Co-administration Of Caffeine Research Articles

Evaluating the Impact of Caffeine on the Incidence of Adverse Events During Treatment with Viloxazine Extended-Release (Qelbree®) in Adults with ADHD

AbstractIntroductionViloxazine ER (viloxazine extended-release capsules (Qelbree®) is a novel, nonstimulant, FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD) in adults and children ≥6 years of age. Viloxazine ER inhibits cytochrome P450-1A2, the enzyme responsible for caffeine metabolism. In a Phase 1 study, the peak exposure (Cmax) of caffeine was unchanged, while the systemic total exposure (AUC) was shown to increase ~5-fold following coadministration of caffeine (200mg) with viloxazine ER (900 mg/day x 4 days) compared to caffeine alone. Except for insomnia (44.4%), and possibly dizziness (8.3%), the incidence of adverse events (AEs) was not notably higher following coadministration vs. either caffeine or viloxazine ER alone. The objective of this analysis was to evaluate the impact of caffeine consumption on the incidence of AEs in adults with ADHD treated with viloxazine ER.MethodsData were analyzed from the Phase 3, double-blind (DB), placebo-controlled trial (NCT04016779) and ensuing (ongoing) open-label extension (OLE) safety trial (NCT04143217) supporting the viloxazine ER indication for adults with ADHD. