News Article | April 19, 2017
Europe's largest and best known salamander species, the fire salamander, is falling victim to a deadly fungus, and new research is making scientists more pessimistic about its future. A 2-year study of a population in Belgium, now entirely wiped out, has revealed that these amphibians can't develop immunity to the fungus, as was hoped. To make matters worse, it turns out the fungus creates a hardy spore that can survive in water for months and also stick to birds' feet, offering a way for it to spread rapidly across the continent. Two other kinds of amphibians, both resistant to the disease, also act as carriers for the highly infectious spores. "This is terrible news," says geneticist Matthew Fisher of Imperial College London, who studies the fungus but was not involved in the new research. "This isn't a problem that's going to go away. It's a problem that's going to get worse." The pathogen, Batrachochytrium salamandrivorans (Bsal), is a chytrid fungus, a type that lives in damp or wet environments and typically consumes dead organic matter. Bsal infects and eats the skin of salamanders, causing lesions, apathy, loss of appetite, and eventually death. Over the past few decades, a related fungus, B. dendrobatidis (Bd), has struck hard at amphibian populations around the world, particularly in the Americas, Australia, Spain, and Portugal. More than 200 species of frogs and toads are thought to have gone extinct, including many kinds of Costa Rica's striking stream-breeding toads. Bsal was identified in a nature reserve in the Netherlands in 2013 after fire salamanders started dying with ulcers and sores similar to those caused by Bd. Fire salamanders (Salamandra salamandra) grow up to 35 centimeters long, can live more than 40 years, and hunt insects and other small prey in forest streams. Their bright yellow spots warn predators of poison around their head and back. In the Dutch nature reserve, the population plummeted 99.9%. The fungus is thought to have arrived in Europe via salamanders or newts imported from Asia for the pet trade. Bsal has since been found in Belgium and Germany in both fire salamanders and alpine newts. As soon as Bsal was spotted in Belgium in April 2014, veterinarian An Martel of Ghent University in Merelbeke, Belgium, and her colleagues began visiting every month to track the population. About 90% of the fire salamanders died within 6 months, and after 2 years all were gone. The fieldwork revealed that adult animals were more likely to get infected, which makes sense because they are in closer contact with each other—through fighting for mating and breeding, for example—than are juveniles. But the death of these adults means that the population likely won't recover. There was no immune response detected in any of the sick animals in the lab, suggesting that it will be impossible to develop a vaccine, the team reports today in . "We really wanted to find solutions to mitigate disease, to save the salamanders, but everything turned out bad," Martel says. The team had also hoped that the fungus would become less virulent—as often occurs when a pathogen reaches a new host that lacks any immunity—but that hasn't happened: Fungal spores taken from the last fire salamanders in the Belgian forest, when dripped onto the backs of healthy salamanders in the lab, were just as lethal as those collected early in the outbreak. "When they come in contact with a single spore, they will die." The paper has more bad news. Researchers knew that Bsal makes spores with a tiny tail called a flagellum, which propels them toward amphibians. If spores dry out, they die. Otherwise, they typically survive for a few days before being eaten by protozoa. But Martel's group discovered that Bsal makes a second type of spore that looks much hardier and is rarely eaten by protozoa. "This will make it almost impossible to eradicate the fungus from the environment," says Martel, who adds that the spores can survive in pond water for more than 2 months. Another experiment showed that soil remained infectious for 48 hours after it was walked on by a sick salamander. In a separate lab test, the spores adhered to goose feet, suggesting they could hitchhike long distances on birds. The group also showed that two species that share the same habitat as the fire salamander are likely carriers of the disease. Midwife toads (Alytes obstetricans) could be infected with the fungus and shed spores for a few weeks, but they didn't get sick. A high dose of the fungus killed alpine newts (Ichthyosaura alpestris), but low doses made them infectious for months without killing them. As has happened with Bd in the Americas, Bsal will lurk in these reservoirs