The pharmacology of thebaine in the chronic spinal dog

The effects of thebaine were studied in nondependent and morphine-dependent chronic spinal dogs as well as in chronic spinal dogs receiving thebaine chronically. Thebaine did not produce any morphine-like effects in nondependent dogs nor did it precipitate an abstinence syndrome in morphine-dependent dogs. Large doses of naltrexone precipitated a mild abstinence syndrome in dogs receiving thebaine chronically; however, no withdrawal abstinence syndrome was observed after abrupt withdrawal. Thebaine is not a morphine-like drug, nor does it produce appreciable physical dependence in the dog.     

Gastrointestinal-tract models and techniques for use in safety pharmacology

Introduction: The human ether-a-go-go-related gene (hERG) encodes a potassium channel responsible for the cardiac delayed rectifier current (I_Kr) involved in ventricular repolarization. Drugs that block hERG have been associated with QT interval prolongation and serious, sometimes fatal, cardiac arrhythmias (including torsade de pointes). While displacement of [³H]dofetilide, a potent methanesulfonanilide hERG blocker, from cells heterologously expressing hERG has been suggested as a screening assay, questions have been raised about its predictive value.Methods: To validate the utility of this assay as a screening tool, we performed a series of saturation and competition binding studies using [³H]dofetilide as ligand and either intact cells or membrane preparations from HEK 293 cells stably transfected with hERG K⁺ channels. The object of these experiments was to (1) compare binding K_i values for 22 hERG blockers using intact cells or membrane homogenates to determine whether maintaining cell integrity enhanced assay reliability; (2) evaluate the ability of different K⁺ concentrations (2, 5, 10, 20, and 60 mM) to modulate hERG binding; and (3) to establish the predictive value of the assay by comparing K_i values from binding studies at 5 and 60 mM [K⁺]_o to functional IC₅₀ values for hERG current block using 56 structurally diverse drugs.Results: We found (a) comparable K_i values in the intact cell and isolated membrane binding assays, although there were some differences in rank order; (b) increasing [K⁺]_o lowered the K_d and increased the B_max for [³H]dofetilide, particularly in the membrane assay; and (c) good correlation between binding K_i values and functional IC₅₀ values for hERG current block.Discussion: In conclusion, increasing K⁺ concentrations results in an increase in both [³H]dofetilide affinity for hERG and available binding sites, particularly when using membrane homogenates. There are no meaningful differences between K_i values when comparing intact cell versus membrane assay, neither are there meaningful trends with increasing [K⁺]_o within assays. There is good correlation between binding K_i values and functional (whole-cell patch clamp) IC₅₀ values at both 5 and 60 mM K⁺ concentrations (R² values of .824 and .863, respectively). The simplicity, predictability, and adaptability to high-throughput platforms make the [³H]dofetilide membrane binding assay a useful tool for screening and ranking compounds for their potential to block the hERG K⁺ channel.     

The use of safety factors for controlling risk

Safety factors often are applied to animal bioassay data on toxic effects to establish dosage levels for which it is hoped there will be negligible deleterious effects on human health. A relationship between safety factors and disease risk is shown, making it possible to determine the size of the safety factor needed in order to maintain low levels of disease risk within animal populations. Also, it is demonstrated that "safe" doses obtained from the application of safety factors to the largest no-observable-effect level are similar to "safe" doses obtained by linear extrapolation.     

Morinda citrifolia (Noni) fruit--phytochemistry, pharmacology, safety

Products derived from Noni fruit (Morinda citrifolia) have been commercialised in the USA since the 1990s and are increasingly distributed all over the world. A large number of beneficial effects have been claimed for Noni. Fruit juice of Noni has been approved as a Novel Food by the European Commission in 2003. This article reviews current knowledge on the phytochemistry, pharmacology, safety aspects of Noni fruit and Noni-derived products, and health-related claims and benefits. The knowledge on the chemical composition of Noni fruit has considerably increased over recent years. A number of in vitro and, to a certain extent, in vivo studies demonstrate a range of potentially beneficial effects. However, clinical data are essentially lacking. To what extent the findings from experimental pharmacological studies are of potential clinical relevance is not clear at present. Based on a toxicological assessment, Noni juice was considered as safe. Due to recent reports of cases of hepatotoxicity, the safety issue has been re-examined in Europe. While the European Food Safety Authority sees no link between adverse effects on liver and consumption of Noni juice, a continuing monitoring of the situation is desirable and some vigilance advised.     

