Dirk O. Stichtenoth

Myths and facts in the use of anti-inflammatory drugs

Background. Because of the prominence of pain-related conditions and the growing complexities of clinical management we aimed to explore and attempt to dispel the several myths that surround these serious therapeutic issues. Aims. We aimed to provide a careful analysis of the evidence and draw factually based guidance for physicians who manage the broad range of patients with pain. Methods. Current myths were identified based on the authors’ clinical, scientific, and academic experience. Each contributor addressed specific topics and made his own selection of primary references and systematic reviews by searching in MEDLINE, EMBASE, and CINAHL databases (1990–2008) as well as in the proceedings of the major digestive and rheumatology meetings. The writing and references provided by each contributor were collectively analyzed and discussed by all authors during several meetings until the final manuscript was prepared and approved. Results. Seven major ‘historical’ myths that may perpetuate habits and beliefs in clinical practice were identified. Each of them was thoroughly examined and dispelled, drawing conclusions that should help guide physicians to better manage patients with pain. Conclusions. Pain relief must be considered a human right, and patients with osteoarthritis pain should be treated appropriately with analgesic or/and anti-inflammatory drugs. The risk of gastrointestinal (GI) complications with traditional non-steroidal anti-inflammatory drugs (t-NSAIDs) is present from the first dose (with both short-term and long-term use), and strategies to prevent GI complications should be considered regardless of the duration of therapy. Compared with t-NSAIDs, coxib use is associated with a small but significant reduction of dyspepsia. While protecting the stomach, proton pump inhibitors do not prevent NSAID-induced intestinal damage. To this end, coxib therapy could be the preferred option, although further randomized studies are needed. A substantial number of patients who need NSAIDs are also taking low-dose aspirin for cardiovascular prophylaxis. From a GI perspective, the combination of aspirin plus a coxib provides a preferred option compared with aspirin plus a t-NSAID, for patients at high GI risk. As the incidence of renovascular adverse effects with t-NSAIDs and coxibs is similar, blood pressure should be monitored and managed appropriately in patients taking these drugs, although they should be avoided in those with severe congestive heart failure. Due to increased cardiovascular risk, which is dependent on the dose, duration of therapy, and base-line cardiovascular risk, both t-NSAIDs and coxibs should be used with caution in patients with underlying prothrombotic states and/or concomitant cardiovascular risk factors.

Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers

ObjectiveCarvedilol is a nonselective β- and α1-receptor antagonist with additional antioxidant properties in vitro. In this study, we assessed the antioxidative potential of carvedilol in cell culture and in antihypertensive doses in healthy men.MethodsIn vitro, human cultured endothelial cells were treated with native low-density lipoprotein (LDL), oxidized LDL or tumor necrosis factor (TNF)α in the absence and in the presence of carvedilol (40xa0µM); 8-iso-prostaglandin (PG)F2α, as parameter of oxidative stress, was determined in the supernatants. In a double-blind, randomized, cross-over study, 17 healthy men received 25xa0mg carvedilol b.i.d., 100xa0mg metoprolol b.i.d. or placebo for 6xa0days. After each treatment, systemic oxidative stress was assessed by measuring urinary excretion of 8-iso-PGF2α and 2,3-dinor-5,6-dihydro-8-iso-PGF2α, and the plasma concentration of 3-nitrotyrosine by means of gas chromatography-tandem mass spectrometry. In addition, thiobarbituric acid-reactive substances (TBARS) in plasma were assessed using spectrophotometry.ResultsNative LDL and oxidized LDL induced 8-iso-PGF2α production in endothelial cells. Carvedilol significantly reduced this effect (e.g., for oxidized LDL: 2.66±0.22xa0pg vs 1.46±0.14xa0pg 8-iso-PGF2α per µg protein, P<0.05). In healthy volunteers, carvedilol and metoprolol markedly decreased blood pressure and heart rate, but had no statistically significant effect on any indicator of oxidative stress measured. Remarkably, a trend toward reduction of urinary isoprostanes and 3-nitrotyrosine in plasma by both active treatments was observed, suggesting a non-specific antioxidative effect by β blockade.ConclusionsIn vitro, the antioxidative potential of carvedilol was confirmed. In healthy men, antihypertensive doses of carvedilol exert no specific inhibition of oxidative stress.

