Piperazine compounds as drugs of abuse Arbo, M.D; Bastos, M.L; Carmo, H.F
Drug and alcohol dependence,
05/2012, Letnik:
122, Številka:
3
Journal Article
Recenzirano
Abstract Synthetic drugs are among the most commonly abused drugs in the world. This abuse is widespread among young people, especially in the dance club and rave scenes. Over the last several years, ...piperazine derived drugs have appeared, mainly available via the internet, and sold as ecstasy pills or under the names of“ Frenzy”,“ Bliss”,“ Charge”,“ Herbal ecstasy”,“ A2”,“ Legal X” and“ Legal E”. Although in the market piperazine designer drugs have the reputation of being safe, several experimental and epidemiological studies indicate risks for humans. Piperazine designer drugs can be divided into two classes, the benzylpiperazines such as N-benzylpiperazine (BZP) and its methylenedioxy analogue 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), and the phenylpiperazines such as 1-(3-chlorophenyl)piperazine (mCPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), and 1-(4-methoxyphenyl)piperazine (MeOPP). Toxicokinetic properties, including metabolic pathways, actions and effects in animals and humans, with some hypothesis of mechanism of action, and analytical approaches for the identification of these drugs are summarized in this review.
Dietary supplements containing bitter orange unripe fruit extract/
p-synephrine are consumed worldwide for lose weight. This study were conducted to determine the concentration of
p-synephrine in ...unripe fruits and leaves from
Citrus aurantium Lin,
C. sinensis Osbeck,
C. deliciosa Ten,
C. limon Burm and
C. limonia Osbeck, collected in Southern Brazil, and to evaluate the acute toxicity of
C. aurantium extract and
p-synephrine. A high performance liquid chromatographic method with diode array detector (HPLC-DAD) was optimized and validated for determination of
p-synephrine. The results indicate that all of analyzed samples present
p-synephrine in amounts that range from 0.012% to 0.099% in the unripe fruits and 0.029 to 0.438% in the leaves. Acute oral administration of
C. aurantium extracts (2.5%
p-synephrine, 300–5000
mg/kg) in mice produced reduction of locomotor activity,
p-synephrine (150–2000
mg/kg) produced piloerection, gasping, salivation, exophtalmia and reduction in locomotor activity, which was confirmed in spontaneous locomotor activity test. All the effects were reversible and persisted for 3–4
h. The toxic effects observed seem to be related with adrenergic stimulation and should alert for possible side effects of
p-synephrine and
C. aurantium.
•TFMPP was the most cytotoxic derivative.•Primary hepatocytes were the most sensitive in vitro model.•CYP450-mediated metabolism contributes to the detoxification.•Reactive species, GSH and ATP ...depletion, loss of Δψm and caspase-3 activation were observed.
Piperazine derived drugs emerged on the drug market in the last decade. The aim of this study was to investigate in vitro the potential hepatotoxicity of the designer drugs N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(4-methoxyphenyl)piperazine (MeOPP) and 1-(3,4-methylenedioxybenzyl)piperazine (MDBP) in two human hepatic cell lines (HepaRG and HepG2) and in primary rat hepatocytes. Cell death was evaluated by the MTT assay, after 24h-incubations. Among the tested drugs, TFMPP was the most cytotoxic. HepaRG cells and primary hepatocytes revealed to be the most and the least resistant cellular models, respectively. To ascertain whether the CYP450 metabolism could explain their higher susceptibility, primary hepatocytes were co-incubated with the piperazines and the CYP450 inhibitors metyrapone and quinidine, showing that CYP450-mediated metabolism contributes to the detoxification of these drugs. Additionally, the intracellular contents of reactive species, ATP, reduced (GSH) and oxidized (GSSG) glutathione, changes in mitochondrial membrane potential (Δψm) and caspase-3 activation were further evaluated in primary cells. Overall, an increase in reactive species formation, followed by intracellular GSH and ATP depletion, loss of Δψm and caspase-3 activation was observed for all piperazines, in a concentration-dependent manner. In conclusion, piperazine designer drugs produce hepatic detrimental effects that can vary in magnitude among the different analogues.
Objectives The purpose of this study was to evaluate interstitial alterations in myocardial remodeling using a radiolabeled Cy5.5-RGD imaging peptide (CRIP) that targets myofibroblasts. Background ...Collagen deposition and interstitial fibrosis contribute to cardiac remodeling and heart failure after myocardial infarction (MI). Evaluation of myofibroblastic proliferation should provide indirect evidence of the extent of fibrosis. Methods Of 46 Swiss-Webster mice, MI was induced in 41 by coronary artery occlusion, and 5 were unmanipulated. Of the 41 mice, 6, 6, and 5 received intravenous technitium-99m labeled CRIP for micro–single-photon emission computed tomography imaging 2, 4, and 12 weeks after MI, respectively; 8 received captopril or captopril with losartan up to 4 weeks after MI. Scrambled CRIP was used 4 weeks after MI in 6 mice; the remaining 10 of 46 mice received unradiolabeled CRIP for histologic characterization. Results Maximum CRIP uptake was observed in the infarct area; quantitative uptake (percent injected dose/g) was highest at 2 weeks (2.75 ± 0.46%), followed by 4 (2.26 ± 0.09%) and 12 (1.74 ± 0.24%) weeks compared with that in unmanipulated mice (0.59 ± 0.19%). Uptake was higher at 12 weeks in the remote areas. CRIP uptake was histologically traced to myofibroblasts. Captopril alone (1.78 ± 0.31%) and with losartan (1.13 ± 0.28%) significantly reduced tracer uptake; scrambled CRIP uptake in infarct area (0.74 ± 0.17%) was similar to CRIP uptake in normal myocardium. Conclusions Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling, and is responsive to antiangiotensin treatment. If proven clinically feasible, such a strategy would help identify post-MI patients likely to develop heart failure.
