tbuckley/cabot-search huggingface dataset:
Optimization of metabolic stability as a goal of modern drug design
Authors: Thomas N. Thompson
Journal: Medicinal Research Reviews (2001)

Abstract Metabolism and other pharmacokinetic (PK) studies have always played a critical role in helping to optimize the bioavailability and duration of action of new drugs thereby increasing their success rate. With the advent of automated combinatorial synthesis, high‐throughput pharmacological testing, and the ability to create extensive databases in the past decade, drug discovery has undergone an amazing evolution. With the increased throughput of drug discovery, metabolism and other PK studies have evolved to keep pace. Often called “early ADME” studies, these studies are characterized by parallel processing and higher throughput than before. This article focuses on a particular class of early ADME (absorption, distribution mechanism, and excretion) studies known as “metabolic stability” studies. The theoretical basis for metabolic stability and its relationship to the concept of metabolic intrinsic clearance is briefly presented. Some key relationships between structure and metabolism are summarized. Several case studies from recent medicinal chemistry literature are reviewed to exemplify how metabolic stability studies influenced drug design and led to improvements in bioavailability and half‐life. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed. © 2001 John Wiley &amp; Sons, Inc. Med Res Rev, 21, No. 5, 412–449, 2001
Contemporary Analysis of Descending Thoracic and Thoracoabdominal Aneurysm Repair
Authors: Roy K. Greenberg, Qingsheng Lu, Eric E. Roselli, Lars G. Svensson, Michael C. Moon, Adrian V. Hernandez, Joseph Dowdall, Marcelo Cury, Catherine Francis, Kathryn Pfaff, Daniel G. Clair, Kenneth Ouriel, Bruce W. Lytle
Journal: Circulation (2008)

Endovascular repair of thoracic aneurysm has demonstrated low risks of mortality and spinal cord ischemia (SCI), but few large series have been published on endovascular thoracoabdominal aneurysm repair, and reports suffer from a lack of accurate comparison with similar open surgical procedures.A consecutive cohort of patients with thoracic and thoracoabdominal aneurysms treated electively with endovascular repair (ER) or surgical repair (SR) techniques between 2001 and 2006 were analyzed. The association between repair technique and SCI was evaluated with univariable analysis. Adjustments for potential confounders and for the propensity to receive ER or SR were also performed in multivariable analysis. A total of 724 patients (352 ER, 372 SR) underwent repair. The mean age was 67 years, and 65% were male. ER patients were on average 9 years older (P<0.001), had more comorbid conditions, and more frequently had prior distal repair (P<0.001) or underwent a type I or IV repair. SR patients more commonly had chronic dissection or required type II or type III repairs (P<0.001). Mortality at 30 days (5.7% ER versus 8.3% SR, P=0.2) and 12 months (15.6% ER versus 15.9% SR, P=0.9) was similar. A borderline difference in SCI was found between repair techniques: 4.3% of ER and 7.5% of SR patients (P=0.08) had SCI. In patients with ER, prior distal aortic operation was associated with the development of SCI in univariable analysis (odds ratio 4.1, 95% confidence interval 1.4 to 11.7). Multivariable analysis showed that the type of required repair (type I, II, III, or IV) was the primary factor associated with the development of SCI in ER and SR patients.No significant difference in the incidence of mortality or SCI was found between ER and SR techniques. The strongest factor associated with SCI remains the extent of the disease. Further studies are indicated to compare ER with patients considered eligible for SR.
Evidence based medicine: does it make a difference?
Authors: Tim Wilson
Journal: BMJ (2005)

Evidence based medicine: does it make a difference? Use wiselyEditor-The term "evidence based medicine" entered the scientific lexicon only a little more than a decade ago. 1 What caused its remarkable spread, and what are the implications of its broad and rapid diffusion?The team that coined the term at first considered using the phrase "scientific medicine" but rejected it because it implied that other approaches were by definition unscientific. 2However, critics have argued that the term evidence based medicine carries a similar moral valence and linguistic slipperiness. 3 Who could argue against the notion of providing care that integrates individual clinical skill and the best external evidence? 4 Originally developed as a method for teaching medical residents, evidence based medicine is being applied ever more broadly to the organisation and delivery of medical services.Multiple stakeholders now seek to assume its mantle for purposes that often contradict its original intent.Managers, equating lack of evidence with lack of effectiveness, use it as a rationale for cutting services.Industry generates evidence of questionable quality to promote its products.Medical researchers come to believe that they hold a monopoly on generating and interpreting evidence.Evidence based medicine, developed as a means of taming the unscientific and messy world of clinical practice, has itself entered the unscientific and messy world of politics. 5ike any technology, evidence based medicine carries risks and benefits and can be used appropriately or inappropriately.Overly inclusive definitions threaten to deprive the term of meaning, and unchecked use increases the risk of misuse.In the past decade, evidence based medicine has contributed much to how we teach, deliver, and think about clinical services.In the coming decade, we must continue to ensure that it is not only used widely but wisely.
College proposes better deal for acute medical patients
Authors: Lynn Eaton
Journal: BMJ (2004)