Neue nichtsteroidale Antirheumatika: Selektive Hemmstoffe der induzierbaren Cyclooxygenase

UNLABELLEDnMODE OF ACTION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: Non-steroidal anti-inflammatory drugs (NSAID) exert their major therapeutic and adverse effects by inhibition of prostanoid synthesis. Also the interactions with antihypertensive drugs and lithium are caused by this mechanism of action. Cyclooxygenation is a key enzymatic step in the synthesis of prostanoids. 1990 2 isoforms of the enzyme cyclooxygenase have been identified: Prostanoids synthesized by the constitutive cyclooxygenase (COX-1) are involved in physiological homeostasis. In contrast, the inducible cyclooxygenase (COX-2) produces large amounts of prostanoids, mainly contributing to the pathophysiological process of inflammation. COX-2 SELECTIVE NSAID: The discovery of the cyclooxgenase-isoenzymes ushered in a new generation of NSAID: A drug with selectivity for COX-2 would inhibit proinflammatory prostanoid synthesis while sparing physiologic prostanoid synthesis. Thus, a selective COX-2 inhibitor should be anti-inflammatory with less or no gastrointestinal or other NSAID-typical adverse effects. The experiences with currently used NSAID, which show an increasing incidence of side effects as COX-1 inhibition increases, and studies with the COX-2 selective NSAID salsalate and meloxicam, which have less adverse effects than nonselective COX inhibitors in equivalent antiphlogistic dosage, prove the concept of selective COX-2 inhibition to avoid the NSAID typical side effects. Newly developed drugs with a very high selectivity for COX-2 are now tested in clinical trials.nnnCONCLUSIONnSo far the results suggest, that selective and highly selective COX-2 inhibitors have significantly fewer gastrointestinal and renal adverse effects and do not inhibit platelet aggregation.Zusammenfassung□ Wirkungsweise der nichtsteroidalen AntirheumatikaNichtsteroidale Antirheumatika (NSAR) üben ihre antiinflammatorischen, analgetischen und antipyretischen Wirkungen durch Hemmung der Prostanoidsynthese aus. Die typischen Nebenwirkungen der NSAR und deren Interaktionen mit Antihypertonika und Lithium sind ebenfalls durch diesen Wirkmechanismus bedingt. Erst 1990 wurde nachgewiesen, daß die physiologische Prostanoidsynthese durch eine konstitutive Cyclooxygenase (COX-1) katalysiert wird, während für die proinflammatorische Prostanoidsynthese ein anderes Isoenzym, die induzierbare Cyclooxygenase (COX-2), verantwortlich ist.□ COX-2-selektive NSARMit dieser Entdeckung entstand eine neue Strategie zur Vermeidung der NSAR-typischen Nebenwirkungen: Ein NSAR sollte möglichst selektiv die COX-2-vermittelte proinflammatorische Prostanoidsynthese hemmen, die COX-1-abhängige physiologische Prostanoidsynthese aber unbeeinflußt lassen. Bei erhaltener therapeutischer Wirksamkeit würde somit keine der typischen NSAR-Nebenwirkungen auftreten. Die Erfahrungen mit den herkömmlichen NSAR, welche um so ausgeprägtere Nebenwirkungen besitzen, je mehr sie die COX-1 hemmen, und Studien mit den COX-2-selektiven NSAR Disalicylsäure und Meloxicam, welche bei guter Wirksamkeit seltener zu gastrointestinalen und renalen Nebenwirkungen führen, belegen die Erfolgsaussichten dieser Strategie. Substanzen mit sehr hoher Selektivität für die COX-2 werden zur Zeit klinisch getestet.□ SchlußfolgerungDie bislang vorliegenden Ergebnisse unterstützen die Annahme, daß sich mit den selektiven und hochselektiven COX-2-Hemmstoffen die NSAR-typischen unerwünschten Wirkungen erheblich reduzieren lassen.Abstract□ Mode of Action of Non-Steroidal Anti-Inflammatory DrugsNon-steroidal antiinflammatory drugs (NSAID) exert their major therapeutic and adverse effects by inhibition of prostanoid synthesis. Also the interactions with antihypertensive drugs and lithium are caused by this mechanism of action. Cyclooxygenation is a key enzymatic step in the synthesis of prostanoids. 1990 2 isoforms of the enzyme cyclooxygenase have been identified: Prostanoids synthesized by the constitutive cyclooxygenase (COX-1) are involved in physiological homeostasis. In contrast, the inducible cyclooxygenase (COX-2) produces large amounts of prostanoids, mainly contributing to the pathophysiological process of inflammation.□ COX-2 Selective NSAIDThe discovery of the cyclooxgenase-isoenzymes ushered in a new generation of NSAID: A drug with selectivity for COX-2 would inhibit proinflammatory prostanoid synthesis while sparing physiologic prostanoid synthesis. Thus, a selective COX-2 inhibitor should be anti-inflammatory with less or no gastrointestinal or other NSAID-typical adverse effects. The experiences with currently used NSAID, which show an increasing incidence of side effects as COX-1 inhibition increases, and studies with the COX-2 selective NSAID salsalate and meloxicam, which have less adverse effects than nonselective COX inhibitors in equivalent antiphlogistic dosage, prove the concept of selective COX-2 inhibition to avoid the NSAID typical side effects. Newly developed drugs with a very high selectivity for COX-2 are now tested in clinical trials.□ ConclusionSo far the results suggest, that selective and highly selective COX-2 inhibitors have significantly fewer gastrointestinal and renal adverse effects and do not inhibit platelet aggregation.

