Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications

Alves, Emanuele Amorim; Brandão, Pedro; Neves, João Filipe; Cravo, Sara; Soares, José X.; Grund, Jean‐Paul C.; Duarte, José Alberto; Afonso, Carlos; Netto, Annibal Duarte Pereira; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

doi:10.1002/hup.2572

Cited by 10 publications

(25 citation statements)

References 55 publications

(94 reference statements)

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“…Although heroin has been shown to cause oxidative stressinduced myocarditis, heroin did not affect the LV function in this AP4C -apical 4-chamber, AP2C -apical 2-chambers, SAX-B -short-axis basal, SAX-M -short-axis medial, SAX-A -short-axis apical study (16)(17)(18). Therefore, if there is no other risk factor to disrupt cardiac functioning (e.g., alcohol use), the use of heroin alone may not result in impairment of the LV function.…”

Section: Discussionmentioning

confidence: 70%

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Speckle Tracking Strain Assessment of Left Ventricle in Synthetic Cannabinoid and Heroin Users

Demirkıran¹

2018

Anatol J Cardiol

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ObjectiveThere is growing evidence regarding the numerous adverse effects of synthetic cannabinoids (SCBs) on the cardiovascular system; however, no studies have shown the cardiovascular effects of opioids using strain echocardiography. This study examines the cardiac structure and function using echocardiographic strain imaging in heroin and synthetic cannabinoid users.MethodsThis double-blind study included patients who were admitted or referred to a rehabilitation center for heroin (n=31) and synthetic cannabinoid users (n=30). Heroin users and synthetic cannabinoid users were compared with healthy volunteers (n=32) using two-dimensional (2D) speckle-tracking (ST) echocardiography.ResultsNo differences were found in the baseline characteristics and 2D echocardiography values. The mean global longitudinal strain value was −20.5%±2.4% for SCB users, −22.3%±2.4% for opioid users, and −22.5%±2.2% for healthy volunteers (p=0.024). The mean apical 2-chamber (AP2C) L-strain values were −20.1%±3.1%, −22.4%±3.0%, and −22.3%±2.8% for SCB users, opioid users, and healthy volunteers, respectively (p=0.032). The mean apical 4-chamber (AP4C) L-strain values were −20.7%±2.5% for SCB users, −23.2%±3.2% for opioid users, and −23.8%±3.1% for healthy volunteers (p<0.001).ConclusionSCBs are potential causes of subclinical left ventricular dysfunction.

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Section: Discussionmentioning

confidence: 70%

“…In addition, biochemical studies have shown creatine kinase, creatine kinase-MB, and uric acid changes. Significant alteration in the levels of reduced and oxidized glutathione in the kidney and heart suggest that oxidative stress may be involved in krokodil-mediated toxicity (17,18).…”

Section: Introductionmentioning

confidence: 99%

Speckle Tracking Strain Assessment of Left Ventricle in Synthetic Cannabinoid and Heroin Users

Demirkıran¹

2018

Anatol J Cardiol

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“…The impurities, particularly the high phosphorus concentrations of krokodil batches, may explain many of the signs and symptoms present in PWIK. 13 Besides pleasure, clinical cases related to PWIK and also animals exposed to krokodil suggest high pain tolerance to the corrosive and necrotizing effects. 13,14 Therefore, we hypothesized that, besides desomorphine, krokodil may uncover new morphinan derivatives capable of relieving moderate and severe pain and contribute to the addictive effects.…”

Section: ■ Introductionmentioning

confidence: 99%

“…13 Besides pleasure, clinical cases related to PWIK and also animals exposed to krokodil suggest high pain tolerance to the corrosive and necrotizing effects. 13,14 Therefore, we hypothesized that, besides desomorphine, krokodil may uncover new morphinan derivatives capable of relieving moderate and severe pain and contribute to the addictive effects. Aiming to identify additional morphinans (as a representative skeleton of a large class of opioids), a suitable analytical methodology, capable of identifying complex mixtures is required.…”

Section: ■ Introductionmentioning

confidence: 99%

“…However, due to its nature, the synthesis produces not only desomorphine but also other side-products as previously described in krokodil samples and biological fluids of people who inject krokodil (PWIK). , Several toxic effects have been reported and claimed to be related to impurities, namely, jaw osteonecrosis presenting as alveolar process exposure in the oral cavity, infections by HIV and hepatitis A, B, and C, skin and venous damage, including ulcers, abscesses, scaly and rough phlebitis, like crocodile skin around the injection sites, gangrene, and limb amputations. − Recently, we observed that repeated subcutaneous administrations of krokodil causes skin necrosis and toxicity to internal organs in Wistar rats, leading to cardiac and renal dysfunction. The impurities, particularly the high phosphorus concentrations of krokodil batches, may explain many of the signs and symptoms present in PWIK …”

Section: Introductionmentioning

confidence: 99%

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Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans

Soares

Alves

Silva

et al. 2017

Chem. Res. Toxicol.

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"Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil.

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Lethal endomyocarditis caused by chronic “Krokodil” intoxication

Sorrentino

Trotta

Colucci

et al. 2018

Forensic Sci Med Pathol

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"Krokodil" is a home-made opioid drug obtained by synthesizing desomorphine from codeine and combining it with other low-cost additives. Initially introduced in the former Soviet countries, it was then imported to Western Europe as a heroin substitute. To our knowledge, this is the first report of an Italian case of lethal krokodil abuse, that occurred in a 39-year-old man, who died suddenly after transportation to the Emergency Department (ED) for hyperthermia associated with sweating, dyspnoea and tachycardia. Post-mortem examination revealed extensive necrotic ulcerative lesions on the forearms, and autopsy showed a hypertrophic heart with ample endocardial vegetation on the aortic valve and patency of the foramen ovale. Histopathological examination of the heart showed ulcero-vegetative lesions of the aortic valve with an abscess on the annulus and extension to the periaortic adipose tissue, as well as diffuse myocardial interstitial inflammatory neutrophilic infiltrates. Toxicological analysis demonstrated a desomorphine metabolite in urine. On the basis of all these findings the cause of death was ruled to be congestive heart failure caused by endocarditis and myocarditis, correlated with chronic abuse of krokodil.

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Repeated subcutaneous administrations of krokodil causes skin necrosis and internal organs toxicity in Wistar rats: putative human implications

Abstract: These findings contribute notably to comprehension of the local and systemic toxicological impact of this complex drug mixture on major organs and will hopefully be useful for the development of appropriate treatment strategies towards the human toxicological effects of krokodil.

Cited by 10 publications

References 55 publications

Speckle Tracking Strain Assessment of Left Ventricle in Synthetic Cannabinoid and Heroin Users

Speckle Tracking Strain Assessment of Left Ventricle in Synthetic Cannabinoid and Heroin Users

Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans

Lethal endomyocarditis caused by chronic “Krokodil” intoxication

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