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- Long-term Safety, Tolerability, and Efficacy of Aclidinium Bromide in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD). [JOURNAL ARTICLE]
- Chest 2014 Oct 1; 146(4_MeetingAbstracts):69A.
Original Investigation SlidePRESENTED ON: Monday, October 27, 2014 at 01:30 PM - 02:30 PMPURPOSE: To assess long-term safety and efficacy of aclidinium bromide (AB) in moderate to severe COPD patients.METHODS: In this open-label, 40-week extension study, patients completing a 12-week double-blind lead-in trial (ACCORD II) were transitioned from randomized treatment (twice-daily [BID] placebo [PBO], AB 200µg, or AB 400µg) to AB 400µg BID. Safety, the primary outcome, was assessed via adverse events (AEs) of new or increased intensity during this extension study. Efficacy parameters included change from baseline (visit 2 lead-in) to week 52 in morning predose (trough) FEV1, peak FEV1, and SGRQ total score. Efficacy was analyzed using an ANCOVA.RESULTS: Of 454 patients completing the lead-in, 448 continued to the extension. Baseline characteristics (visit 2 lead-in) were similar across sequences, except for unexpected imbalances in FEV1 (1.46L PBO-AB400; 1.40L AB200-AB400; 1.25L AB400-AB400) and in the distribution of severe, stage III COPD (37.4% PBO-AB 400; 45.5% AB200-AB400; 53.1% AB400-AB400). The percentage of patients reporting ≥1 AE was similar across groups; the most common (≥5%) were COPD exacerbation (18.1%) and upper respiratory tract infection (5.8%). Most AEs were mild or moderate, and few were related to treatment (~8% in each sequence): 7.5% PBO-AB400; 8.4% AB200-AB400; and, 8.8% AB400-AB400. Discontinuations due to AEs occurred in 6.8% PBO- AB400, 6.5% AB200-AB200, and 4.8% (AB400-AB400) of patients. Most frequently reported potential anticholinergic events (≥1%) were urinary tract infection (2.5%) and constipation (1.3%), with similar rates across groups. At 52 weeks, changes from baseline in trough FEV1 were 44 mL (PBO-AB400), 29 mL (AB200-AB400) and 48 mL (AB400-AB400). Changes from baseline to week 52 in peak FEV1 were 184mL (PBO-AB400), 176mL (AB200-AB400) and 172mL (AB400-AB400). Changes from baseline to week 52 in SGRQ were -8.25 (PBO-AB400), -6.19 (AB200-AB400) and -6.82 (AB400-AB400) units.AB 400µg was well-tolerated over 1 year, with a similar safety profile among treatment sequences. Although unexpected baseline imbalances across groups may have affected the observed treatment benefits of AB, improvements from baseline in efficacy endpoints during the lead-in were generally sustained over 52 weeks.Aclidinium 400µg BID is a well-tolerated and effective treatment option for moderate to severe COPD patients. This study was funded by Almirall S.A. and by Forest Research Institute, Inc., a wholly owned subsidiary of Forest Laboratories, Inc.Stephen Rennard: Other: Honoraria for lectures from AARC, Almirall, Am Col Osteopathic Physicians, Asan Medical Center, American Thoracic Society, California Society of Allergy, CME Incite, COPD Foundation, Creative Educational Concepts, Dey, Duke University, Forest, France Foundation, HSC Medical Education, Information TV, Lung Association, Novartis, Horsham, Nycomed, Otsuka, PeerVoice, Pfizer, Shaw Science, University of Washington, University of Alabama Birmingham, VA Sioux Falls, Consultant fee, speaker bureau, advisory committee, etc.: ABIM, Able Associates, Adelphi Research, Align2Action, Almirall, APT Pharma/Britnall, Astra-Zeneca, American Thoracic Society, Beilenson, Boehringer Ingelheim, Boehringer Ingelheim (ACCP), BoomCom, Britnall and Nicolini, Capital Research, Chiesi, Clarus Acuity, CommonHealth, Complete Medical Group, Consult Complete, COPDForum, DataMonitor, Decision Resources, Dunn Group, Easton Associates, Equinox, Forest, Frankel