Concomitant Caffeine Research Articles

Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats.

Administration of caffeine with 3,4-methylenedioxymethamphetamine (MDMA) alters the pharmacological properties of MDMA in rats. The current study examined whether caffeine alters the behavioural and neurochemical effects of mephedrone, which has similar psychoactive effects to MDMA. Rats received either saline, mephedrone (10 mg/kg), caffeine (10 mg/kg) or combined caffeine and mephedrone intraperitoneally twice weekly on consecutive days for three weeks. Locomotor activity (days 1 and 16), novel object discrimination (NOD, day 2), elevated plus maze (EPM) exploration (day 8), rectal temperature changes (day 9) and pre-pulse inhibition (PPI) of acoustic startle response (day 15) were assessed. Seven days after the final injection, brain regions were collected for the measurement of 5-hydroxytryptamine (5-HT), dopamine and their metabolites. Combined caffeine and mephedrone further enhanced the locomotor response observed following either drug administered alone, and converted mephedrone-induced hypothermia to hyperthermia. Co-administration also abolished mephedrone-induced anxiogenic response on the EPM, but had no effect on NOD or PPI. Importantly, no long-term neurotoxicity was detected following repeated mephedrone alone or when co-administered with caffeine. In conclusion, the study suggests a potentially dangerous effect of concomitant caffeine and mephedrone, and highlights the importance of taking polydrug use into consideration when investigating the acute adverse effect profile of popular recreational drugs.

Concomitant Caffeine Increases Binge Consumption of Ethanol in Adolescent and Adult Mice, But Produces Additive Motor Stimulation Only in Adolescent Animals.

Binge co-consumption of highly caffeinated energy drinks with alcohol (ethanol [EtOH]) has become a common practice among adolescents/young adults and has been associated with an increased incidence of hazardous behaviors. Animal models are critical in advancing our understanding the neurobehavioral consequences of this form of binge drinking. Surprisingly, virtually no work has explored caffeine and EtOH co-consumption or its long-term consequences in adolescent animals. The primary objective of the current study was to extend a previously established mouse model of voluntary binge caffeine and EtOH co-consumption to explore adolescent consumption and responses compared to adults. Adolescent and adult male C57BL/6J mice had daily limited access to caffeine (0.03% w/v), EtOH (20% v/v), a combined EtOH/caffeine solution, or water for 14days via the binge-like drinking paradigm, drinking-in-the-dark (DID). Home cage locomotor activity was measured during DID in a subset of mice. Following DID, all mice rested for 18days so that adolescents reached adulthood, whereupon all mice underwent 7days of continuous access 2-bottle choice drinking for 10% (v/v) EtOH or water. Co-consumption with caffeine significantly increased EtOH intake and resultant blood ethanol concentrations in both adolescent and adult mice. In addition, adolescent mice exhibited a uniquely robust locomotor stimulant response to caffeine and EtOH co-consumption. Later EtOH intake and preference was not influenced, however, by prior fluid consumption history via DID. Together with findings from the human literature, our results suggest that caffeine co-consumption may positively influence binge alcohol consumption in adolescents/young adults. Importantly, this age group may be particularly sensitive to the additive stimulant effects of caffeinated alcohol consumption, an effect which may be related to the high incidence of associated negative outcomes in this population. These observations are particularly concerning considering the heightened plasticity of the adolescent brain.

Caffeine prevents antihyperalgesic effect of gabapentin in an animal model of CRPS-I: evidence for the involvement of spinal adenosine A1 receptor.

