Pharmacokinetics and pharmacodynamics of pentoxifylline and metabolites

Pentoxifylline is a haemorheologic drug with complex pharmacokinetics and pharmacodynamics due to both reversible metabolism and the formation of active metabolites. In humans, pentoxifylline is metabolised to at least seven phase 1 metabolites (M1-M7). The reversible metabolism of pentoxifylline to the enantiomers of M1 has only been partly studied. This thesis investigates the pharmacokinetics of pentoxifylline and metabolites and their contributions to the haemorheological effects. When pentoxifylline is administered either orally or intravenously to healthy humans the plasma concentrations of M5 and S-M1 are higher than the pentoxifylline concentrations, whereas the ones for M4 are lower and R-M1 much lower. In-vitro studies showed that this can be mainly explained by a 15 times faster formation of S-M1 than R-M1 from pentoxifylline. Had the enantiomers been present at equal concentrations the reversible metabolism would have been 4 times faster from S-M1 than from R-M1. Pentoxifylline, R-M1, and M5 increases retinal blood flow after administration of pentoxifylline to healthy humans. In the following potency order R-M1, rac-M1, S-M1, pentoxifylline and M4 significantly inhibit platelet aggregation in a concentration-dependent manner in whole blood from healthy humans. The thesis also includes a phase two, double-blind, placebo-controlled randomised clinical trial investigating pentoxifylline and vitamin E treatment for prevention of radiation-induced side effects in 83 women with breast cancer. The study showed that the combination of pentoxifylline and vitamin E was well tolerated and may be used for prevention of some radiation-induced side effects, e.g. increased arm volume and pain described as stiffness in the skin

The Wearable Cardioverter-Defibrillator

The wearable cardioverter-defibrillator (WCD) is a rechargeable external device that can be worn under the clothing all day long and protects the wearer from potentially life-threatening ventricular tachyarrhythmias. When a dangerous arrhythmia is detected, the WCD can deliver high-energy shocks. The WCD has been shown to be effective in accurately detecting and appropriately treating ventricular tachycardia (VT) and ventricular fibrillation (VF). It is intended for temporary use as a bridge to an implantable cardioverter-defibrillator (ICD), heart transplantation, or left ventricular assist device; patients with heart failure with reduced ejection fraction may benefit from the WCD while their condition improves. It can be used temporarily after explant of an ICD until reimplantation is deemed possible. In select patients with myocardial infarction, a WCD may be useful during the immediate period after infarction. It is indicated for use when a permanently implanted ICD must be explanted because of infection; the patient can use the WCD until the infection resolves, and a new ICD can be implanted. The role of the WCD is emerging as an important therapeutic option to protect patients at elevated risk of sudden cardiac death (SCD)

The Subcutaneous Implantable Cardioverter-Defibrillator

The subcutaneous ICD (S-ICD) represents an important advancement in defibrillation therapy that obviates the need for a transvenous lead, the most frequent complication with transvenous devices. The S-ICD has been shown similarly safe and effective as transvenous ICD therapy, but the two devices are not interchangeable. The S-ICD is only suitable for patients who do not require bradycardia or antitachycardia pacing functionality. In patients with underlying diseases associated with polymorphic ventricular tachycardia and a long life expectancy, an S-ICD may be the preferred choice. Moreover, it is advantageous in the situation of increased risk of endocarditis, i.e., previous device system infection and immunosuppression, including hemodialysis. In patients with abnormal vascular access and/or right-sided heart structural abnormalities, it may be the only option. The S-ICD is bulkier, the battery longevity is shorter, and the device cost is higher, even though remote follow-up is possible. A two- or three-incision implant procedure has been described with a lateral placement of the device and a single subcutaneous lead. The rate of inappropriate therapy for both S-ICD and transvenous systems is similar, but S-ICD inappropriate shocks are more frequently attributable to oversensing, which can often be resolved with sensing adjustments

Leadless Pacemakers

Leadless or transcatheter pacemakers have recently been introduced to market with important benefits and some limitations. Implanted entirely within the right ventricle, these devices eliminate the need for transvenous pacing leads and pacemaker pockets and thus reduce the risk of infections and lead-related problems. Currently, they offer only VVI/R pacing and they cannot provide atrial sensing, antitachycardia pacing, or AV synchrony. They offer a number of features (such as rate response) and electrogram storage, albeit more limited than in a transvenous system. Real-world clinical data are needed to better comment on projected battery life, which manufacturers suggest will be at least equivalent to transvenous devices. Extracting an implanted leadless pacemaker remains a challenge, although proprietary snare and removal systems are available. However, a leadless pacemaker at end of service may be programmed to OOO and left in place; a revised device may be implanted adjacent. These innovative new devices may have important uses in special populations. Initial data on implant success and adverse events are favorable. Currently, there are two leadless pacemakers available: the Micra™ device by Medtronic and the Nanostim™ device by Abbott (formerly St. Jude Medical)