Group, Fulcrum, Gerson Lehman, Globe Life Sciences, Guidepoint, Health Advanced, Hoffman LaRoche, Informed, Insyght, KOL Connection, Leerink Swan, M. Pankove, McKinsey, MDRxFinancial, Medimmune, Merck, Novartis, Nycomed, Oriel, Osterman, Peal, Penn Technology, Pennside, Pfizer, PharmaVentures, Pharmaxis, Prescott, Price Waterhouse, Propagate, Pulmonary Reviews, Pulmatrix, Reckner Associates, Recruiting Resource, Roche, Sankyo, Schering, Schlesinger Medical, Scimed, Smith Research, Sudler and Hennessey, Summer Street Research, Talecris, Think Equity, UBC, Uptake Medical, Vantage Point Management Gary Ferguson: Grant monies (from industry related sources): Forest Research Institute, Consultant fee, speaker bureau, advisory committee, etc.: Forest Research Institute Edward Kerwin: Consultant fee, speaker bureau, advisory committee, etc.: Amphastar, Astra Zeneca, Forest, Ironwood, Merck, Mylan, Novartis, Pearl, Pfizer, Sanofi Aventis, Sunovion, Targacept, Teva and Theravance, Other: Conducted multicenter clinical research trials for approximately seventy pharmaceutical companies Ludmyla Rekeda: Employee: Forest Research Institute Esther Garcia Gil: Employee: Almirall S.A.No Product/Research Disclosure Information.
- Constipation: An Unusual Presentation of Ulcerative Pancolitis in an Elderly Adult. [LETTER]
- J Am Geriatr Soc 2014 Oct; 62(10):2013-2014.
- Economic evaluation of linaclotide for the treatment of adult patients with irritable bowel syndrome with constipation in the United States. [JOURNAL ARTICLE]
- J Med Econ 2014 Oct 21.:1-31.
Abstract Objectives: To use techniques of decision-analytic modeling to evaluate the effectiveness and costs of linaclotide versus lubiprostone in the treatment of adult patients with irritable bowel syndrome with constipation (IBS-C). Methods: Using model inputs derived from published literature, linaclotide Phase III trial data and a physician survey, a decision-tree model was constructed. Response to therapy was defined as (1) a ≥ 14-point increase from baseline in IBS-Quality of Life (IBS-QOL) Questionnaire overall score at Week 12 or (2) one of the top two responses (moderately/significantly relieved) on a seven-point IBS symptom relief question in ≥ 2 of 3 months. Patients who do not respond to therapy are assumed to fail therapy and accrue costs associated with a treatment failure. Model time horizon is aligned with clinical trial duration of 12 weeks. Model outputs include number of responders, quality-adjusted life-years (QALYs), and total costs (including direct and indirect). Both one-way and probabilistic sensitivity analyses were conducted. Results: Treatment for IBS-C with linaclotide produced more responders than lubiprostone for both response definitions (19.3% vs. 13.0% and 61.8% vs. 57.2% for IBS-QOL and symptom relief, respectively), lower per-patient costs ($803 vs. $911 and $977 vs. $1,056), and higher QALYs (0.1921 vs. 0.1917 and 0.1909 vs. 0.1894) over the 12-week time horizon.. Results were similar for most one-way sensitivity analyses. In probabilistic sensitivity analyses, the majority of simulations resulted in linaclotide having higher treatment response rates and lower per-patient costs. Limitations: There are no available head-to-head trials that compare linaclotide with lubiprostone; therefore, placebo-adjusted estimates of relative efficacy were derived for model inputs. The time horizon for this model is relatively short, as it was limited to the duration of available clinical trial data. Conclusions: Linaclotide was found to be a less costly option versus lubiprostone for the treatment of adult patients with IBS-C.
- Potential effect of Sildenafil beyond pulmonary hypertension in a patient with diffuse systemic sclerosis and cryoglobulinemic vasculitis. [Journal Article]
- Springerplus 2014.:559.
Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc), has a dramatic impact on prognosis and survival and is a leading cause of death.A 40 years old female patient with difuse cutaneous SSc (dcSSc) presented with progressive dyspnea, choking sensation, cough, abdominal distension, constipation and dysphagia to solids. The muscle power was mildly reduced and multiple purpuric eruptions were present on the legs of variable sizes. The patient was ANCA negative and had positive cryoglobulinemia. The hepatitis C virus test was positive and the skin biopsy histopathology proved small vessel (leucocytoclastic) vasculitis. The modified Rodnan total skin score (MRSS) was 37. There was deterioration of the pulmonary function tests and transesophageal echocardiography revealed PAH (RVSP 60 mmHg). Sildenafil 50 mg/day resulted in a remarkable improvement of the dyspnea and Raynauds' with a significant improvement of the skin tightness as the MRSS became 22. The small vessel vasculitic rash remarkably improved and the RVSP became 34 mmHg with a dramatic improvement of the PAH.Sildenafil enhances vasodilatation, has antiproliferative effects and is effective in the treatment of PAH. The remarkable improvement in the vasculitic skin lesions in this case after sildenafil is the second report after the described dramatic improvement of small vessel vasculitis in a case with Takayasu arteritis. The emerging trends make it necessary to exploit the full therapeutic potential of Sildenafil in scleroderma and PAH with other extrapulmonary manifestations.We report a very rare association of dcSSc with small vessel cryoglobulinemic vasculitis with a remarkable improvement after sildenafil.
- Late-onset hypercalcemia in Williams-Beuren syndrome: importance of early and frequent screening and intervention. [JOURNAL ARTICLE]
- J Pediatr Endocrinol Metab 2014 Oct 18.
Abstract Williams-Beuren syndrome (WBS) affects multiple systems and has a known association with infantile hypercalcemia that is typically mild and transient. We report a 12-month-old female previously diagnosed with WBS by a chromosomal microarray, who was admitted for failure to thrive. Upon evaluation, serum calcium of 19.0 mg/dL (4.75 mmol/L) (normal 9-11 mg/dL, SI: 2.25-2.75 mmol/L) and serum ionized calcium of 2.33 mmol/L (normal 1.22-1.37 mmol/L) were revealed. Her hypercalcemia correlated with symptoms of irritability, poor feeding, mild hypotonia, and constipation, which were increasingly present for 6 months prior to admission. This calcium level is one of the highest reported in association with WBS. Additionally, while hypercalcemia associated with WBS typically resolves by the first year, this case represents a later presentation as compared to other reports. The patient initially responded to conservative treatment with intravenous fluids administration, loop diuretic therapy, and dietary calcium restriction. However, she subsequently had rebound hypercalcemia 5 weeks after treatment and received one dose of intravenous bisphosphonate with subsequent resolution of her hypercalcemia. Our report highlights the importance of screening, early management, and recognition of late presentation hypercalcemia in the setting of WBS.
- Solitary Bone Plasmacytoma Progressing into Retroperitoneal Plasma Cell Myeloma with No Related End Organ or Tissue Impairment: A Case Report and Review of the Literature. [JOURNAL ARTICLE]
- Turk J Haematol 2014 Sep 5; 31(3):286-289.
Solitary bone plasmacytomas and plasma cell myeloma are clonal proliferations of plasma cells. Many patients with solitary bone plasmacytomas develop plasma cell myeloma on follow-up. We present a case of a 70-year-old man who presented with fracture and a lytic lesion in the subtrochanteric region of the left femur and was assigned a diagnosis of solitary bone plasmacytoma. He received local curative radiotherapy. However, 4 months later his serum M protein and β2-microglobulin levels increased to 2.31 g/dL and 5.965 mg/L, respectively. He complained of abdominal fullness and constipation. Ultrasound and non-contrast CT imaging revealed multiple retroperitoneal masses. Colonoscopic examination was normal. Biopsy of the a retroperitoneal mass confirmed it to be a plasmacytoma. Repeat hemogram, blood urea, serum creatinine, skeletal survey, and bone marrow examination revealed no abnormalities. This is an unusual presentation of plasma cell myeloma, which manifested as multiple huge extramedullary retroperitoneal masses and arose from a solitary bone plasmacytoma, without related end organ or tissue impairment and bone marrow plasmacytosis. The patient succumbed to his disease 8 months after the appearance of the retroperitoneal masses. This case highlights the importance of close monitoring of patients diagnosed with solitary bone plasmacytoma with increased serum M protein and serum β2-microglobulin levels, so that early therapy can be instituted to prevent conversion to plasma cell myeloma.
- Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e108982.
Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined.To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients.The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated.University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination.Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.
- The association of age of toilet training and dysfunctional voiding. [Journal Article]
- Res Rep Urol 2014.:127-30.
To determine whether age of toilet training is associated with dysfunctional voiding in children.We compared patients referred to the urologic clinics for voiding dysfunction with age-matched controls without urinary complaints. Characteristics including age and reason for toilet training, method of training, and encopresis or constipation were compared between both groups.Initiation of toilet training prior to 24 months and later than 36 months of age were associated with dysfunctional voiding. However, dysfunctional voiding due to late toilet training was also associated with constipation.Dysfunctional voiding may be due to delayed emptying of the bowel and bladder by children. The symptoms of dysfunctional voiding are more common when toilet training early, as immature children may be less likely to empty in a timely manner, or when training late due to (or in association with) constipation.
- Clinical evaluation of fatigue in Japanese patients with Parkinson's disease. [Journal Article]
- Brain Behav 2014 Sep; 4(5):643-9.
Fatigue is a common nonmotor symptom of Parkinson's disease (PD). Although the causes of fatigue were estimated in the previous reports, fatigue is not fully understood. To determine the frequency of and factors related to fatigue in patients with PD, we carried out clinical assessments in our university hospital.We used the Japanese version of the Parkinson Fatigue Scale (J-PFS). The J-PFS was administered to 110 patients with PD, and a cutoff point of 3.3 was used for the diagnosis of fatigue. Subsequently, demographic characteristics, clinical features, and medications utilized were evaluated to elucidate the factors related to fatigue. In particular, we focused on the relationship between fatigue and gait disorder assessed via the portable gait rhythmogram.The frequency of fatigue in patients with PD was 52.7%. Univariate analysis revealed that factors significantly associated with fatigue were many motor symptoms and nonmotor symptoms. In addition, multivariate analysis revealed that gait disorder and constipation were independent factors related to fatigue. Furthermore, short-step walking and bradykinesia in gait disorder had especially a relationship with fatigue.More than half of our patients were judged having fatigue. Several factors, including motor and nonmotor symptoms, might be related to fatigue in patients with PD.
- Piebald mutation on a C57BL/6J background. [JOURNAL ARTICLE]
- J Vet Med Sci 2014 Oct 20.
The classic piebald mutation in the endothelin receptor type B (Ednrb) gene was found on rolling Nagoya genetic background (PROD-s/s) mice with white coat spotting. To examine whether genetic background influenced the phenotype in the piebald mutant mice, we generated a congenic strain (B6.PROD-s/s), produced by repeated backcrosses to the C57BL/6J (B6) strain. Although B6.PROD-s/s mice showed white coat spotting, 7% of B6.PROD-s/s mice died between 2 and 5 weeks after birth due to megacolon. The PROD-s/s, s/s and Japanese fancy mouse 1 (JF1) strains, which also have piebald mutations on different genetic backgrounds with B6, showed only pigmentation defects without megacolon. In expression analyses, rectums of B6.PROD-s/s with megacolon mice showed ∼5% of the level of Ednrb gene expression versus B6 mice. In histological analyses, aganglionosis was detected in the rectum of megacolon animals. The aganglionic rectum was thought to lead to severe constipation and intestinal blockage, resulting in megacolon. We also observed an abnormal intestinal flora, including a marked increase in Bacteroidaceae and Erysipelotrichaceae and a marked decrease in Lactobacillus and Clostridiales, likely inducing endotoxin production and a failure of the mucosal barrier system, leading ultimately to death. These results indicate that the genetic background plays a key role in the development of enteric ganglion neurons, controlled by the Ednrb gene, and that B6 has modifier gene (s) regarding aganglionosis.