of disease even after local populations of fire salamanders vanish. Any fire salamanders that arrive from elsewhere will likely get infected by newts or toads. According to results from previous infection trials, most salamander species in Europe are likely just as vulnerable to Bsal. The fire salamander has a range that extends across Europe, and the fear is that the fungus will reach endangered salamanders. With small populations, these species could more easily be driven extinct, Fisher says. "The assumption is that they are all at risk," he says, and the findings in the new paper "have really upped their risk status." Martel and European colleagues recently started monitoring for Bsal in seven countries. It is possible to cure amphibians in the lab. For animals that can take the heat, like fire salamanders, 10 days at 25°C will kill the fungus. Other species can be cured with a combination of two drugs. But there is no practical solution for animals in the wild, especially when their habitat is contaminated with fungal spores. Herpetologist Jaime Bosch of the National Museum of Natural History in Madrid had a rare success in eliminating a chytrid fungus from the wild. A few years ago, he and colleagues got rid of Bd on the Spanish island of Mallorca by temporarily removing some 2000 tadpoles of the Mallorcan midwife toad (Alytes muletensis) and disinfecting their ponds with powerful chemicals. But this success would be hard to replicate in less isolated locations, he says. "Right now, we are very far away from having any solution." The only hope in the meantime, Bosch and others say, is to slow the spread of the disease by ending the importation of amphibians. The United States, a hot spot of amphibian diversity, has already taken steps in that direction. Last year, the U.S. Fish and Wildlife Service banned the import of 201 species of salamanders on the grounds that they might introduce the fungus. Joe Mendelson, a herpetologist at Zoo Atlanta, says the new research suggests the list should be expanded to include other carriers such as the toad and newt studied in the new paper. "This is a very important piece of work, and it's terrifying," he says. "If Bsal gets loose in the United States," he says, "it's going to be bad."
News Article | April 20, 2017
Urgent action is needed to protect wild salamanders in Europe from a deadly infection, say scientists. The disease may end up wiping out all vulnerable species, with zoos and gene banks the only conservation option, they warn. A fungal infection introduced to northern Europe several years ago behaves as a "perfect storm", say experts. It persists in the environment and may be spread by newts and birds. The fungus, known as B. salamandrivorans, or Bsal, killed almost all fire salamanders in an outbreak in The Netherlands in 2014. Since then, there have been outbreaks in wild salamanders and newts in Belgium and Germany. Researchers led by An Martel of Ghent University in Belgium, are calling for urgent monitoring across Europe. However, they say that there are few options to prevent the disease spreading in the wild, meaning conservation efforts should focus on zoos, captive breeding and gene banks. Commenting on the study, published in the journal, Nature, Matthew Fisher of Imperial College London, said the fungus was not unlike the "perfect pathogen" portrayed in the science-fiction film, Alien. "More must be done to try to conserve fire salamanders and other susceptible amphibian species that have restricted ranges and are under direct threat of extinction from Bsal," he said. "It is currently unclear how Bsal can be combated in the the wild beyond establishing 'amphibian arks' to safeguard susceptible species are the infection marches relentlessly onwards." The fire salamander (Salamandra salamandra) is one of the best-known salamander species in Europe. Scientists expect local extinctions to occur, but say it will take a long time for the infection to reach populations in southern Europe, such as those in Spain and Portugal. Prof Fisher said the real danger is for species of salamander that have very restricted ranges. Some, such as Lanza's alpine salamander and the golden-striped salamander, are on the European Red List of amphibians. "If Bsal reaches these species, they could go rapidly extinct," Prof Fisher told BBC News. Great crested newts are very susceptible to Bsal, he said. So far, the infection has not emerged in the natural environment in the UK, although it is present in captive populations. "It is imperative that Bsal is not introduced to the UK natural environment as that could lead to declines or even extinctions in conserved UK species - primarily great crested newts," said Prof Fisher.
