A scale for assessing the severity of diseases and adverse drug reactions: Application to drug benefit and risk

Physicians were interviewed to assess their willingness to risk adverse drug reactions among patients. These untoward reactions were ranked according to severity and weighted against the primary illness being treated. A specially designed questionnaire in the form of a matrix was used. Severity was divided into seven classes denoted by progressively increasing numerical scores, W1 to W7, whose values could be calculated from analysis of the completed questionnaires. The questionnaires presented several cases, in each of which an illness of specified severity was to be treated with a drug whose untoward reactions differ in severity from that of the primary illness. Each case involved a different permutation of the severities. Analysis of the completed questionnaires yielded the mean values of the scores which were found to range from W1 = 1.00 (the mildest case) to W7 = 817 (the most serious case). It is our opinion that this type of scale is preferable to nonnumerical descriptions of severity such as mild or serious, since, when combined with data on frequency of occurrence, a numerical scale permits a determination of expectation of both benefit and risk

Estimation of the affinity of naloxone at supraspinal and spinal opioid receptors in vivo: Studies with receptor selective agonists

The apparent affinity of naloxone at cerebral and spinal sites was estimated using selective mu [D-Ala2, Gly-ol5]-enkephalin (DAGO) and delta [D-Pen2, D-Pen5]enkephalin] (DPDPE) opioid agonists in the mouse warm water tail-withdrawal test in vivo; the mu agonist morphine was employed as a reference compound. The approach was to determine the naloxone pA2 using a time-dependent method with both agonist and antagonist given intracerebroventricularly (i.c.v.) or intrathecally (i.th.); naloxone was always given 5 min before the agonist. Complete time-response curves were determined for each agonist at each site in the absence, and in the presence, of a single, fixed i.c.v. or i.th. dose of naloxone. From these i.c.v. or i.th. pairs of time-response curves, pairs of dose-response lines were constructed at various times; these lines showed decreasing displacement with time, indicative of the disappearance of naloxone. The graph of log (dose ratio - 1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this plot, the apparent pA2 and naloxone half-life was calculated at each site and against each agonist. The affinity of naloxone was not significantly different when compared between agonists after i.c.v. administration. A small difference was seen between the affinity of i.th. naloxone against DPDPE and DAGO; the i.th. naloxone pA2 against morphine, however, was not different than that for DPDPE and DAGO. The naloxone half-life varied between 6.6 and 16.9 min, values close to those previously reported for this compound. These results suggest that the agonists studied may produce their i.c.v. analgesic effects at the same receptor type or that alternatively, the naloxone pA2 may be fortuitously similar for mu and delta receptors in vivo. Additionally, while the affinity of naloxone appears different for the receptors activated by i.th. DAGO and DPDPE, further work may be necessary before firm conclusions regarding the nature of the spinal analgesic receptor(s) can be drawn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25982/1/0000048.pd

Spinal-Supraspinal and Intrinsic m-Opioid Receptor Agonist-Norepinephrine Reuptake Inhibitor (MOR-NRI) Synergy of Tapentadol in Diabetic Heat Hyperalgesia in Mice

ABSTRACT Tapentadol is a m-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 mg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED 50 0.42 mg/animal i.t., 0.18 mg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED 50 0.053 mg/animal i.t. 1 i.c.v.). Morphine (0.001-10 mg/animal) also showed central efficacy and synergy (ED 50 0.547 mg/animal i.t., 0.004 mg/animal i.c.v., 0.014 mg/animal i.t. 1 i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED 50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the a 2 -adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy

Commentary on Neostigmine Interactions with Non steroidal Anti-inflammatory Drugs by Miranda et al.

The article by Miranda et al. presents data showing significant synergism between NEO and certain NSAIDs administered i.p. in the mouse. Their conclusions follow from isobolar analysis accompanied by statistical confidence limits that show significant differences between the additive (expected) and experimental potencies. This commentary discusses the features of the graphical method of analysis and points out other experimental designs and the methods used to analyse them

Pocket book of integrals and mathematical formulas

Preface to the Fifth EditionPreface to the Fourth EditionPreface to the Third EditionPreface to the Second EditionPreface to the First EditionAuthorGreek LettersElementary Algebra and GeometryFundamental Properties (Real Numbers)ExponentsFractional ExponentsIrrational ExponentsLogarithmsFactorialsBinomial TheoremFactors and ExpansionProgressionComplex NumbersPolar FormPermutationsCombinationsAlgebraic EquationsGeometryPythagorean TheoremDeterminants, Matrices, and Linear Systems of EquationsDeterminantsEvaluation by CofactorsProperties of DeterminantsMatricesOperationsPropertiesTransposeIdent

Quantitative Methods for Assessing Drug Synergism

Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug’s potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination