Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.

Echocardiographic evaluation of mitral tethering for 'chordal cutting' procedure.

'Chordal cutting' is a recently proposed surgical option for the treatment of functional mitral regurgitation due to leaflet tethering. With this technique the surgeon sections second order chordae, restores leaflet's convexity towards the left atrium and eliminates mitral incompetence. Preoperative assessment of tethering mechanism, degree of leaflet distortion, surface of coaptation, annular dilation, origin and quantification of valve incompetence by echocardiographic means is essential in indicating this surgical option. Intraoperative transesophageal evaluation is crucial to assess the morphology and the absence or degree of residual incompetence after procedure.

Echocardiographic images in mitral valve repair by "edge to edge" technique.

The "edge to edge" or "double orifice" technique is a new surgical option of mitral repair when functional valve insufficiency is present, due to ischemic or dilated cardiomyopathy. This technique is not frequently used and radically changes mitral anatomy and hemodynamic. Therefore, echocardiographic examination is completely different and implies good experience to evaluate postoperative valve function. For these reasons we present a case report of a patient who underwent this repair and was evaluated in the follow up by standard transthoracic echocardiography: the anatomical and functional assessment that was satisfactory compared with transesophageal examination is documented.

[Successive ischemic events to a first acute myocardial infarct treated with fibrinolysis. An analysis of GISSI-2 patients considered reperfused by a clinical criterion. Participants in the GISSI-2 study. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico]. / Eventi ischemici successivi a primo infarto miocardico acuto trattato con fibrinolisi. Analisi dei pazienti del GISSI-2 ritenuti ricanalizzati con criterio clinico. A nome dei partecipanti allo studio GISSI-2.

BACKGROUND: The fast normalisation of the ST, after thrombolysis, is early sign related to coronary artery reperfusion and to prognosis of acute myocardial infarction (AMI). The aim of this analysis is the evaluation, in the large patients cohort of the GISSI-2 trial, of the relationship between the ST segment evolution after fibrinolytic therapy of AMI and recurrent ischaemic events [angina-reinfarction-ischaemia to exercise testing (ET)] at 30 and 180 days from randomisation. METHODS: Patients with first confirmed IMA and ECG before randomisation and 4 hours later, are chosen from GISSI-2 trial. A decrease > or = 50% of the sigma ST elevation is adopted as cutoff for predicting coronary artery patency. Recanalisation is deemed to have occurred in group A patients versus not reperfused group B patients. The studied events are: angina, reinfarction, mortality, at 30 and 180 days from randomisation; ischemia to ET SL of 4-6 week. The results are presented in terms of Mantel-Haenszel odds ratios (OR) and 95% confidence intervals. RESULTS: Group A patients n. 5307 experienced versus group B patients n. 2718 a higher incidence of--in-hospital angina: 10.3% vs 7.9% OR 1.30 (1.11-1.52)-180 days reinfarction: 2.9% Vs 1.7% OR 1.66 (1.19-2.30)-Ischaemia to ET 25.4% vs 21.4% OR 1.24 (1.08-1.43), and a lower in-hospital mortality: 3.8% vs 8.5% OR 0.39 (0.32-0.48). CONCLUSIONS: Patients having indirect signs of early reperfusion post thrombolysis for IMA experience a higher in-hospital and 180 days recurrent ischaemia and a lower mortality; this fact can allow early identification of the patients who can receive a benefit from different therapeutical strategies.

[False chordae tendineae]. / Le false corde tendinee.

False tendons (FT) are fibrous or fibromuscular structures which cross the ventricular cavity with no connections with valvular leaflets. They were considered for a long time as normal structures but now cardiologists are interested because of the possible association with the so-called innocent murmur, and even more so for the role they can have in eliciting ventricular arrhythmias. Some Authors believe that arrhythmias can arise from the false tendons because they contain not only fibrous tissue but also muscular and conduction tissue. Arrhythmias can be triggered either by stretching of the Purkinje fibers or by distortion of the ventricular wall, where false tendons arise. At the same time they can act as reentry circuits due to their non-homogeneous structure. Due to the fact that false tendons may arise anywhere from the ventricular cavity, they have been classified according either to anatomic or echocardiographic criteria: the latter being more complex and difficult than the former for the difficulty in locating the attachment areas. In our echocardiographic laboratory we simply distinguish two types of false tendons: type I which parallel the interventricular septum or bridges from the postero-basal portion of the septum to the posterior left ventricular wall; type II which crosses the ventricular cavity more distally, towards the apex. In the anatomic studies the prevalence of the FT is rather homogeneous, ranging from 46 to 54.9%, while it is extremely variable in the echocardiographic studies, ranging from 0.2 to 71%. This is possibly due not only to the examiner's skills, or the equipment's quality but also to the population studied. Among the patients referred to our cardiac paediatric unit we have found false tendons in 80 (29.3%) out of 273 children without cardiac disease, age ranging from i day to 13 yrs. Males were affected twice more than females, 63.7% vs 36.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Mitral valve prolapse and endocarditis prophylaxis]. / Prolasso della valvola mitrale e profilassi della endocardite.

This paper briefly reviews the anatomy, epidemiology and clinical aspects of the Mitral Valve Prolapse (MVP), and focuses attention on the association between infective endocarditis and prolapse, particularly after oral surgery. It is recommended that all MVP patients, irrespective of whether they have mitral regurgitation or not, receive correct prophylactic treatment. The pharmacological approach suggested, based on the most recent advances in antibiotic pharmacodynamics, is designed in accordance with specific patient risks.

Comparative effects of ibopamine and captopril in mild congestive heart failure. Focus on the long-term effects of inodilation on ventricular arrhythmias.

Twenty-three patients with mild heart failure (I-II NYHA classes) on digitalis and diuretics were assigned to the following treatment in a random and double-blind fashion: ibopamine-captopril, ibopamine-placebo, captopril-placebo, and placebo-placebo. The doses of captopril and ibopamine were respectively 25 mg t.i.d. and 100 mg t.i.d. The incremental exercise time (until exhaustion) and the peak VO2 (oxygen consumption), the indexes of left ventricular function (by echo and nuclear stethoscope) and ventricular arrhythmias (evaluated by prolonged Holter monitoring) were assessed before randomization, at 45 days and at 3 months. Ejection fraction, exercise time, peak VO2, ventricular arrhythmias and heart rate (at rest and during exercise) appeared to be equally unaffected by each treatment. Our results show that ibopamine exerts no significant effects on either heart rate or ventricular arrhythmias and that indexes of left ventricular function are not modified by any treatment in mild congestive heart failure.