Wischik C.M.,University of Aberdeen |
Staff R.T.,Royal Infirmary |
Wischik D.J.,University College London |
Bentham P.,University of Birmingham |
And 4 more authors.
Journal of Alzheimer's Disease | Year: 2015
Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD. © 2015 - IOS Press and the authors. All rights reserved.
Davis M.W.,Takeda Pharmaceutical |
Wason S.,Takeda Pharmaceutical |
DiGiacinto J.L.,Salamandra LLC
Consultant Pharmacist | Year: 2013
Objective: Review the magnitude and clinical relevance of drug-drug interactions between a new formulation of colchicine, used to treat gout, and antibiotics. Setting and Practice Description: Relevant to community and institutional pharmacists servicing patients with gout. Practice Innovation: Pharmacists have clear roles for the identification of drug-drug interactions, providing recommendations for alternative therapy or dose adjustments/ modifications, and monitoring for interactionrelated adverse events. Main Outcome Measures: Colchicine is metabolized via cytochrome P450 3A4 (CYP3A4); therefore, coadministration with agents that inhibit this isoenzyme can produce elevated colchicine plasma concentrations, resulting in severe and sometimes fatal adverse events. Knowledge of the potential for drug-drug interactions involving antibiotics (e.g., macrolide antibiotics, azole antifungals) allows pharmacists to help patients avoid serious adverse events. Results: Pharmacokinetic studies have demonstrated that the maximum plasma concentration (Cmax) and drug exposure (as assessed by area under the plasma concentration time curve [AUC]) of colchicine are increased by 277% and 282%, respectively, after coadministration with clarithromycin. Similarly, coadministration with ketoconazole increases colchicine Cmax and AUC by 102% and 212%, respectively. Other antibiotics that are strong CYP3A4 inhibitors include itraconazole and telithromycin, whereas erythromycin and fluconazole are moderate inhibitors of the isoenzyme CYP3A4. Coadministration of CYP3A4 inhibitors (particularly clarithromycin) and colchicine has resulted in acute colchicine toxicity manifested by severe gastrointestional toxicity, bone marrow suppression, multiorgan failure, and death. Conclusion: Pharmacist awareness of potentially clinically significant interactions between colchicine and antibiotics that inhibit CYP3A4 can help to ensure the efficacy of colchicine is realized while mitigating serious toxicities and minimizing the risk of adverse events.
Baddeley T.C.,University of Aberdeen |
McCaffrey J.,Salamandra LLC |
Storey J.M.D.,University of Aberdeen |
Cheung J.K.S.,University of Aberdeen |
And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015
Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT+) forms; as a chloride salt [methylthioniniumchloride (MTC), "methylene blue"], it is stabilized in its MT+ form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT+ form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
Terkeltaub R.A.,San Diego Medical Center |
Furst D.E.,University of California at Los Angeles |
Digiacinto J.L.,Salamandra LLC |
Kook K.A.,Salamandra LLC |
Davis M.W.,URL Pharma
Arthritis and Rheumatism | Year: 2011
Objective Drug-drug interactions can limit the safety of colchicine for treating rheumatic diseases. Seven separate drug-drug interaction (DDI) studies were performed to elucidate the in vivo effects of concomitant treatment with colchicine and known inhibitors of cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (cyclosporine, ketoconazole, ritonavir, clarithromycin, azithromycin, verapamil ER [extended release]), and diltiazem ER) on the pharmacokinetics of colchicine. The objective was to develop colchicine-dosing algorithms with improved safety. Methods All studies were open-label, non-randomized, single-center, one-sequence, two-period DDI experiments, using two 0.6-mg doses of colchicine, separated by a minimum 14-day washout period, followed by administration of the approved on-label regimen of known CYP3A4/P-glycoprotein inhibitors. Plasma concentrations of colchicine, but not the reference CYP3A4/P-glycoprotein inhibitors, were determined, and the pharmacokinetic parameters were calculated. Results The ratios of the maximum concentration and area under the curve from time 0 to infinity for colchicine plus CYP3A4/P-glycoprotein inhibitors versus colchicine alone were >125% across all studies, with the exception of studies involving azithromycin. Significant DDIs were present when single doses of colchicine were coadministered with most of the selected CYP3A4/P-glycoprotein inhibitors. Recommended colchicine dose reductions of 33-66% for the treatment of acute gout and 50-75% for prophylaxis were calculated for concomitant therapy with each agent, with the exception of no dose adjustment when colchicine is used in combination with azithromycin. Conclusion These studies provide quantitative evidence regarding drug interactions and necessary adjustments in the dose of colchicine if colchicine treatment is continued during therapy with multiple CYP3A4/P-glycoprotein inhibitors. We demonstrated the need for specific reductions in the dose of colchicine when it is used in combination with 2 broadly prescribed calcium channel blockers (verapamil ER and diltiazem ER) and that the dose of colchicine does not need to be adjusted when it is used in combination with azithromycin. Copyright © 2011 by the American College of Rheumatology.