Vasopressors and Inotropes in Sepsis Stratton, Leeanne; Berlin, David A; Arbo, John E
Emergency medicine clinics of North America,
02/2017, Letnik:
35, Številka:
1
Journal Article
Recenzirano
Vasopressor and inotropes are beneficial in shock states. Norepinephrine is considered the first-line vasopressor for patients with sepsis-associated hypotension. Dobutamine is considered the ...first-line inotrope in sepsis, and should be considered for patients with evidence of myocardial dysfunction or ongoing signs of hypoperfusion. Vasopressor and inotrope therapy has complex effects that are often difficult to predict; emergency providers should consider the physiology and clinical trial data. It is essential to continually reevaluate the patient to determine if the selected treatment is having the intended result.
Purpose
This study aimed to evaluate the effects of the subchronic consumption of energy drinks and their constituents (caffeine and taurine) in male Wistar rats using behavioural and oxidative ...measures.
Methods
Energy drinks (ED 5, 7.5, and 10 mL/kg) or their constituents, caffeine (3.2 mg/kg) and taurine (40 mg/kg), either separately or in combination, were administered orally to animals for 28 days. Attention was measured though the ox-maze apparatus and the object recognition memory test. Following behavioural analyses, markers of oxidative stress, including SOD, CAT, GPx, thiol content, and free radicals, were measured in the prefrontal cortex, hippocampus, and striatum.
Results
The latency time to find the first reward was lower in animals that received caffeine, taurine, or a combination of both (
P
= 0.003; ANOVA/Bonferroni). In addition, these animals took less time to complete the ox-maze task (
P
= 0.0001; ANOVA/Bonferroni), and had better short-term memory (
P
< 0.01, Kruskal–Wallis). The ED 10 group showed improvement in the attention task, but did not differ on other measures. In addition, there was an imbalance in enzymatic markers of oxidative stress in the prefrontal cortex, the hippocampus, and the striatum. In the group that received both caffeine and taurine, there was a significant increase in the production of free radicals in the prefrontal cortex and in the hippocampus (
P
< 0.0001; ANOVA/Bonferroni).
Conclusions
Exposure to a combination of caffeine and taurine improved memory and attention, and led to an imbalance in the antioxidant defence system. These results differed from those of the group that was exposed to the energy drink. This might be related to other components contained in the energy drink, such as vitamins and minerals, which may have altered the ability of caffeine and taurine to modulate memory and attention.
Metabolic syndrome is a major risk factor for the development of cardiovascular diseases and diabetes, among other conditions. Studies have shown that aging and metabolic syndrome share several ...metabolic alterations, and that aged individuals, in particular females, are at an increased risk of developing metabolic disorders. Although several studies have investigated the effects of hypercaloric diets in the development of obesity and metabolic syndrome in young animals, few studies have investigated these parameters in aged animals, especially in females. Therefore, the aim of this study was to investigate the effects of a hypercaloric diet in metabolic parameters of young and aged female rats, including its effects on lipid and glycemic profile and on liver lipid content. When compared to young animals, the aged rats presented increased serum levels of triglycerides and decreased serum levels of HDL cholesterol and glycemia, as well as increased hepatic levels of triglycerides and total cholesterol. The hypercaloric diet increased food intake, body weight gain and adiposity index, leading both young and aged animals to a dyslipidemia, represented by increased serum levels of triglycerides. The hypercaloric diet increased the glycemia and the HOMA index only in the young animals. On the other hand, the diet increased the frequency of hepatocellular microvacuolar degeneration only in the aged animals. In summary, it was observed that the females from different ages respond differently to hypercaloric diet intake: while the aged animals were more resistant to the changes in the glycemic profile, they were more susceptible to the hepatic damage caused by this diet.
•Aged females are at an increased risk of developing metabolic disorders.•The effects of a hypercaloric diet in young and aged female rats were investigated.•The diet increased the weight and led both young and aged animals to a dyslipidemia.•Aged females were more resistant to changes in the glycemic profile caused by the diet.•Aged females were more susceptible to the hepatic damage caused by the diet.
Abstract Purpose Right atrial pressure (RAP) is considered a surrogate for right ventricular filling pressure or cardiac preload. It is an important parameter for fluid management in patients with ...septic shock. It is commonly approximated by the central venous pressure (CVP) either invasively using a catheter placed in the superior vena cava or by bedside ultrasound, in which the size and respiratory variations of the inferior vena cava (IVC) are measured from the subcostal view. Doppler imaging of the tricuspid valve from the apical 4-chamber view has been proposed as an alternative approach for the estimation of RAP. The tricuspid E/Ea ratio is measured, where E is the peak velocity of the early diastolic tricuspid inflow and Ea is the peak velocity of the early diastolic relaxation of the lateral tricuspid annulus. We hypothesized that the tricuspid E/Ea ratio may represent an alternative to IVC metrics, using invasive CVP as the criterion standard, for the assessment of RAP in critically ill septic patients. Materials and methods A convenience sample of 30 septic patients, both mechanically ventilated and non–mechanically ventilated, was enrolled. Using a portable ultrasound system, maximum velocity of tricuspid E and Ea was measured from the apical 4-chamber view; and IVC diameter and degree of collapse were measured from the subcostal view. Decision tree induction was used to determine the performance of each model compared with invasive CVP. Results Our results suggest that a tricuspid E/Ea ratio of greater than 4.7 can predict a CVP greater than 10 mm Hg in septic patients with sensitivity greater than 85% and specificity greater than 90%. Conclusions In this pilot study, Doppler imaging of the tricuspid valve provided a valuable alternative for noninvasive bedside estimation of RAP in septic patients.
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