Creation of the recombinant tissue plasminogen activator (rt-PA) image and its influence on practice habits

AbstractAmerican physicians have commonly practiced thrombolytic therapy for acute myocardial infarction with the recombinant form of tissue plasminogen activator (rt-PA), although its cost is much higher than that of streptokinase. The greater popularity of rt-PA is based on the belief that it is a more effective and a safer drug for achieving myocardial salvage and mortality reduction. However, a series of studies testing this assumption have not substantiated its greater efficacy or safety with respect to not only streptokinase but also urokinase and anisoylated plasminogen-streptokinase activator complex (APSAC).This editorial reviews the sequence of events that led to the creation of the rt-PA image, the mistaken premises on which it was based and the questions that need to be addressed if we are to strengthen the scientific method for evaluating similar types of drugs and its influence on practice habits including the costs to the health system

Plasmic Degradation of Crosslinked Fibrin CHARACTERIZATION OF NEW MACROMOLECULAR SOLUBLE COMPLEXES AND A MODEL OF THEIR STRUCTURE

A B S T R A C T Crosslinked fibrin was digested by plasmin, and three soluble complexes larger than DD/E were purified and characterized. After gel filtration chromatography, the purified complexes were shown to have molecular weights of 465,000, 703,000, and 850,000, as determined by equilibrium sedimentation. Each of the complexes was dissociated into two or more fragments by SDS-polyacrylamide gel electrophoresis. The structure of these subunit fragments was deduced from determinations of their molecular weights and polypeptide chain composition and from known sites of plasmin cleavage of fibrin. Fragments larger than DD have been identified that contain intact yry crosslinks as well as fragments resulting from cleavages at or near this site. The former include DY (mol wt 247,000), YY (mol wt 285,000), DXD (mol wt 461,000), and YXD (mol wt 500,000); and the latter include fragments XD (mol wt 334,000) and XY (mol wt 391,000). A schematic model was developed to explain the structure of the large noncovalently bound complexes based on their molecular weight and observed component fragments. Our scheme supports the twostranded half-staggered overlap model as the basic unit of fibrin structure, in which each complex consists of fragments from two adjacent complementary antiparallel fibrin strands. The smallest derivative, complex 1, is the DD/E complex; complex 2 contains apposed DY and YD fragments, and complex 3 consists of fragments DXD and YY. Complex 4 is less wellcharacterized, but its intact structure is projected to consist of YXD and DXY fragments from adjacent fibrin strands. Each complex is heterogeneous in subunit composition, reflecting additional plasmin cleavages within and/or adjacent to its theoretical boundaries. Since most ofthe protein initially released into solution from degrading fibrin is as complexes larger than DD/E

Intra-arterial administration of recombinant tissue-type plasminogen activator (rt-PA) causes more intracranial bleeding than does intravenous rt-PA in a transient rat middle cerebral artery occlusion model

<p>Abstract</p> <p>Background</p> <p>Intra-arterial (IA) administration of rt-PA for ischemic stroke has the potential for greater thrombolytic efficacy, especially for a large thrombus in the M1 or M2 segment of the middle cerebral artery (MCA). Intracranial hemorrhage (ICH) is a concern with IA or intravenous (IV) administration especially as the therapeutic window is extended. However, because IA administration delivers a higher local concentration of agent, the incidence and severity of ICH may be greater than with similar doses IV. We investigated the safety of rt-PA administration by IA compared to IV infusion following 6 hours of MCA occlusion (MCAo) with reflow in the spontaneously hypertensive rat (SHR).</p> <p>Methods</p> <p>Male SHRs were subjected to 6 hours MCAo with 18 hours reflow using a snare ligature model. They were treated with IA saline, IA rt-PA (1, 5, 10, 30 mg/kg), or IV rt-PA (10 and 30 mg/kg) by a 10 to 60 minute infusion beginning approximately 1 minute before reflow. The rats were recovered for 24 hours after MCAo onset at which time Bleeding Score, infarct volume, and Modified Bederson Score were measured.</p> <p>Results</p> <p>Greater hemorrhagic transformation occurred with 10 and 30 mg/kg rt-PA administered IA than IV. The IV 10 mg/kg rt-PA dosage induced significantly less bleeding than did the 1 or 5 mg/kg IA groups. No significant increase in infarct volume was observed after IA or IV treatment. Rats treated with 30 mg/kg rt-PA by either the IA or IV route had greater neurological dysfunction compared to all other groups.</p> <p>Conclusions</p> <p>Administration of rt-PA by the IA route following 6 hours of MCAo results in greater ICH and worse functional recovery than comparable dosages IV. Significantly greater bleeding was observed when the IA dose was a tenth of the IV dose. The increased bleeding did not translate in larger infarct volumes.</p

Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 μm), accumulation mode particles (ACP, 0.1-1.0 μm), PM₁₀(particulate matter <10 μm in diameter), elemental (EC) and organic carbon (OC), gaseous pollutants (nitrogen monoxide [NO], nitrogen dioxide [NO₂], carbon monoxide [CO], and sulphur dioxide [SO₂]) were collected at a central monitoring site and meteorological data were received from an official network. For each person and visit the individual 24-hour average of pollutants immediately preceding the blood withdrawal (lag 0) up to day 5 (lag1-4) and 5-day running means were calculated.</p> <p>Results</p> <p>Increased levels of fibrinogen were observed for an increase in one interquartile range of UFP, PM₁₀, EC, OC, CO, and NO revealing the strongest effect for lag 3. E-selectin increased in association with ACP and PM₁₀with a delay of one day. The ACP effect was also seen with the 5-day-mean. The pattern found for D-dimer was inconsistent. Prothrombin fragment 1+2 decreased with lag 4 consistently for all particulate pollutants. Von Willebrand factor antigen (vWF) showed a consistent decrease in association with almost all air pollutants with all lags except for lag 0. No associations were found for C-reactive protein, soluble intercellular adhesion molecule 1, serum amyloid A and factor VII.</p> <p>Conclusion</p> <p>These results suggest that elevated concentrations of air pollution are associated with changes in some blood markers of inflammation and coagulation in patients with chronic pulmonary disease. The clinical implications of these findings need further investigation.</p

Synthesis, structures, and reactivity of isomers of [RuCp*(1,4- (Me2N)2C6H4)]2

[RuCp*(1,3,5-R3C6H3)]2 {Cp* = &eta;5-pentamethylcyclopentadienyl, R = Me, Et} have previously been found to be moderately air stable, yet highly reducing, with estimated D+/0.5D2 (where D2 and D+ represent the dimer and the corresponding monomeric cation, respectively) redox potentials of ca. &minus;2.0 V vs. FeCp2+/0. These properties have led to their use as n-dopants for organic semiconductors. Use of arenes substituted with &pi;-electron donors is anticipated to lead to even more strongly reducing dimers. [RuCp*(1-(Me2N)-3,5-Me2C6H3)]+PF6&minus; and [RuCp*(1,4-(Me2N)2C6H4)]+PF6&minus; have been synthesized and electrochemically and crystallographically characterized; both exhibit D+/D potentials slightly more cathodic than [RuCp*(1,3,5-R3C6H3)]+. Reduction of [RuCp*(1,4-(Me2N)2C6H4)]+PF6&minus; using silica-supported sodium&ndash;potassium alloy leads to a mixture of isomers of [RuCp*(1,4-(Me2N)2C6H4)]2, two of which have been crystallographically characterized. One of these isomers has a similar molecular structure to [RuCp*(1,3,5-Et3C6H3)]2; the central C&ndash;C bond is exo,exo, i.e., on the opposite face of both six-membered rings from the metals. A D+/0.5D2 potential of &minus;2.4 V is estimated for this exo,exo dimer, more reducing than that of [RuCp*(1,3,5-R3C6H3)]2 (&minus;2.0 V). This isomer reacts much more rapidly with both air and electron acceptors than [RuCp*(1,3,5-R3C6H3)]2 due to a much more cathodic D2˙+/D2 potential. The other isomer to be crystallographically characterized, along with a third isomer, are both dimerized in an exo,endo fashion, representing the first examples of such dimers. Density functional theory calculations and reactivity studies indicate that the central bonds of these two isomers are weaker than those of the exo,exo isomer, or of [RuCp*(1,3,5-R3C6H3)]2, leading to estimated D+/0.5D2 potentials of &minus;2.5 and &minus;2.6 V vs. FeCp2+/0. At the same time the D2˙+/D2 potentials for the exo,endo dimers are anodically shifted relative to those of [RuCp*(1,3,5-R3C6H3)]2, resulting in much greater air stability than for the exo,exo isomer. &nbsp;</p

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson\u27s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design

Rituximab for treatment of inhibitors in haemophilia A: A Phase II Study

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m2 weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5–10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression