Colchicine, terug van nooit weggeweest

Colchicine: ancient and brand new Colchicine is an alkaloid initially extracted from an autumn crocus. Its use dates back to the 6th century BC, with the first indication being gout. In the last 50 years, further insights into its mechanism of action emerged along with an expansion of the number of indications. Colchicine inhibits the chemotaxis of leukocytes. Recently, it was discovered that in addition to its action on the microtubules, there is also an effect on the NLRP3 inflammasome. Colchicine has a narrow therapeutic index and caution is advised in patients with renal and hepatic failure. It’s a CYP3A4 and P-gp substrate. Therefore, concomitant use with CYP3A4 and P-gp inhibitors is contraindicated given the greatly increased risk of toxicity. Its most frequent side effect is diarrhea and severe intoxications can be lethal. The main rheumatologic indications are the treatment of gout in the acute phase, attack prevention and amyloidosis in familial Mediterranean fever, and ulcerations in Behçet’s disease. The cardiovascular use of colchicine in acute and relapsing/chronic pericarditis has been well established. Recent studies also show a beneficial effect in case of acute and chronic coronary artery disease. Additional studies for the implementation of colchicine for these indications are ongoing.

A brief overview of acute poisoning in sheep

Acute poisoning in sheep can occur following ingestion of toxic plants, including plants that they may eat normally such as ivy (Hedera spp.) and plants they avoid unless other forage is unavailable. Poisoning with plants containing grayanotoxins (Pieris and Rhododendron spp.) is very common in sheep, particularly when the weather is poor and they are hungry. Oak (Quercus spp.) poisoning is also relatively common in sheep, particular in years with a heavy acorn crop. Numerous plants contain cardiac glycosides and are a potential risk to sheep. Sudden death is frequently the first signs of plant toxicosis in livestock. Bites from adders (Vipera berus berus) may also occur in sheep but are likely to be underreported as the actual biting event is not witnessed. Envenomation may result in swelling and haematological, renal, hepatic and cardiac effects. Overdosage of drugs with a narrow therapeutic index may also be a risk. One such example is closantel which can result in blindness. Management of acute poisoning in sheep is supportive including removal from exposure, and providing analgesia, rehydration and potentially a rumenotomy for plant exposure in valuable animals.

Estimated Manipulation of Tablets and Capsules to Meet Dose Requirements for Chinese Children: A Cross-Sectional Study

Objectives: To estimate the frequency of manipulations of all tablets and capsules prescribed for children in a teaching and tertiary children's hospital in China over the course of 1 month. Moreover, hypothetical reduction of manipulation according to the availability of low-strength tablets/capsules licensed by the Chinese National Medical Products Administration (CNMPA) was evaluated.Methods: Information on all tablets and capsules prescribed in the hospital from March 17 to April 16, 2019 was collected. It was assumed that tablets or capsules were manipulated if the prescribed dose would have required only a proportion of the intact dose form. Manipulation typically includes splitting or crushing tablets, opening capsules and dispersing in water, or combinations of these method. Moreover, we defined an “avoidable manipulation,” when the dose could be rounded and/or when alternative products with a reduced strength or in liquid formulation were available in the hospital, and a “inappropriate manipulation,” which involved manipulated medications with a direct contraindication for any manipulation, such as those with a narrow therapeutic index or hazardous ingredients, or modified release dosage-forms. The frequencies of total, avoidable, and inappropriate manipulation were estimated, along with the hypothetical reduction of manipulation according to the availability of CNMPA-approved drug doses.Results: A total of 17,123 prescriptions for 142 medications were identified to have required a manipulation among 78,366 prescriptions administered during the study period, with 43 different proportions of subdivisions, ranging from a 19/20 to 1/180 product strength reduction. Half, quarter, and trisection were the most common subdivisions administered. Overall, 19% of the manipulated prescriptions were determined to be avoidable, and 19% of the manipulations involved medications with a clear recommendation to not manipulate. In addition, 21% of the manipulated prescriptions could have been potentially avoided if all of the approved preparations with the lowest strength would have been available at the hospital. Any manipulations undertaken were carried out by pharmacists and family care givers.Conclusions: More than 20% of tablets and capsules prescriptions need manipulated, included a high incidence of avoidable and inappropriate manipulation.