This study was designed to determine whether 3 weeks of gabapentin treatment is effective in alleviating neuropathic pain-like behavior in animal models of complex regional pain syndrome type-I and partial sciatic nerve ligation (PSNL). We investigated the contribution of adenosine subtypes to the antihyperalgesic effect of gabapentin by examining the effect of caffeine, a non-selective adenosine A1 and A2 receptor antagonist or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 subtype receptor antagonist on this effect. Neuropathic pain was produced by unilateral prolonged hind paw ischemia and reperfusion (I/R) or PSNL procedures which resulted in stimulus-evoked mechanical hyperalgesia. After procedures, animals received gabapentin (10, 30, or 100 mg/kg intraperitoneal, respectively), caffeine (10 mg/kg intraperitoneal or 150 nmol intrathecally) or DPCPX (3 µg intrathecally) alone or in combination. Mice were tested for tactile mechanical hyperalgesia at 1, 2, and 3 weeks following procedures. Gabapentin produced dose-related inhibition of mechanical hyperalgesia over a 3-week period, and this effect was blocked by concomitant caffeine or DPCPX administration 1 week after injuries. The results of this study demonstrated that the mechanism through which gabapentin produces its effect may involve the activation of adenosine A1 subtype receptor.

Venlafaxine Attenuates Heat Hyperalgesia Independent of Adenosine or Opioid System in a Rat Model of Peripheral Neuropathy.

Primarily opioidergic and adenosine mechanisms are considered to be involved in the antinociceptive effects of antidepressants. This study was designed to determine the efficacy of acute venlafaxine administration in alleviating symptoms of neuropathic pain and the role of endogenous adenosine and opioid systems in this effect of venlafaxine. We have evaluated the effect of caffeine, a non-selective adenosine A1 and A2 receptor antagonist and naloxone as an antagonist of opioid receptors on the antinociceptive effects of venlafaxine. Chronic constriction injury of the sciatic nerve resulted in thermal hyperalgesia, mechanical and cold allodynia in the rats. Animals were received on the 7(th) day after surgery, when the model had been fully established, venlafaxine (20 and 40 mg/Kg i.p.), or venlafaxine (40 mg/Kg) in combination with caffeine (5 mg/Kg i.p.) or naloxone (1 mg/Kg s.c.). Rats were tested for thermal reaction latencies, mechanical and cold allodynia 45 min after drug injection. Acute venlafaxine (40 mg/Kg i.p.) administration consistently decreased the thermal hyperalgesia and this effect was not blocked by concomitant caffeine or naloxone administration. There was no effect by either drug or the drug combination on the tactile and cold allodynia. The results of this study indicate that venlafaxine (40 mg/Kg i.p.) is effective in alleviating thermal hyperalgesia and this effect is independent through manipulation of adenosine or opioid system. This observation demonstrates that venlafaxine, which is a mixed inhibitor of norepinephrine and serotonin reuptake, differs from the other antidepressants in the mechanism of its antinociception action.

Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators.

Concomitant consumption of caffeine with recreational psychostimulant drugs of abuse can provoke severe acute adverse reactions in addition to longer term consequences. The mechanisms by which caffeine increases the toxicity of psychostimulants include changes in body temperature regulation, cardiotoxicity and lowering of the seizure threshold. Caffeine also influences the stimulatory, discriminative and reinforcing effects of psychostimulant drugs. In this review, we consider our current understanding of such caffeine-related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), which has been most recently described and characterized. Co-administration of caffeine profoundly enhances the acute toxicity of MDMA in rats, as manifested by high core body temperature, tachycardia and increased mortality. In addition, co-administration of caffeine enhances the long-term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug-induced toxicity comprising MDMA-related enhancement of dopamine release coupled to a caffeine-mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine-related drug interactions with cocaine, d-amphetamine and ephedrine where similar mechanisms are implicated. Understanding the underlying mechanisms will guide appropriate intervention strategies for the management of severe reactions and potential for increased drug-related toxicity, resulting from concomitant caffeine consumption.

Effect of green tea catechins with or without caffeine on anthropometric measures: a systematic review and meta-analysis