The Royal College of Physicians has set out a new blueprint for providing acute care in the NHS in what it calls “one of the most important” reports it has produced in recent years.

The college believes its proposals will dramatically improve the quality and safety of people who are acutely ill, because it will ensure that those patients have the undivided attention of specialist acute care teams, rather than specialists in other types of care who are doing shifts on the acute ward on a rotation.

It recommends there should be …
HEAT LABILE OPSONINS TO PNEUMOCOCCUS
Authors: Mary Ruth Smith, W. Barry Wood
Journal: The Journal of Experimental Medicine (1969)

Heat labile opsonins (HLO) in normal rat serum to both encapsulated and unencapsulated pneumococci (a) have the same heat lability as complement (C); (b) are active at 37 degrees C but not at 0 degrees C; (c) are inactivated proportionately to hemolytic C by the addition of immune aggregates to the serum; (d) are adsorbed from serum nonspecifically by bacteria at 37 degrees C but not at 0 degrees C; (e) are Ca(++)- and/or Mg(++)-dependent in their action; and (f) are inactivated by zymosan and a purified cobra venom factor, and in the case of encapsulated pneumococci, at least, by NH(4)OH. Like other opsonins, HLO to pneumococci act primarily on the bacteria rather than on the phagocytes. Their combined properties indicate that they involve multiple components of the hemolytic C system. Since HLO are immunologically polyspecific, they presumably play a broad protective role in the early (preantibody) phase of acute bacterial infections.
Electroforming of Implantable Tubular Magnetic Microrobots for Wireless Ophthalmologic Applications
Authors: George Chatzipirpiridis, Olgaç Ergeneman, Juho Pokki, Franziska Ullrich, Stefano Fusco, José A. Ortega, Kartik M. Sivaraman, Bradley J. Nelson, Salvador Pané
Journal: Advanced Healthcare Materials (2014)

Magnetic tubular implantable micro­robots are batch fabricated by electroforming. These microdevices can be used in targeted drug delivery and minimally invasive surgery for ophthalmologic applications. These tubular shapes are fitted into a 23-gauge needle enabling sutureless injections. Using a 5-degree-of-freedom magnetic manipulation system, the microimplants are conveniently maneuvered in biological environments. To increase their functionality, the tubes are coated with biocompatible films and can be successfully filled with drugs.
P196 Percutaneous Ultrasound-Guided Biopsy of Intrathoracic Parietal Masses – a Safe Alternative to CT-Guided Biopsy?
Authors: TRG Simpson, G Constantinescu, P Mellor, S Lohani, B Khan, M Mushtaq, I Abdelhadi, B Bhattacharjee, V Serafimov
Journal: Thorax (2012)

<h3>Background</h3> The current gold standard method for sampling intrathoracic lesions is via a CT-guided approach. However, most parietal-attached intrathoracic lesions can be visualised with ultrasound and sampled. <h3>Aims</h3> A prospective audit of consecutive patients with CT-identified intrathoracic parietal-attached lesions, sampled percutaneously by an ultrasound-guided approach, was carried out to assess efficacy and safety. The lung MDT was instrumental in selecting patients. <h3>Materials and Methods</h3> Seventeen consecutive patients were audited over a span of 8 months. This cohort included 12 males and 5 females with an age range from 42 to 84 years (median 63 years). The biopsies were performed by 4 skilled investigators assisted by a specialist nurse, using an 18 gauge single-trochar puncture under standard aseptic conditions. A Toshiba Applio ultrasound unit, with Doppler-flow map capabilities was used to avoid vessel puncture. Patients recovered in the radiology department observation ward. <h3>Results</h3> Interpretable specimens were obtained in 16 patients. A single patient needed a repeat, successful, US-guided procedure. The median duration for the procedure was 26 minutes, with a median observation time before discharge of a further 40 minutes. Two patients developed small pneumothoraces and one patient suffered minor haemoptysis, none of which required admission. <h3>Conclusion</h3> Where applicable, this technique is safe, fast, avoids radiation and may result in fewer complications compared to the CT-guided approach. Fewer personnel are required and CT scanner time is freed for other uses. Moreover, in the hands of an ultrasound-skilled respiratory physician, this method correctly applied would provide an earlier route to diagnosis for the Lung MDT.
Acute Hemodynamic Effects of Nitroglycerin in Pulmonary Hypertension
Authors: RONALD G. PEARL
Journal: Annals of Internal Medicine (1983)