Bidirectional Influences of Cranberry on the Pharmacokinetics and Pharmacodynamics of Warfarin with Mechanism Elucidation

Cranberry is a dietary supplement popularly used for the prophylaxis of urinary tract infection. Interestingly, cranberry–warfarin interactions in clinical reports have shown bidirectional outcomes. (±) Warfarin, a widely prescribed anticoagulant, but with a narrow therapeutic index, contains equal amounts of S- and R-warfarin, of which S-warfarin is more active. The aim of this study was to investigate the effects of different ingestion times of cranberry on the pharmacokinetics and pharmacodynamics of warfarin. Rats were orally administered (±) warfarin (0.2 mg/kg) with and without cranberry (5.0 g/kg) at 0.5 h prior to the warfarin, and at 10 h after the warfarin. The plasma concentrations of S- and R-warfarin were determined by LC/MS. The results indicate that cranberry ingested at 0.5 h before (±) warfarin significantly decreased the systemic exposures of S-warfarin and R-warfarin. Conversely, when cranberry was ingested at 10 h after (±) warfarin, the elimination of S-warfarin was significantly inhibited, and the anticoagulation effect of (±) warfarin was significantly enhanced. The results of the mechanism studies indicate that cranberry activated the breast cancer resistance protein (BCRP), which mediated the efflux transports of S-warfarin and R-warfarin. Moreover, the metabolites of cranberry inhibited cytochrome P450 (CYP) 2C9, the main metabolizing enzyme for S-warfarin. In conclusion, cranberry affected the pharmacokinetics of (±) warfarin in a bidirectional manner by activating the BCRP by CJ during absorption and inhibiting the BCRP and CYP2C9 by CMs during elimination, depending on the ingestion time of CJ. The combined use of cranberry with warfarin should be avoided.

Case Report: Low Hematocrit Leading to Tacrolimus Toxicity

Tacrolimus is a calcineurin inhibitor characterized by a narrow therapeutic index and high intra- and inter-individual pharmacokinetic variability. Therapeutic drug monitoring in whole-blood is the standard monitoring procedure. However, tacrolimus extensively binds to erythrocytes, and tacrolimus whole-blood distribution and whole-blood trough concentrations are strongly affected by hematocrit. High whole-blood tacrolimus concentrations at low hematocrit may result in high unbound plasma concentrations and increased toxicity. We present the case of a 16-year-old girl with kidney and liver transplant in whom low concentrations of tacrolimus in the context of low hematocrit led to significant increase in the dosage of tacrolimus and participate, along with a genetic polymorphism of ABCB1, in nephrotoxicity.

Advances and Limitations of Antibody Drug Conjugates for Cancer

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

Systematic treatment and prevention of cardiac digoxin toxicity

Digoxin has a narrow therapeutic index, such as complicated pharmacokinetics and dynamics. Many drug interactions may occur when the administration of one drug alters the clinical effects of another. As a result, digoxin toxicity can be a common condition within clinical settings that might lead to the development of many morbidities and even mortality. Many studies were published to investigate the efficacy and safety of different management modalities to enhance the outcomes that follow digoxin administration. The aim of the study was to discuss the approaches to systematically treat and prevent the development of cardiac digoxin toxicity. The findings are based on evidence from previous studies in the literature. To be specific, Fab fragments are the most effective modalities that can be used to treat severe cases within ideal periods. However, evidence regarding their administration for asymptomatic or mild cases is still poor regarding the cost-efficacy and the development of serious adverse events. Physicians should primarily care for a better intervention as it is usually associated with a significantly more enhanced prognosis and clinical outcomes. Nevertheless, adequate monitoring of the patients and evaluation of their personal and medical history are important steps in the process, and further approaches are still needed. Also, detailed information about our intended outcomes is furtherly discussed within the manuscript.

Lithium carbonate toxicity in an elderly patient: a case report

A case report of a 73-year-old man admitted in the intensive care unit with acute renal failure and lithium toxicity is reported. Lithium is a gold standard drug for bipolar disorder. It has a narrow therapeutic index and requires blood level monitoring frequently. Hemodialysis is the last resort in management of lithium toxicity but in between high rebound levels during the dialysis result in persistent CNS toxicity.