. MTII infusion decreased with tim e in OLETF rats, indicating the development of tachyphylaxis. In normal control rats, naloxone alone decreased AgRP expression in the hypothalamus but failed to induce anorexia. Moreover, there was no additional anorexic effect with co-treatment of naloxone and MTII. In OLETF rats, naloxone alone did not show an anorexic effect despite increased POMC expression in the hypothalamus. However, naloxone sensitized the anorexic effect of MTII when treated together. Conclusion: These results suggest that naloxone augmented the anorexic effect of MTII when treated together in OLETF rats, but had no effect alone. These results suggest that a combination therapy of naloxone and a melanocortin receptor activator would be an effective modality for treatment of obesity. (J Kor Endocr Soc 23:18~26 2008)

Gastrointestinal Complications of Dual Antiplatelet Therapy

Case presentation: A 59-year-old man with a history of hypertension, dyslipidemia, and smoking was hospitalized with acute coronary syndrome requiring emergency percutaneous coronary intervention with 4 drug-eluting stents. His discharge medications included dual antiplatelet therapy with aspirin 325 mg/d and clopidogrel 75 mg/d. Three weeks after discharge, he returned to the Emergency Department with bloody stools and a hematocrit of 23% (previously 36%) and required 3 U of packed red blood cells. Endoscopy showed a bleeding duodenal ulcer with adherent clot (Figure). Endoscopic image of bleeding duodenal ulcer with clot on top. This image was taken in a patient with a history similar to that of our patient. Arrow points to the base of duodenal ulcer with active bleeding. Picture contributed by Sarathchandra Reddy, MD, and Edwin Chun Ouyang, MD, PhD, Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Mass. We prescribe dual antiplatelet therapy with aspirin and clopidogrel to prevent and treat cardiovascular, cerebrovascular, and peripheral arterial disease. According to American Heart Association statistics, 700 000 patients had stroke, 13 million had coronary artery disease, and 8 to 12 million suffered from peripheral arterial disease in 2002. Each year, 1.2 million patients in the United States receive dual antiplatelet therapy with aspirin and clopidogrel after percutaneous coronary intervention with drug-eluting stents. The number of patients in the United States who receive dual antiplatelet therapy for various vascular conditions such as coronary artery disease, transient ischemic attack, thrombotic stroke, and peripheral vascular disease probably exceeds several million. The use of aspirin compared with placebo reduces the risk of myocardial infarction, stroke, or death from vascular causes by ≈25%.1 In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, administration of clopidogrel decreased the relative risk of vascular events by 8.7% compared with aspirin.2 The …

Evidence of tachyphylaxis associated with salmeterol treatment of chronic obstructive pulmonary disease patients

Bronchodilator therapy is lifelong mandatory for chronic obstructive pulmonary disease patients. There is evidence of loss of bronchodilator effectiveness over time with beta2-agonists but not with anticholinergics. The aim of this study was to examine the development of tachyphylaxis to the long-acting beta2-agonist salmeterol using as a control therapeutic regimen the combination of ipratropium bromide and salbutamol sulphate. Fifty-six subjects participated in a 20-week, crossover randomised clinical trial. The parameters forced expiratory volume at 1 s (FEV1), peak expiratory flow rate (PEFR) and FEV1/forced vital capacity were measured via spirometry and the parameters triangle DeltaFEV1%pre, triangle DeltaPEFR%pre and triangle DeltaAUC(0-2 h) were calculated. FEV1 increased significantly after two weeks of treatment with the combination treatment but not with the salmeterol. The observed diminished increase could be attributed to the development of tolerance to the long acting beta2-agonist. Salmeterol seems to be an effective bronchodilator, however, its duration of action over time and its peak effect might be subject to tachyphylaxis.

Treating erectile dysfunction when PDE5 inhibitors fail

New oral drugs, especially phosphodiesterase type 5 (PDE5) inhibitors, have revolutionalised the treatment of erectile dysfunction by decreasing reliance on more invasive options. These inhibitors compete with cyclic GMP (guanosine...