Therapy of pulmonary hypertension is limited by the low potency and adverse effects of current pulmonary vasodilators. The hemodynamic effects of nitroglycerin in human pulmonary hypertension are not known. We administered nitroglycerin to nine patients with chronic pulmonary hypertension. Nitroglycerin increased cardiac index 40% (p < 0.01), increased stroke volume 40% (p < 0.01), decreased pulmonary vascular resistance 40% (p < 0.01), and decreased mean pulmonary artery pressure 15% (p < 0.01). Pulmonary vascular resistance decreased more than 25% in eight of the nine patients. In four patients the effects of intravenous nitroglycerin were reproduced by topical nitroglycerin preparations; cardiac index increased 50%, stroke volume increased 48%, pulmonary vascular resistance decreased 43%, and mean pulmonary artery pressure decreased 19%. Five of six patients treated with long-acting nitrates had substantial improvement of their symptoms. We conclude that therapy with nitroglycerin can be effective in patients with severe pulmonary hypertension.
Effects of lead and natriuretic hormone on kinetics of sodium-potassium-activated adenosine triphosphatase: possible relevance to hypertension.
Authors: E Weiler, F Khalil-Manesh, H Gonick
Journal: Environmental Health Perspectives (1988)

Inhibition of vascular smooth muscle sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) has been postulated as a central mechanism in enhancing vascular contractility. In the present study, kinetics of inhibition of Na-K-ATPase by lead, ouabain, and natriuretic hormone (NH) was studied in a purified hog cerebral cortex enzyme preparation. Determination of I50 values for lead, ouabain, and NH revealed that NH is the most potent inhibitor of the enzyme system (0.8 x 10(-6) M ouabain equivalents). Kinetic analyses indicated that lead and NH exhibited different inhibitory mechanisms. The inhibition by lead was noncompetitive with respect to potassium and competitive with respect to sodium and MgATP. Natriuretic hormone was noncompetitive with respect to potassium, uncompetitive with respect to MgATP, and exhibited no inhibitory effect with respect to sodium. Synergism between lead and NH in the inhibition of Na-K-ATPase raises the possibility that lead may be a contributory factor in hypertension via this mechanism.
Cutting Cost without Cutting the Quality of Care
Authors: Alain C. Enthoven
Journal: New England Journal of Medicine (1978)

THE invitation to give the Shattuck Lecture posed a problem for me. How could an economist from California relate to Dr. Benjamin Shattuck, colonial physician in Templeton, Massachusetts, and the distinguished line of Shattuck physicians that followed him? Then I discovered Lemuel Shattuck (1793–1859), not a physician, but a businessman, a founder of the American Statistical Association and principal author of the Report of a General Plan for the Promotion of Public and Personal Health, published in 1850.1 Lemuel's interest was not primarily in how the medical profession could lift itself above quackery, a problem very much on the mind . . .
Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model.
Authors: T Kakuta, J W Currier, C C Haudenschild, T J Ryan, D P Faxon
Journal: Circulation (1994)