Unique pentafluorobenzylation and collision-induced dissociation for specific and accurate GC–MS/MS quantification of the catecholamine metabolite 3,4-dihydroxyphenylglycol (DHPG) in human urine ☆

In the human body, the catecholamine norepinephrine is mainly metabolized to 3,4-dihydroxyphenylglycol (DHPG) which therefore serves as an important biomarker for norepinephrines metabolism. Most data on DHPG concentrations in human plasma and urine has been generated by using HPLC-ECD or GC-MS technologies. Here, we describe a stable-isotope dilution GC-MS/MS method for the quantitative determination of DHPG in human urine using trideutero-DHPG (d(3)-DHPG) as internal standard and a two-step derivatization process with pentafluorobenzyl bromide (PFB-Br) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Two pentafluorobenzyl (PFB) trimethylsilyl (TMS) derivatives were obtained and identified, i.e., two isomeric DHPG-PFB-(TMS)(3) derivatives and the later eluting DHPG-tetrafluorobenzyl-(TMS)(2) derivative, i.e., DHPG-TFB-(TMS)(2). To our knowledge the DHPG-TFB-(TMS)(2) derivative and the underlying reaction have not been reported previously. In this reaction both vicinal aromatic hydroxyl groups of DHPG react with PFB-Br to form a heterocyclic seven-membered [1,4]dioxepin compound. The DHPG-TFB-(TMS)(2) derivative was used for quantitative GC-MS/MS analysis in the electron-capturing negative-ion chemical ionization mode by selected-reaction monitoring of m/z 351 from m/z 401 for DHPG and of m/z 352 from m/z 404 for d(3)-DHPG. Validation experiments on human urine samples spiked with DHPG in a narrow (0-33 nM) and a wide range (0-901 nM) revealed high recovery (86-104%) and low imprecision (RSD; 0.01-2.8%). LOD and relative LLOQ (rLLOQ) values of the method for DHPG were determined to be 76 amol and 9.4%, respectively. In urine of 28 patients suffering from chronic inflammatory rheumatic diseases, DHPG was measured at a mean concentration of 238 nM (38.3 μg/g creatinine). The DHPG concentration in the respective control group of 40 healthy subjects was measured to be 328 nM (39.2 μg/g creatinine). Given the unique derivatization reaction and collision-induced dissociation, and the straightforwardness the present method is highly specific, accurate, precise, and should be useful in clinical settings.

Blood donors on medication. Are deferral periods necessary

Abstract. Objectives: Drugs and their metabolites in transfused blood components may cause effects in the recipient. If the treated disorder is not to be regarded as an exclusion criterion from blood donation, donors on medication should be deferred for a period consistent with the drugs pharmacokinetics. General principles and methods: Peak plasma drug concentrations of 3% or less of the therapeutic concentration were regarded to be safe for the recipient of a blood product. For teratogenic drugs a much lower safety level of less than 0.000001% has been proposed. For the calculation of deferral periods, both the type of blood component to be prepared and the drugs pharmacokinetics for a given formulation were considered. Suggested waiting periods: For drugs with known teratogenic risks, we suggest a deferral period of 28 plasma-elimination half-lives. For non-teratogenic drugs, a simple, conservative approach could be based on waiting for five plasma-elimination half-lives, thus reaching the required 3% safety level already in any donor. If, however, the type of blood component to be prepared is also considered, a more differentiated approach appears to be appropriate: for blood components containing 50xa0ml or less plasma from a single donor, donor medication may be disregarded because of the high dilution in the recipients plasma volume, whereas for blood components with higher plasma contents (250xa0ml on average) from a single donor on medication the 3% safety level will be achieved by observing the deferral period of five plasma-elimination half-lives mentioned. A guideline for 191 drugs and drug classes has been elaborated accordingly.