Five-choice serial reaction time task performance following catecholamine depletion of rat medial prefrontal cortex: implications for attention deficit in schizophrenia

The symptoms of schizophrenia are highly variable and include a variety of cognitive deficits, including attentional deficit. These cognitive deficits may involve dopamine (DA) underactivity in the prefrontal cortex (PFC) (Weinberger, Egan, Bertolino, Callicott, Mattay, Lipska, et al., 2001). The purpose of this thesis was to test the hypothesis that reduced DA in the PFC alters attention by examining the effects of reduced DA in the medial PFC (mPFC) of rats on a sustained attention task. Rats in the DA-lesioned group were administered 6-hydroxydopamine (6-OHDA) in the mPFC. Following 6-OHDA administration, rats in the DA-lesioned and shamlesioned group were trained to nose poke into a lit aperture for food reward in the 5-choice serial reaction time task (5-CSRTT), a rodent analogue of the Continuous Performance Task used to assess sustained attention in schizophrenics (Robbins, 2002). The 6-OHDA administration resulted in depletions of both DA (33% of controls) and norepinephrine (NE) (50% of controls). Rats\u27 performance was assessed by comparing the frequency of correct, incorrect, omitted, and premature responses in testing conditions where the duration of stimulus in the 5-CSRTT was randomly varied from 2.5 to 0.25 seconds. No significant differences between lesioned and control rats were observed in any behavioral testing parameters. However, there was a trend toward increased numbers of omissions and reduced correct responses seen in lesioned rats especially at the shortest stimulus durations. The trend supports the hypothesis that reduced DA in the PFC contributes to attentional dysfunction in schizophrenia. Future studies should examine the behavioral effects of 6-OHDA lesions using larger sample sizes. Also, future studies should examine rats\u27 5-CSRTT performance at stimulus durations less than 0.25 seconds to further explore the trend toward poorer performance seen in 6-OHDA lesioned rats

Statins and muscle pain

Introduction: Statins remain among the most frequently prescribed drugs and constitute a cornerstone in the prevention of cardiovascular disease. However, muscle symptoms are often reported from patients on statins. Muscle symptoms are frequently reported as adverse events associated with statin therapy.Areas covered: In the present narrative review, statin-associated muscle pain is discussed. It elucidates potential mechanisms and possible targets for management.Expert opinion: In general, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Reported symptoms are difficult to quantify. Rarely is it possible to establish a causal link between statins and muscle pain. In randomized controlled trials, statins are well tolerated, and muscle-pain related side-effects is similar to placebo. There are also nocebo effects of statins. Exchange of statin may be beneficial although all statins have been associated with muscle pain. In some patients reduction of dose is worth trying, especially in primary prevention Although the benefits of statins outweigh potential risks in the vast majority of cases, careful clinical judgment may be necessary in certain cases to manage potential side effects on an individual basis

Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by the phenotype of a dilated left ventricle with systolic dysfunction. It is classified as hereditary when it is deemed of genetic origin; more than 50 genes are reported to be related to the condition. Symptoms include, among others, dyspnea, fatigue, arrhythmias, and syncope. Unfortunately, sudden cardiac death may be the first manifestation of the disease. Risk stratification regarding sudden death in hereditary DCM as well as preventive management poses a challenge due to the heterogeneity of the disease. The purpose of this chapter is to present the epidemiology, risk stratification, and preventive strategies of sudden cardiac death in hereditary DCM

Game mechanics engine

Game logic and game rules exists in all computer games, but they are created di erently for all game engines. This game engine dependency exists because of how the internal object model is implemented in the engine, as a place where game logic data is intermingled with the data needed by the low- level subsystems. This thesis propose a game object model design, based on existing theory, that removes this dependency and establish a general game logic framework. The thesis then expands on this logic framework and existing engine design theory to create a concept of a genre-independent engine that can provide an alternative to the normal game engine. This new genre-independent alternative is referred to as a game mechanics engin

Atrial Fibrillation and the Role of Thumb ECGs

Atrial fibrillation (AF) may be underdiagnosed, and there is much that remains unknown about this prevalent and potentially life-threatening arrhythmia. AF epidemiology has been thwarted in part by the fact that about a third of patients with AF have no symptoms, those with symptoms may experience them intermittently or have vague symptoms, and it can be challenging to capture an episode on a 12-lead ECG, which is required for diagnosis. There are many significant knowledge gaps in our understanding of AF etiology and progression. A new user-friendly device that allows for frequent self-monitoring of the heart rhythm has been introduced. With the thumb ECG, patients can record a tracing multiple times a day. A smartphone app will soon allow them to interact with their healthcare providers about these ECG recordings. An ECG parser will allow for an algorithm-directed, rapid, automatic interpretation of these recordings with high specificity and sensitivity. This may help researchers learn more about the so-called silent AF, AF progression (and possible remission), and risk factors for AF. This technology holds great promise for patient care as well as for research into AF