Strategies to evaluate the safety of bioengineered foods

A number of genetically modified (GM) crops bioengineered to express agronomic traits including herbicide resistance and insect tolerance have been commercialized. Safety studies conducted for the whole grains and food and feed fractions obtained from GM crops (i.e., bioengineered foods) bear similarities to and distinctive differences from those applied to substances intentionally added to foods (e.g., food ingredients). Similarities are apparent in common animal models, route of exposure, duration, and response variables typically assessed in toxicology studies. However, because of differences in the nutritional and physical properties of food ingredients and bioengineered foods and in the fundamental goals of the overall safety assessment strategies for these different classes of substances, there are recognizable differences in the individual components of the safety assessment process. The fundamental strategic difference is that the process for food ingredients is structured toward quantitative risk assessment whereas that for bioengineered foods is structured for the purpose of qualitative risk assessment. The strategy for safety assessment of bioengineered foods focuses on evaluating the safety of the transgenic proteins used to impart the desired trait or traits and to demonstrate compositional similarity between the grains of GM and non-GM comparator crops using analytical chemistry and, in some cases, feeding studies. Despite these differences, the similarities in the design of safety studies conducted with bioengineered foods should be recognized by toxicologists. The current paper reviews the basic principles of safety assessment for bioengineered foods and compares them with the testing strategies applied to typical food ingredients. From this comparison it can be seen that the strategies used to assess the safety of bioengineered foods are at least as robust as that used to assess the safety of typical food ingredients.     

P01 Methods to evaluate the quality of written pharmacology assessments

Internationally there are increased challenges for accountability and quality assurance in the teaching and assessment of pharmacology. Validity, reliability, difficulty, depth of knowledge and degree of discrimination are important criteria for the measurement of the quality of pharmacology assessments. The objective of this presentation is to discuss quantitative methods used to evaluate these quality criteria in written assessments. These methods have been used in the integrated, modular and Problem-based Learning （PBL） BPharm programme of the University of Limpopo （Medunsa Campus） and Tshwane University of Technology, in which pharmacology plays a crucial role.     

The use of sputum cell counts to evaluate asthma medications

Total and differential cell counts from hypertonic-induced, dithiothreitol-dispersed sputum provide reproducible measurements of airway inflammatory cell counts, which are responsive to treatment with anti-inflammatory drugs. They have helped to understand the kinetics of inflammatory cell changes in asthma after the reduction of corticosteroids and the subsequent re-introduction of treatment. They have identified that the presence of sputum eosinophilia in asthma, chronic cough and chronic airflow limitation is a predictor of steroid-responsiveness and of lack of 'asthma control'. They can be used to study the dose-response effect of inhaled corticosteroids and may be useful to establish the relative potency of different corticosteroid formulations and delivery devices. Sputum cell counts are also useful to study the potential anti-inflammatory effects of drugs like theophylline, long-acting beta-adrenoceptor agonists, leukotriene antagonists and newer drugs in development. They may be helpful to select add-on therapy to corticosteroids in 'difficult-to-control' asthma.     

Update of general pharmacology/safety pharmacology studies in Japan

The General Pharmacology Working Group of the Japanese Pharmaceutical Manufacturers Association review the current status of safety pharmacology list procedures. © 1996 Wiley-Liss, Inc.     

Diuretics. Clinical pharmacology and therapeutic use (Part I)

25 years have elapsed since the introduction of the first effective oral diuretic, chlorothiazide. Diuretics are now amongst the most widely prescribed drugs in clinical practice worldwide. Availability of these drugs has not only brought therapeutic benefit to countless numbers of patients but it has at the same time provided valuable research tools with which to investigate the functional behaviour of the kidney and other electrolyte-transporting tissues. Despite many remaining gaps in our knowledge of the biochemical processes involved in diuretic drug action, available compounds can be divided into 5 groups on the basis of their preferential effects on different segments of the nephron involved in tubular reabsorption of sodium chloride and water. Firstly, there is heterogeneous group of chemicals that share the common property of powerful, short-lived diuretic effects that are complete within 4 to 6 hours. These agents act on the thick ascending limb of Henle's loop and are known as 'high ceiling' or 'loop' diuretics. The second group are the benzothiadiazines and their many related heterocyclic variants, all of which localise their effects to the early portion of the distal tubule. The third group comprises the potassium-sparing diuretics which act exclusively on the Na+-K+/H+ exchange mechanisms in the late distal tubule and cortical collecting duct. The action of drugs in groups 2 and 3 is prolonged to between 12 and 24 hours. The fourth group consists of diuretics that are chemically related to ethacrynic acid but have the unusual property of combining within the same molecule the property of saluresis and uricosuria. These compounds have actions, to different individual extents, in the proximal tubule, thick ascending limb, and early distal tubule and are known as 'polyvalent' diuretics. Finally, there is a mixed group of weak or adjunctive diuretics which includes the vasodilator xanthines such as aminophylline, and the osmotically active compounds such as mannitol. Available evidence on the molecular mechanisms of action of diuretics in each group is reviewed. The haemodynamic, humoral and physical factors involved in control of electrolyte and fluid handling by the kidney in normal conditions and pathological states are discussed in relation to rational choices of different diuretics in the treatment of various oedematous and non-oedematous conditions.     