Blood Donors on Medication – an Approach to Minimize Drug Burden for Recipients of Blood Products and to Limit Deferral of Donors

Background: Blood products derived from donors on medication can contain drugs which might pose a risk for the recipients or influence the quality of the product itself. Material and Methods: To judge the eligibility of blood donors on medication, 4 drug classes have been formed with respect to their pharmacological properties, and blood products have been divided in accordance with their single-donor plasma contents. Results: For drugs with dose-dependent pharmacodynamics, no deferral periods are necessary for donation of blood products containing less than 50 ml single-donor plasma for application to adults. Waiting periods of tmax + 5 t1/2 were calculated for the other blood products. Teratogenic drugs do not require special considerations (exception: retinoids, thalidomide and lenalidomide, dutasteride or finasteride with waiting periods for all blood products). A deferral period of tmax + 24 t1/2 is proposed for every blood product from blood donors on genotoxic drugs. Drugs without systemic effects can be neglected. Irreversible inhibitors of platelet function cause a 10-day waiting period if production of platelet concentrates is intended. Conclusion: Donors on medication are allowed to donate blood for blood products containing less than 50 ml plasma of a single donor, like red blood cell concentrates, for the use in adults without deferral periods, except those taking retinoids, thalidomide, lenalidomide, dutasteride, finasteride, or genotoxic drugs.

Knowledge on drug dosages of ward physicians

Abstract.Objective: Dosing errors are a common source for preventable adverse drug events. This study evaluated the knowledge of German hospital physicians with respect to the daily dosage of frequently used drugs. Methods: A questionnaire survey was carried out among 168 ward physicians from three university and four municipal hospital departments of internal medicine asking for the daily dosage of 17 frequently used drugs. Results: One hundred twenty-seven of 168 physicians returned a completed questionnaire, a response rate of 75.6%. Only 50% of the dose estimates were within the therapeutic range. Even in cases of frequent prescription 7% of the stated doses were overdosed and 15% were underdosed. Conclusions: The results of this survey suggest that adverse drug events and the lack of therapeutic effect due to dosing errors could be prevented by an improved knowledge of daily dosages.

Soll ich die Dosis reduzieren

Frage von Dr. med. M. K., Internistin: Wegen eines bislang therapieresistenten Granuloma anulare disseminatum erhielt eine Patientin bei geringem Glukose-6-Phosphat-Dehydrogenase-Mangel eine vom Dermatologen rezeptierte Dapsonbehandlung, bei einem Körpergewicht von 56 kg Dapson fatol 100 mg/d. Schon nach drei Tagen trat eine zyanotische Verfärbung der Lippen ein, nach zwölf Tagen fiel der Hb um 2,5 g/dl auf 12 g/dl ab, mit zunehmender Belastungsdyspnoe. MethHb wurde nach sechs Tagen mit 1% sicher falsch zu niedrig bestimmt bei zuletzt deutlicher Lippenzyanose. Die Therapie wurde vom fachspeptome einer Methämoglobinämie ohne o. g. Zeichen einer Überempfindlichkeitsreaktion vor. Zudem ist ein Glukose-6-Phosphat-Dehydrogenase-Mangel bei Ihrer Patientin bekannt. Bei Patienten mit Glukose-6-Phosphat-Dehydrogenase-Mangel ist das Risiko dosisabhängiger unerwünschter Nebenwirkungen, insbesondere einer Methämoglobinämie, deutlich erhöht. Bei solchen Patienten bedarf die Anwendung von Dapson einer besonders strengen Nutzen-Risiko-Abwägung und – bei Entscheidung zur Therapie – einer Dosisreduktion auf die Hälfte der normalen Dosis von täglich 50 bis 100 mg Dapson. Das von Ihnen geplante Vorgehen (einschleichend 25 mg Dapson/d, dann 2 x 25 mg/d unter engmaschiger Kontrolle von Hb und MethHb) entspricht somit der Dosisempfehlung zur Dapsontherapie bei Patienten mit Glukose-6Phosphat-Dehydrogenase-Mangel.

Effects on the kidney: role of COX-2 inhibitors

Renal side-effects of non-steroidal anti-inflammatory drugs (NSAIDs) range from mild to life threatening and a life-long necessity for dialysis. They can be divided into three categories [1–3]: (1) Renal side-effects of NSAIDs due to inhibition of prostanoid synthesis. Most of the unwanted renal effects of NSAIDs are related to this mechanism, including reduction in renal blood flow and glomerular filtration rate, sodium and water retention, and hyperkalemia. (2) Analgesic nephropathy. Habitual use of NSAIDs and non-NSAID analgesics can cause analgesic nephropathy with the characteristic papillary necrosis. Most likely chronic hypoperfusion of the renal medulla caused by NSAIDs leads to ischaemic damage [1]. For the non-NSAID analgesics the mechanism of damage is unknown [4]. (3) Acute interstitial nephritis, which is a cell-mediated immune response to NSAIDs and many other drugs [3].

Book Review · Buchbesprechung

‘Dirty Medicine. The Handbook’, the latest book from the British investigative writer Martin J. Walker, does a good job of summing itself up in its long subtitle: ‘Dirty Medicine. The Handbook. Of Doctors, Epidemiologists, Researchers, Advisers, Insurance Scammers, Quackbusters, Bad Journalists, Corporate Scientists, Industry Shills, and Other Agents Who Do Now, or Have in The Past Worked For, Sided With, Supported or Simply Been a Part of Corporate Interests, Manufacturing, Pushing, or Promoting, Products or Ideologies Antagonistic to The Private and Public Health of Workers, Consumers, Citizens, Patients, Alternative Practitioners and Science in The Public Interest; Who They Are, How to Recognise Them and Their Organisations, and What to Do About Them.’ The handbook, an extension and reworking of his previous book ‘Dirty Medicine. Science, Big Business and the Assault on Natural Health Care’, provides a who’s who of individuals, groups and websites with a history of attacking complementary and alternative medicine (CAM), particularly in Britain. Starting with an overview, he links the rise of the ‘health fraud’ movement, ‘quackbusters’ and ‘skeptics’ with the rise of corporate science, noting that science is no longer the domain only of scientists, but of public relation companies who provide ‘trained mercenaries to fight the sciences battles’. Continuing with the language of war, he describes the battle tactics of the pharmaceutical industry as akin to those initiated and perfected by the tobacco and asbestos industries. Writing of an organised plan against natural medicine, he states that, as there is no major profit in natural medicine, it has to be ‘controlled and destabilised’ to protect pharmaceutical profits, which increased when medical science became more focused on problems to be fixed rather than the patient as a person. In alphabetical order he gives background information ranging from a line to a page on what he calls ‘health corporatists’: individuals, organisations, ad hoc groups and websites. Pharmaceutical company, personal, and committee links, and their history in relation to attacks against individuals or groups involved in CAM, are outlined. Following these chapters he provides a counterbalance: the antidote groups and individuals historically and currently battling for freedom of treatment and exposing the tactics behind CAM censorship. Some have had their careers damaged or destroyed in the process. In the closing chapter, entitled ‘Organising and Fighting Back’ he pulls no punches in relation to how serious he considers the war against CAM, warning against underestimating the dangers and the lengths to which pharmaceutical companies are willing to go to protect their profits, stating ‘we can define our enemy very simply as those who consistently use lies and manipulation to put profits before people and corporations before communities’. I suspect there are those who will consider much of Walker’s writing as the ravings of a conspiracy theorist who sees apparent links everywhere and who demonises the pharmaceutical industry. In the current climate, however, his work is not so easy to dismiss. Welcoming genuine and honest scientific debate within the scientific community, his major objections are to the often undisclosed conflicts of interest which exist in the media, industry, academia and government, and the way in which the damage caused by allopathic medicine is swept under the carpet. A recent example of this was the failure of BMJ editor Fiona Godlee to disclose the journal’s financial relationship with Merck and GlaxoSmithKline (both measles, mumps and rubella (MMR) vaccine manufacturers) in relation to her editorial and commissioning of 3 articles by a journalist about the Andrew Wakefield case. Wakefield, an English research doctor, lost his licence to practice following a suggestion (in a co-authored paper) that further investigations were needed to see if there was a link between the MMR vaccine and gastrointestinal disease/developmental regression [1]. In her response to criticism, Godlee stated ‘We didn’t declare these competing interests because it didn’t occur to us to do so’ [2]. Her subsequent declaration of advertising and sponsorship income from Merck and GlaxoSmithKline still failed to disclose the partnership agreement between the BMJ and Merck providing online education. While it is within the realms of possibility that the failure of the BMJ to disclose their links to companies that benefitted from Wakefield being considered guilty was an innocent (albeit sloppy) mistake by a journal editor, it is this lack of transparency that, unfortunately, creates a need for research such as that found in the handbook. Anyone who has been confused by the constant rejection of a good research paper, who has been refused the opportunity to rebut criticism in the letters page, or whose comments in a public forum were deleted might better understand the reasons by following the money or political links, some of which are outlined there. Although every link to pharmaceutical companies cannot be automatically considered manipulative and some critics of CAM are driven by an