Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

The self-medication hypothesis of addictive disorders derives primarily from clinical observations of patients with substance use disorders. Individuals discover that the specific actions or effects of each class of drugs relieve or change a range of painful affect states. Self-medication factors occur in a context of self-regulation vulnerabilities--primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Persons with substance use disorders suffer in the extreme with their feelings, either being overwhelmed with painful affects or seeming not to feel their emotions at all. Substances of abuse help such individuals to relieve painful affects or to experience or control emotions when they are absent or confusing. Diagnostic studies provide evidence that variously supports and fails to support a self-medication hypothesis of addictive disorders. The cause-consequence controversy involving psychopathology and substance use/abuse is reviewed and critiqued. In contrast, clinical observations and empirical studies that focus on painful affects and subjective states of distress more consistently suggest that such states of suffering are important psychological determinants in using, becoming dependent upon, and relapsing to addictive substances. Subjective states of distress and suffering involved in motives to self-medicate with substances of abuse are considered with respect to nicotine dependence and to schizophrenia and posttraumatic stress disorder comorbid with a substance use disorder.

The Self-medication Hypothesis of Substance Use Disorders: A Reconsideration and Recent Applications

Background: A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. Methods: We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel 8300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were echeduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an ocluded infarct-related artery (defined by a Thrombolysus in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. Results: The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds ol the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. Conclusions: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.

Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

Use of Extended-Release Methylphenidate (Concerta) in Treatment of Cocaine Dependence in a Patient Presenting With Attention Deficit Hyperactivity Disorder

Ertapenem is a parenteral broad-spectrum carbapenem active against Gram-negative pathogens, which has been approved for treatment of different infectious situations in adults and children. Favourable pharmacokinetics and pharmacodynamics have been established in young adults. In the elderly, dosing regimen adaptations are not recommended. Nevertheless, pharmacokinetic studies in paediatrics have not been published yet. The aim of this study was to document whether age influenced ertapenem disposition by comparing its pharmacokinetics in three groups of rats. Rats were separated into three groups: very young rats 21-day-old, 10-week-old and 7-month-old rats. A population pharmacokinetic model was built and evaluated, using the NONMEM software. Pharmacokinetic parameters, interindividual variability and residual variability were estimated. The final model was evaluated by a bootstrap procedure and visual predictive check. The ertapenem concentration-time data were best described by a one-compartment model with zero-order input and first-order elimination. Effect of very young and old ages was estimated on central volume and clearance. Model evaluation indicated that the model was robust and parameter estimates were accurate. Central volume was found to be dependent on age and increase with age. Although the dosing regimen was weight adjusted, clearance was found to depend not only on age but also on weight. This study clearly documents changes in ertapenem pharmacokinetics according to group of age. These results suggest that paediatric dosing regimen cannot be directly extrapolated from a pharmacokinetic model in young adults unless it took into account age-induced modifications.

Population pharmacokinetics of ertapenem in juvenile and old rats.

Introduction: For many years, applications for baclofen have widened in the treatment of substance abuse disorder (SUD), mainly alcohol use disorder, with a growing rate of off-label prescriptions in Europe. Clinical effects seem to be both a decrease of craving and anxiety, leading to a decrease of drug or alcohol consumption. We described baclofen poisoning circumstances, therapeutic options and outcomes when used in substance use disorders.Areas covered: This review summarizes the toxicological considerations where baclofen was prescribed in humans for substance use or abuse disorder in randomized clinical trials, case series, case reports and observational studies between 1990 and 2020 according to the Preferred Reporting Items for Systemic reviews and Meta-Analysis.Expert opinion: The most frequent cause of severe intoxication is self-poisoning. A dose above 180 mg are expected to cause severe toxicity and death. The treatment is only symptomatic as no antidote is available. Off-label prescription remains unsafe because the optimal dose is not known and varies greatly between patients. As SUD are frequently associated with psychiatric disorders and such patients may have suicidal thoughts, the risk of self-poisoning is high. Potential co-ingestants should also be considered, especially CNS depressants, and they need to be closely monitored.

Toxicological considerations in the prescription of baclofen for the treatment of substance use disorders.

BACKGROUND Trihexyphenidyl (THP) is an anticholinergic drug misused to procure hallucination, sedation, and anxiolysis. The aim of this cohort was to show and describe, within a public health risk management policy, the risks of a long-standing but relatively unknown addiction: THP addiction. METHODS On Reunion island, a cohort with systematic data collection has been set up by addictologists working in the Centres for Addiction Prevention and Treatment, in the university hospital, and in general practices who have active lists of patients misusing THP. Data collection included socioeconomic data and clinical data concerning addiction. RESULTS This cohort included 69 patients during November 2016. The average age of the patients was 36 years; 97% were men; 93% had living accommodation but only 32 % were employed. In this cohort drug administration was exclusively oral. The most common reasons for use were anxiolytic (46%), stimulation (26%), and sedation (10%), the main effects described were dyskinesia and behavioral disorders. Over half (61%) of the patients reported a coaddiction, mainly to benzodiazepines, cannabis, tobacco, alcohol, and buprenorphine. CONCLUSIONS This cohort describing the clinical characteristics of 69 patients is the largest cohort studied for THP addiction. Patients from the Centres for Addiction Prevention and Treatment were the youngest and most recently addicted, whereas general practice patients had been addicted for longer and were more socially integrated. This clinical description of THP addiction therefore enables us to identify the patients who are the most at risk, to set up an adapted care protocol.

Misuse of Trihexyphenidyl (Artane) on Réunion Island.

The aim of this study was to document the influence of hyperthermia on the pharmacokinetics of ertapenem. Two groups of Wistar rats, normothermic (n = 6) and hyperthermic (n = 8), were injected a single intravenous bolus of ertapenem (15 mg/kg of body weight). Hyperthermia-induced animals were placed in a water-bath at 47 degrees C and control group animals were kept in a water-bath at 25 degrees C to obtain a stable mean core temperature of 39.8 and 36.9 degrees C respectively. Hyperthermia induced significant higher plasma concentrations and exposure, whereas total apparent clearance and volume of distribution were significantly decreased. If confirmed in humans, these results will be of interest to take into account such modifications in hyperthermic clinical situations.

Nicolas Simon

Papers

Use of Extended-Release Methylphenidate (Concerta) in Treatment of Cocaine Dependence in a Patient Presenting With Attention Deficit Hyperactivity Disorder

Population pharmacokinetics of ertapenem in juvenile and old rats.

Toxicological considerations in the prescription of baclofen for the treatment of substance use disorders.

Misuse of Trihexyphenidyl (Artane) on Réunion Island.

Effects of hyperthermia on pharmacokinetics of ertapenem in rats.