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Modern Applied Statistics With S

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.

https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1046/j.1365-2125.2003.01892.x

Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications

The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

https://link.springer.com/content/pdf/10.1602%2Fneurorx.2.1.86.pdf

Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family

I am delighted to announce the exciting news that we have received just under 900 abstracts for presentation in the scientific program of the VIth World Congress on Pain in Adelaide, April l-6, 1990. This 1s about a 50% increase in the number of abstracts submitted for the 1987 Congress in Hamburg and it represents by far the greatest number of scientific papers ever offered for the an IASP Congress. This surely reflects the healthy state of IASP and is also a very encouraging indlcator of the high level of activity in basic and clinical research in the field of pain throughout the world. Based upon our previous experience with the ratio of congress delegates to scientific abstracts, the Adelaide Congresses promises to be the largest world congress on pain we have so far held.

International association for the study of pain

Population pharmacodynamic (PD) models describe the time course of drug effects, relating exposure to response, and providing a more robust understanding of drug action than single assessments PD models can test alternative dose regimens through simulation, allowing for informed assessment of potential dose regimens and study designs This is the third paper in a three-part series, providing an introduction into methods for developing and evaluating population PD models Example files are available in the Supplementary Data

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1038/psp.2013.71

Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods.

Modeling is an important tool in drug development; population modeling is a complex process requiring robust underlying procedures for ensuring clean data, appropriate computing platforms, adequate resources, and effective communication. Although requiring an investment in resources, it can save time and money by providing a platform for integrating all information gathered on new therapeutic agents. This article provides a brief overview of aspects of modeling and simulation as applied to many areas in drug development.

/pdf/basic-concepts-in-population-modeling-simulation-and-model-in1but0133.pdf

Basic Concepts in Population Modeling, Simulation, and Model‐Based Drug Development

UNLABELLED Indicator dilution theory predicts that the first-pass pulmonary and systemic arterial concentrations of a drug will be inversely related to the cardiac output For high-clearance drugs, these first-pass concentrations may contribute significantly to the measured arterial concentrations, which would therefore also be inversely related to cardiac output We examined the cardiac output dependence of the initial kinetics of propofol in two separate studies using chronically instrumented sheep in which propofol (100 mg) was infused IV over 2 min In the first study, steady-state periods of low, medium, and high cardiac output were achieved by altering carbon dioxide tension in six halothane-anesthetized sheep The initial area under the curve and peak value of the pulmonary artery propofol concentrations were inversely related to cardiac output (R2 = 057 and 066, respectively) For the systemic arterial concentrations, these R2 values were 068 and 071, respectively In our second study, transient reductions in cardiac output were achieved in five conscious sheep by administering a short infusion of metaraminol concurrently with propofol Cardiac output was lowered by 22 L/min, and the area under the curve to 10 min of the arterial concentrations increased to 143% of control IMPLICATIONS The initial arterial concentrations of propofol after IV administration were shown to be inversely related to cardiac output This implies that cardiac output may be a determinant of the induction of anesthesia with propofol

Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration.

Food, gastrointestinal pH, and models of oral drug absorption

Lidocaine hydrochloride (HCl) (80-320 mg), bupivacaine HCl (20-80 mg), and ropivacaine HCl (30-120 mg) were administered as intravenous bolus doses to conscious sheep (n = 18; average body weight 45 kg) that had previously placed intravascular cannulae for hemodynamic monitoring and for obtaining blood samples The mean convulsive doses and arterial blood concentrations were approximately 110 mg and 40 mg/L, respectively, for lidocaine HCl, 45 mg and 14 mg/L for bupivacaine HCl, and 60 mg and 20 mg/L for ropivacaine HCl After subconvulsive doses of each agent, there were minimal cardiovascular effects After convulsive doses, there were marked increases in heart rate, mean arterial pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, left ventricular end diastolic pressure, and myocardial contractility Ventricular fibrillation caused death in two sheep after bupivacaine (80 mg) and in two sheep after ropivacaine (90 and 120 mg) administration With sublethal doses, the hemodynamic responses to these agents were qualitatively and quantitatively similar when compared with their local anesthetic potencies

Richard N. Upton

Papers

Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods.

Basic Concepts in Population Modeling, Simulation, and Model‐Based Drug Development

Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration.

Food, gastrointestinal pH, and models of oral drug absorption

Hemodynamic and central nervous system effects of intravenous bolus doses of lidocaine, bupivacaine, and ropivacaine in sheep.