Effects of inhaled nitric oxide on hemostasis in healthy adults treated with heparin: a randomized, controlled, blinded crossover study

<p>Abstract</p> <p>Background</p> <p>Effects of nitric oxide (NO) on hemostasis have been studied in various investigational settings, but data regarding inhaled NO on bleeding and platelet function are conflicting. It is not known if inhaled NO has an effect when administered with drugs that influence hemostasis. This trial evaluated effects of inhaled NO on hemostasis in the presence of heparin using aspirin as a positive control.</p> <p>Patients/Methods</p> <p>Twelve healthy adult males were enrolled in a single-center, randomized, single-blind, four-way crossover trial. Subjects received 80 ppm NO or medical air (placebo) inhalation for 30 min with simultaneous injection of placebo or heparin. Aspirin capsules were used as a positive control. Parameters of hemostasis were measured before treatment and at post-treatment intervals.</p> <p>Results</p> <p>Activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased only in groups that received heparin. Areas under the curve for ACT in heparin groups receiving inhaled NO were judged to be equivalent to those receiving medical air for both 0- to 4-h (ratio: 1.00; 90% CI, 0.90-1.11) and 0- to 24-h time intervals (ratio: 1.01; 90% CI, 0.92-1.12). Changes in bleeding time and platelet aggregation were observed only in aspirin groups. No clinically significant changes in hemoglobin, red blood cell counts or haematocrit were observed in any group.</p> <p>Conclusions</p> <p>Inhaled NO, when administered with heparin, exhibited no significant additive effects on ACT, PT, aPTT, bleeding time or platelet aggregation.</p

Creating Clinically Useful \u3ci\u3eIn Silico\u3c/i\u3e Models of Intracranial Pressure Dynamics

To create clinically useful computer simulation models of intracranial pressure (ICP) dynamics by using prospective clinical data to estimate subject-specific physiologic parameters

A Computer Model of Intracranial Pressure Dynamics During Traumatic Brain Injury that Explicitly Models Fluid Flows and Volumes

This report documents a computer model of intracranial pressure (ICP) dynamics that is used to evaluate clinical treatment options for elevated ICP during traumatic brain injury (TBI). The model uses fluid volumes as primary state variables and explicitly models fluid flows as well as the resistance, compliance, and pressure associated with each of the compartments (arteries and arterioles, capillary bed, veins, venous sinus, ventricles, and brain parenchyma). The model has been tested to assure that it reproduces a correct physiologic response to intra-and extra-parenchymal hemorrhage and edema, and to therapies directed at reducing ICP such as cerebral spinal fluid drainage, mannitol administration, head elevation, and mild hyperventilation. The model is able to replicate observed clinical behavior in many cases, including elevated ICP associated with severe cerebral edema, subdural hematoma, and cerebrospinal fluid blockage. The model also successfully reproduces tne cerebrovascular regulatory mechanisms that are activated during TBI in response to various abnormalities such as high or low systemic blood pressure. We conclude that incorporating fluid volumes and flows into a model of lCP dynamics significantly improved its clinical utility. Additional improvements are anticipated (or wil1 accrue or will result) as the specific mechanisms that modify cerebral compliance and autoregulation during TBI and elevated ICP are further delineated

SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A

Introduction SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full‐length recombinant (r) FVIII (anti‐haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer. Aim To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25‐75 IU/kg in patients with severe haemophilia A (FVIII activity <1%). Methods Multinational, phase 1, prospective, open‐label, two‐period, fixed‐sequence, dose‐escalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3). Results Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatment‐related adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatment‐related changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5‐fold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25‐75 IU/kg dose range

Visual problems associated with traumatic brain injury:Vision with traumatic brain injury

Traumatic brain injury (TBI) and its associated concussion are major causes of disability and death. All ages can be affected but children, young adults and the elderly are particularly susceptible. A decline in mortality has resulted in many more individuals living with a disability caused by TBI including those affecting vision. This review describes: (1) the major clinical and pathological features of TBI; (2) the visual signs and symptoms associated with the disorder; and (3) discusses the assessment of quality of life and visual rehabilitation of the patient. Defects in primary vision such as visual acuity and visual fields, eye movement including vergence, saccadic and smooth pursuit movements, and in more complex aspects of vision involving visual perception, motion vision (‘akinopsia’), and visuo-spatial function have all been reported in TBI. Eye movement dysfunction may be an early sign of TBI. Hence, TBI can result in a variety of visual problems, many patients exhibiting multiple visual defects in combination with a decline in overall health. Patients with chronic dysfunction following TBI may require occupational, vestibular, cognitive and other forms of physical therapy. Such patients may also benefit from visual rehabilitation, including reading-related oculomotor training and the prescribing of spectacles with a variety of tints and prism combinations

A Review of Physiological Simulation Models of Intracranial Pressure Dynamics

This paper reviews the literature regarding the development, testing, and application of physiology-based computer simulation models of intracranial pressure dynamics. Detailed comparative information is provided in tabular format about the model variables and logic, any data collected, model testing and validation methods, and model results. Several syntheses are given that summarize the research carried out by influential research teams and researchers, review important findings, and discuss the methods employed, limitations, and opportunities for further research

Reproducing Published Results from \u3ci\u3eIn Silico\u3c/i\u3e Computer Models of the Acute Inflammatory Response to Severe Sepsis

Recent studies describe computer simulation models of the acute or systemic inflammatory response (AIR or SIR) to severe sepsis, a condition that can lead to multiple organ failure and death. One study used an agent-based model, while the other used differential equations (DEs) to simulate a randomized clinical trial. Both studies obtained results similar to the actual results from a successful clinical drug trial of severe sepsis, suggesting that in silico (simulated) randomized clinical trials may be used to design more effective in vivo clinical trials