小儿用复方磺胺甲(口恶)唑片的体内质量评价

目的:通过生物利用度等药动学参数的研究来评价小儿用复方磺胺甲恶唑片的质量.方法:用尿药法测定两个批号小儿用复方磺胺甲恶唑片药动学参数.结果:小儿用复方磺(口恶)唑片制剂工艺稳定,用法合理、口服生物利用度高.     

Diuretics. Clinical pharmacology and therapeutic use (Part II)

25 years have elapsed since the introduction of the first effective oral diuretic, chlorothiazide. Diuretics are now amongst the most widely prescribed drugs in clinical practice worldwide. Availability of these drugs has not only brought therapeutic benefit to countless numbers of patients but it has at the same time provided valuable research tools with which to investigate the functional behaviour of the kidney and other electrolyte-transporting tissues. Despite many remaining gaps in our knowledge of the biochemical processes involved in diuretic drug action, available compounds can be divided into 5 groups on the basis of their preferential effects on different segments of the nephron involved in tubular reabsorption of sodium chloride and water. Firstly, there is a heterogeneous group of chemicals that share the common property of powerful, short-lived diuretic effects that are complete within 4 to 6 hours. These agents act on the thick ascending limb of Henle's loop and are known as 'high ceiling' or 'loop' diuretics. The second group are the benzothiadiazines and their many related heterocyclic variants, all of which localise their effects to the early portion of the distal tubule. The third group comprises the potassium-sparing diuretics which act exclusively on the Na+-K+/H+ exchange mechanisms in the late distal tubule and cortical collecting duct. The action of drugs in groups 2 and 3 is prolonged to between 12 and 24 hours. The fourth group consists of diuretics that are chemically related to ethacrynic acid but have the unusual property of combining within the same molecule the property of saluresis and uricosuria. These compounds have actions, to different individual extents, in the proximal tubule, thick ascending limb, and early distal tubule and are known as 'polyvalent' diuretics. Finally, there is a mixed group of weak or adjunctive diuretics which includes the vasodilator xanthines such as aminophylline, and the osmotically active compounds such as mannitol. The metabolic consequences of continued diuretic usage are considered along with non-metabolic sequelae such as ototoxicity or interactions with other concurrent treatments. The relationships between the clinical benefits conferred and the potential harms generated by long term diuretic therapy are also discussed.     

The pharmacology and safety of paliperidone extended-release in the treatment of schizophrenia

Paliperidone extended-release (ER) is a newly commercialised antipsychotic formulated using the principal active metabolite of risperidone, 9-hydroxyrisperidone. It has been developed as an osmotic controlled-release oral delivery system that minimizes peak-trough fluctuations in plasma concentrations, allowing once-daily administration and theoretically leading to a decreased incidence of adverse effects. Available data from preregistration, multicenter, short-term, double-blind, placebo-controlled studies indicate that paliperidone ER, at dosages of 3 – 15 mg/day, is relatively safe and well tolerated in adult patients with schizophrenia. As with risperidone, paliperidone may cause extrapyramidal symptoms and hyperprolactinemia in a dose-dependent manner. Preliminary long-term studies (up to 52 weeks) appear to confirm the findings from short-term trials indicating a low liability for paliperidone ER to cause metabolic effects (i.e., weight gain, hyperglycaemia and lipid dysregulation). Safety data from elderly patients appear to be promising. Due to negligible hepatic biotransformation, paliperidone ER is unlikely to be involved in clinically significant metabolic drug–drug interactions.     

The pharmacology and safety of paliperidone extended-release in the treatment of schizophrenia

Paliperidone extended-release (ER) is a newly commercialised antipsychotic formulated using the principal active metabolite of risperidone, 9-hydroxyrisperidone. It has been developed as an osmotic controlled-release oral delivery system that minimizes peak-trough fluctuations in plasma concentrations, allowing once-daily administration and theoretically leading to a decreased incidence of adverse effects. Available data from preregistration, multicenter, short-term, double-blind, placebo-controlled studies indicate that paliperidone ER, at dosages of 3-15 mg/day, is relatively safe and well tolerated in adult patients with schizophrenia. As with risperidone, paliperidone may cause extrapyramidal symptoms and hyperprolactinemia in a dose-dependent manner. Preliminary long-term studies (up to 52 weeks) appear to confirm the findings from short-term trials indicating a low liability for paliperidone ER to cause metabolic effects (i.e., weight gain, hyperglycaemia and lipid dysregulation). Safety data from elderly patients appear to be promising. Due to negligible hepatic biotransformation, paliperidone ER is unlikely to be involved in clinically significant metabolic drug-drug interactions.     

A framework to assess the translation of safety pharmacology data to humans

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.