High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study
Terkeltaub R.A.,University of California at San Diego |
Furst D.E.,University of California at Los Angeles |
Bennett K.,Salamandra LLC |
Kook K.A.,Salamandra LLC |
And 2 more authors.
Arthritis and Rheumatism | Year: 2010
Objective. Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. Methods. This multicenter, randomized, doubleblind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was ≥50% pain reduction at 24 hours without rescue medication. Results. There were 184 patients in the intent-totreat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. Conclusion. Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo. © 2010, American College of Rheumatology.
Wason S.,URL Pharma Inc. |
Wason S.,Mutual Pharmaceutical Company Inc. |
DiGiacinto J.L.,Salamandra LLC |
Davis M.W.,URL Pharma Inc. |
Davis M.W.,Mutual Pharmaceutical Company Inc.
Clinical Therapeutics | Year: 2012
Background: The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug- drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported. Objective: Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers. Methods: Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mgdose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes. Results: Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered withSeville orange juice, a moderate inhibitor, Cmax and AUC were decreased by s≃24% and s≃20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in Tmax. Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events. Conclusions: In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased Tmax, but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials. gov identifiers: NCT00960193 and NCT00984009.(Clin Ther. 2012;34:2161-2173) 2012 Elsevier HS Journals, Inc. All rights reserved.
Single-Dose Bioequivalence of 105-mg Fenofibric Acid Tablets Versus 145-mg Fenofibrate Tablets Under Fasting and Fed Conditions: A Report of Two Phase I, Open-Label, Single-Dose, Randomized, Crossover Clinical Trials
Godfrey A.R.,PRACS Institute Ltd. |
DiGiacinto J.,Salamandra LLC |
Davis M.W.,Mutual Pharmaceutical Company
Clinical Therapeutics | Year: 2011
Background: Fenofibrate is used to treat primary hypercholesterolemia, mixed lipidemia, and hypertriglyceridemia in adults who do not respond to nonpharmacologic measures. Fenofibrate is a prodrug that is rapidly and completely hydrolyzed to fenofibric acid, the active moiety. A new orally administered agent, fenofibric acid, was developed as an alternative to fenofibrate. Objective: Two separate studies were conducted to evaluate the bioequivalence of fenofibric acid relative to fenofibrate under fasted and fed (standard breakfast) conditions, characterize the pharmacokinetic profile, and assess the safety and tolerability of fenofibric acid. Methods: In study 1 (fasted), during each study period, volunteers received a single 105-mg dose of fenofibric acid or single 145-mg dose of fenofibrate (depending on their randomization scheme) after an overnight fast (a minimum fast of 10 hours). A 7-day washout period followed the first treatment period, after which the volunteers received the alternate treatment. Study 2 followed a similar dosing scheme and differed only in that volunteers received their single dose after being fed a standard meal (575 calories, of which 36% were contributed by fat). Serial blood samples in both studies were collected up to 72 hours after drug administration. The pharmacokinetic parameters of interest for assessing bioequivalence were AUC 0-t, AUC 0-∞, C max, and T max. The