Green tea catechins (GTCs) with or without caffeine have been studied in randomized controlled trials (RCTs) for their effect on anthropometric measures and have yielded conflicting results. The objective was to perform a systematic review and meta-analysis of RCTs of GTCs on anthropometric variables, including body mass index (BMI), body weight, waist circumference (WC), and waist-to-hip ratio (WHR). A systematic literature search of MEDLINE, EMBASE, CENTRAL, and the Natural Medicines Comprehensive Database was conducted through April 2009. RCTs that evaluated GTCs with or without caffeine and that reported BMI, body weight, WC, or WHR were included. The weighted mean difference of change from baseline (with 95% CIs) was calculated by using a random-effects model. Fifteen studies (n = 1243 patients) met the inclusion criteria. On meta-analysis, GTCs with caffeine decreased BMI (-0.55; 95% CI: -0.65, -0.40), body weight (-1.38 kg; 95% CI: -1.70, -1.06), and WC (-1.93 cm; 95% CI: -2.82, -1.04) but not WHR compared with caffeine alone. GTC ingestion with caffeine also significantly decreased body weight (-0.44 kg; 95% CI: -0.72, -0.15) when compared with a caffeine-free control. Studies that evaluated GTCs without concomitant caffeine administration did not show benefits on any of the assessed anthropometric endpoints. The administration of GTCs with caffeine is associated with statistically significant reductions in BMI, body weight, and WC; however, the clinical significance of these reductions is modest at best. Current data do not suggest that GTCs alone positively alter anthropometric measurements.

Investigation of the effects of concomitant caffeine administration on the metabolic disposition of pyrazinamide in rats.

The utility of pyrazinamide (PZA) in the short-course antituberculous treatment is well established. All available data support the idea that the PZA metabolite pyrazinoic acid (PA) is the active compound against M. tuberculosis. This situation warranted a deeper investigation of possible interactions with respect to its metabolic disposition. Caffeine, which is widely used as a drug and is a common constituent of most diets, shares with PZA the same metabolic enzyme, xanthine oxidase (XO). This study investigated if, and in what manner, concomitant administration of caffeine affects PZA metabolism. PZA and caffeine, in various doses (PZA=50 or 100 mg kg(-1) and caffeine= 0, 50, 100, and 150 mg kg(-1)), were administered to female Sprague-Dawley rats. PZA and its three main metabolites were quantified in 24 h urine samples by reversed phase-HPLC Concomitant administration of 100 mg kg(-1) caffeine and 50 mg kg(-1) PZA increased from the excretion (p<0.05) of the most water-soluble and the least toxic PZA metabolite 5-hydroxypyrazinoic acid (5-OH-PA) from 66.18+/-10.87 to 94.56+/-8.65 micromol/24 h. This effect was more pronounced when 100 mg kg(-1) of PZA was administered increasing excretion of 5-OH-PA from 113.28+/-70 to 173.23+/-17.82 micromol/24 h. These results show that the metabolic disposition of PZA is affected by concomitant caffeine intake.

Ketoprofen-Induced Cyclooxygenase Inhibition in Renal Medulla and Platelets of Rats Treated with Caffeine

It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID₅₀ 0.3 mg/kg p.o.) reduction of PGE₂ biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE₂ biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE₂ biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B₂ biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE₂ biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE₂ biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition.

Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions

This study was designed to determine (1) whether chronic amitriptyline administration was effective in alleviating symptoms of neuropathic pain in a rat model of spinal nerve injury, and (2) whether the effect of amitriptyline involved manipulation of endogenous adenosine, by determining the effect of caffeine, a non-selective adenosine A 1 and A 2 receptor antagonist, on its actions. Nerve injury was produced by unilateral spinal nerve ligation of the fifth and sixth lumbar nerves distal to the dorsal root ganglion, and this resulted in stimulus-evoked thermal hyperalgesia and static tactile mechanical allodynia. Animals received pre- and post-surgical intraperitoneal doses of amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in combination, and following surgery, were administered amitriptyline (15–18 mg/kg/day) and caffeine (6–8 mg/kg/day), alone or in combination, in the drinking water. Rats were tested for thermal reaction latencies and static tactile thresholds at 7, 14 and 21 days following surgery. In the paw ipsilateral to the nerve ligation, chronic amitriptyline administration consistently decreased the thermal hyperalgesia produced by spinal nerve ligation over a 3-week period, and this effect was blocked by concomitant caffeine administration at all time intervals. In the contralateral paw, thermal withdrawal latencies were more variable, with the most reproducible finding being a reduction in thermal thresholds in the amitriptyline–caffeine combination group. There was no effect by either drug or the drug combination on the static tactile allodynia produced by spinal nerve ligation in the ipsilateral paw. However, chronic amitriptyline administration induced a tactile hyperaesthesia in the contralateral paw at all time intervals, and this effect was exacerbated by concomitant chronic caffeine administration. The results of this study indicate that chronic administration of amitriptyline is effective in alleviating thermal hyperalgesia, but not static tactile allodynia, in the hindpaw ipsilateral to nerve injury, and the block of this effect by caffeine suggests that this effect is partially achieved through manipulation of endogenous adenosine systems. Additionally, chronic amitriptyline administration induces contralateral hyperaesthetic responses that are augmented by caffeine. Both the symptom-specific effect, and adenosine involvement in amitriptyline action may be important considerations governing its use in neuropathic pain.