In de novo human atherosclerosis, compensatory vessel enlargement limits the effect of intimal plaque formation on lumen narrowing. We hypothesized that arterial remodeling may also play an important role in determining the chronic lumen size after angioplasty and tested this hypothesis using the hypercholesterolemic rabbit iliac artery angioplasty model.Morphometric analysis of histological cross-sectional areas of vessels from animals killed immediately after angioplasty (acute group, n = 11) were compared with the same areas from animals killed 4 weeks after the procedure (chronic group, n = 37), when restenosis occurs in this model. The area circumscribed by the internal elastic lamina (IEL) increased by 20% from acute to 4 week follow-up after angioplasty (acute group, 2.36 +/- 0.45 mm2, chronic group, 2.84 +/- 0.89 mm2). Over the same time period, intimal area increased by 0.82 mm2. Despite this increase in intimal area, lumen area decreased by only 0.34 mm2 because of the compensatory enlargement of the IEL area. In the chronic group, polynomial regression analysis revealed a quadratic relation between intimal area and lumen area (R2 = .35, P < .001). A lumen area of 0.45 mm2 (the nadir of the quadratic relation) was used to divide the chronic group into two subgroups: restenotic (n = 21; lumen area, < 0.45 mm2) and nonrestenotic (n = 16; lumen area, > 0.45 mm2). By definition, there was a significant difference in lumen area between the two subgroups (0.15 +/- 0.15 mm2 for restenotic; 0.73 +/- 0.18 mm2 for nonrestenotic). Surprisingly, the intimal areas in the two subgroups were virtually identical (2.41 +/- 0.92 mm2 for restenotic, 2.49 +/- 0.69 mm2 for nonrestenotic, P = NS). The difference in the lumen area between restenotic and nonrestenotic vessels was a result of the significantly greater IEL area in the nonrestenotic subgroup (3.22 +/- 0.83 mm2 for nonrestenotic, 2.56 +/- 0.84 mm2 for restenotic, P < .05). In both restenotic and nonrestenotic vessels, the IEL area increased with increases in intimal area. In the restenotic arteries, the slope of this correlation was < 1, showing inadequate compensatory enlargement for the intimal plaque. In the nonrestenotic vessels, the slope was > 1, limiting the effect of intimal plaque on luminal narrowing.These data indicate that the iliac artery in an atherosclerotic rabbit model compensates for intimal formation after angioplasty by vessel enlargement. Furthermore, the degree of vessel enlargement is more important than intimal area in determining the chronic lumen size.
Inhibition of interleukin‐5 with a monoclonal antibody attenuates allergic inflammation
Authors: M. Danzig, F. Cuss
Journal: Allergy (1997)

IL-5 is a prominent and perhaps an essential element in the induction of allergic inflammation in human asthma and other allergic diseases. Despite the strong biochemical and clinical correlates between lung eosinophilia and asthma, there is no clear understanding of how eosinophils exacerbate asthma. Antigen administration to sensitized animals produces eosinophilic infiltration that is very similar to that in man, and is prevented by administration of a neutralizing monoclonal antibody against IL-5. Mice in which the IL-5 gene is absent are unable to mount eosinophilic responses to antigen and do not sustain lung damage, but otherwise develop normally. The study of the biology of IL-5 has not only clarified the links between eosinophilia and airway hyperreactivity, but also strongly suggests that anti-IL-5 therapy may be an effective, safe, and novel way of treating human asthma and perhaps other eosinophilic diseases. There are many different potential approaches to the inhibition of IL-5, but the one most likely to provide "proof of principle" in "asthma in the wild" in man is a monoclonal antibody against IL-5.
Fixed-Dose Combinations of Antituberculous Medications To Prevent Drug Resistance
Authors: Thomas Moulding
Journal: Annals of Internal Medicine (1995)

The treatment of tuberculosis requires at least two drugs to retard the development of drug resistance. Unfortunately, patients may take only one drug (monotherapy) when more than one is prescribed. Fixed-dose combinations with two or more antituberculous drugs in one capsule or tablet are available to prevent this. In the United States, these drugs are Rifamate (Marion Merrell Dow), which contains isoniazid plus rifampin, and Rifater (Marion Merrell Dow), which contains isoniazid plus rifampin and pyrazinamide. Because these preparations make monotherapy impossible, they are clearly preferable to individual drugs. In the United States in 1993, however, only 15% to 18% of rifampin was sold in the form of fixed-dose combinations. To correct this deficiency, fixed-dose combinations should be widely promoted and accepted as a primary way to prevent drug-resistant tuberculosis. There are two caveats regarding these preparations. First, many fixed-dose combinations, especially those in developing countries, achieve inadequate blood levels of one or more of the component drugs, especially rifampin. Our recommendations apply only to preparations with proven bioavailability. Second, because the name Rifamate is similar to the name rifampin, mistakes in prescribing and dispensing can result in the patient receiving rifampin alone when Rifamate is intended. A name change from Rifamate to a highly distinctive name such as Rif-Isoniazid is needed to prevent such occurrences.
Stenting in Severe Chronic Pancreatitis: Results of Medium-Term Follow-Up in Seventy-Six Patients
Authors: M. Cremer, J. Devière, M. Delhaye, M. Baize, A. Vandermeeren
Journal: Endoscopy (1991)

Between January 1985 and September 1989, 75 patients presenting with severe chronic pancreatitis with distal stricture and upstream dilatation underwent stenting of the main pancreatic duct (MPD) through the major papilla (n = 54) or minor papilla (n = 21) in order to drain the predominant duct through a 10 F plastic prosthesis. All patients had undergone biliary and pancreatic sphincterotomy with a few cases of complications, and the majority (84 %) also ESWL in the period from October 1987 onwards without complications. Relief of pain (94 %) occurred parallel to a decrease in the MPD diameter. In a mean follow-up period of 37 months improvement of the nutrition status and relief of pain was seen. Clogging of these large plastic stents was treated by replacement or by another endoscopic or surgical procedure. Complications were treated endoscopically. Further measures necessary due to failure of stenting consisted of laterolateral pancreatico-jejunostomy in 15 % of patients and placement of self-expanding 18 F metal mesh stents in 29 %. There was no mortality due to surgery. It is concluded that stenting of distal strictures in the MPD can lead to rapid resolution of pancreatic pain due to ductal hypertension and is the best means for determining the cause of pain, providing an alternative to surgery. Significant improvement of a stricture by prolonged stenting is however unusual, and such patients treated endoscopically require close follow-up with stent replacement approximately once a year.
Spontaneous Remission of Cushing's Disease
Authors: John P. Hayslett, George L. Cohn
Journal: New England Journal of Medicine (1967)

SINCE Cushing1 called attention to the syndrome that now bears his name, it has been recognized that the clinical manifestations of Cushing's disease are associated with adrenocortical hyper-function and the secretion of excessive amounts of cortisol. The adrenal abnormalities may be classified as nontumorous hyperplasia, benign adenoma and adrenal carcinoma.Although the intensity of the symptoms may vary, the disorder has been characterized by an unfavorable prognosis and a progressively deteriorating course. The life expectancy2 of the untreated patient is reported as three to ten years, with an average duration of five to seven years. Patients with malignant adrenocortical tumors . . .
Effects of Particle Size Fractions on Reducing Heart Rate Variability in Cardiac and Hypertensive Patients
Authors: Kai-Jen Chuang, Chang-Chuan Chan, Nan-Ting Chen, Ta-Chen Su, Lian-Yu Lin
Journal: Environmental Health Perspectives (2005)

It is still unknown whether the associations between particulate matter (PM) and heart rate variability (HRV) differ by particle sizes with aerodynamic diameters between 0.3 microm and 1.0 microm (PM(0.3-1.0)), between 1.0 microm and 2.5 microm (PM(1.0-2.5)), and between 2.5 microm and 10 microm (PM(2.5-10)). We measured electrocardiographics and PM exposures in 10 patients with coronary heart disease and 16 patients with either prehypertension or hypertension. The outcome variables were standard deviation of all normal-to-normal (NN) intervals (SDNN), the square root of the mean of the sum of the squares of differences between adjacent NN intervals (r-MSSD), low frequency (LF; 0.04-0.15 Hz), high frequency (HF; 0.15-0.40 Hz), and LF:HF ratio for HRV. The pollution variables were mass concentrations of PM(0.3-1.0), PM(1.0-2.5), and PM(2.5-10). We used linear mixed-effects models to examine the association between PM exposures and log10-transformed HRV indices, adjusting for key personal and environmental attributes. We found that PM(0.3-1.0) exposures at 1- to 4-hr moving averages were associated with SDNN and r-MSSD in both cardiac and hypertensive patients. For an interquartile increase in PM(0.3-1.0), there were 1.49-4.88% decreases in SDNN and 2.73-8.25% decreases in r-MSSD. PM(0.3-1.0) exposures were also associated with decreases in LF and HF for hypertensive patients at 1- to 3-hr moving averages except for cardiac patients at moving averages of 2 or 3 hr. By contrast, we found that HRV was not associated with either PM(1.0-2.5) or PM(2.5-10). HRV reduction in susceptible population was associated with PM(0.3-1.0) but was not associated with either PM(1.0-2.5) or PM(2.5-10).