criterion for a lack of difference between products was a 90% CI between 0.80 and 1.25 for the fenofibric acid:fenofibrate ratios for AUC 0-t, AUC 0-∞, and C max. Tolerability was assessed by adverse events (AEs), laboratory parameters, vital signs, and physical examinations. Results: Volunteers in study 1 (fasted; n = 54) were aged 18 to 43 years; 19 (35%) were men and 35 (65%) were women; mean weight was 155.2 pounds (range, 103.0-267.0 pounds); and 48 (89%) were white, 1 (2%) was black, and 5 (9%) were white/American Indian/Alaskan native/Asian. Volunteers in study 2 (fed; n = 54) were aged 18 to 43 years; 27 (50%) were men and 27 (50%) were women; mean weight was 161.9 pounds (range, 112.0-225.0 pounds); and 51 (94%) were white (including 2 Hispanic) and 3 (6%) were black. The 90% CIs about the ratio of the fenofibric acid geometric mean to the fenofibrate geometric mean were within the 80% and 125% limits for the pharmacokinetic parameters C max, AUC 0-t, and AUC 0-∞ of the ln-transformed data in both study 1 (fasted) and study 2. In study 1 (fasted), 14 volunteers (26%) experienced a total of 29 AEs; the most common nonlaboratory AEs were dizziness (6%) and headache (4%). In study 2, 12 volunteers (22%) experienced a total of 19 AEs; the most common nonlaboratory AEs were headache (17%) and dry throat (4%). AEs were generally mild or moderate in intensity. Conclusions: In these 2 single-dose studies, these healthy volunteers administered a single oral dose of 105-mg fenofibric acid met the US Food and Drug Administration regulatory criteria for assuming bioequivalence to a single oral dose of 145-mg fenofibrate tablets with respect to the rate and extent of fenofibric acid absorption in both fed and fasted states. Fenofibric acid at the dose studied was well tolerated in this population. ClinicalTrials.gov identifiers: NCT00961116 and NCT00960687. © 2011 Elsevier HS Journals, Inc.
Wason S.,URL Pharma Inc |
Digiacinto J.L.,Salamandra LLC |
Davis M.W.,URL Pharma Inc
Postgraduate Medicine | Year: 2012
Objective: Colchicine and cyclosporine are often administered together, particularly in patients who have undergone solid-organ transplantation. However, the potential for drug-drug interactions between these agents resulting in colchicine toxicity is high. Methods: This study sought to determine the effect of cyclosporine (100-mg capsule) on the pharmacokinetics of the US Food and Drug Administration-approved formulation of colchicine (0.6-mg tablet) after single oral-dose administration in 24 healthy subjects under fasted conditions in a phase 1, single-sequence, 2-period drug-drug interaction trial. Results: Coadministration of cyclosporine increased colchicine maximum observed plasma concentration, area under the plasma concentration-time curve to the last measurable time point, and area under the plasma concentration-time curve to time infinity on average by 224%, 216%, and 215% (ie, almost doubled), respectively, and decreased colchicine oral clearance on average by 72% (from 48.24 to 13.42 L/h), indicating substantially higher colchicine exposures when combined with cyclosporine, compared with colchicine alone. Conclusion: The dose of colchicine should be reduced by $ 50% when colchicine and cyclosporine are administered concurrently for treatment and prophylaxis of gout fares or treatment of patients with familial Mediterranean fever. Health care professionals should be vigilant for potential adverse events during colchicine/cyclosporine coadministration, notably in patients who have undergone solid-organ transplantation. © Postgraduate Medicine.