Interactive Effects of Ethanol and Caffeine on Rat Fetal Hepatocyte Replication and EGF Receptor Expression

This study reports on the interactive effects of ethanol and caffeine on growth of rat fetal hepatocytes. Exposure of cultured rat fetal hepatocytes (RFH) to ethanol in concentrations above 1 mg/ml, causes a blockade of EGF-dependent cell replication along with an overexpression of surface EGF receptors (EGF-R). However, RFHs exposed for 24 hours to ethanol at a concentration of 1 mg/ml alone had little effect on cell replication. Caffeine, when combined with this concentration of alcohol, progressively impaired RFH growth by up to 100%. Caffeine alone up to 10 micrograms/ml, on the other hand, caused a progressive increase in RFH replication associated with a 69% enhancement of DNA synthesis. Caffeine concentrations in excess of 50 micrograms/ml had no effect on replicative capacity. Concomitant caffeine exposure had no effect on the ethanol-related increase in cell DNA content, yet it caused a further enhancement of the cell protein accural induced by ethanol alone. Caffeine (10 micrograms/ml) alone had no effect on EGF-R expression, while ethanol (2 mg/ml) increased it by almost 200%. Addition of caffeine to ethanol reduced this enhanced EGF binding by 45%. Scatchard analysis indicated that no treatment altered ligand affinity for the receptor, but that the alterations in binding caused by ethanol and the caffeine/ethanol combination reflected changes in binding capacity, in both low and high affinity components. It is concluded that (1) ethanol blocks EGF-mediated replication accompanied by a reduction in DNA synthesis, (2) caffeine alone at low concentrations has the opposite effect and can actually potentiate the EGF-mediated mitogenic response, (3) caffeine in combination with ethanol acts synergistically to reduce RFH replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ethanol and/or caffeine on fetal development and placental amino acid uptake in rats.

The effects of ethanol alone or in combination with caffeine on fetal viability, growth and placental amino acid uptake function in the rat were examined. Compared to pair-fed control values, chronic ethanol exposure reduced fetal survival by 24%, fetal weight by 17%, along with weight decreases of fetal brain (16%), heart (31%), and kidney (48%) as compared to pair-fed control values. Placental weight was significantly increased by 17%. Concomitant caffeine intake generally exacerbated these effects with a further reduction in fetal survival, fetal body and visceral weights. Caffeine intake alone had no consistent effect on these parameters. Acute in vitro (3 mg/ml) and chronic in vivo ethanol exposure reduced placental net uptake of alpha-aminoisobutyric acid (AIB) by 32 and 45%, respectively. Neither acute in vitro (10 micrograms/ml) nor prior chronic caffeine exposure altered villous AIB uptake. Concomitant ethanol and caffeine treatment increased AIB uptake as compared to ethanol alone. However, AIB uptake continued to be reduced (by 22%) as compared to pair-fed control values.

Effect of serum caffeine level on pneumocardiogram of premature infants treated for apnea with theophylline

It is speculated that measurement of serum theophylline concentration alone, without concomitant caffeine level determination, may lead to a false negative (normal) pneumocardiogram due to possible existence of therapeutic caffeine level resulting from the methylation of theophylline. Treatment of neonatal apnea with theophylline as documented by a normal follow-up pneumocardiogram should be considered successful only when the levels of both theophylline and caffeine have been documented subtherapeutic at time of re-test.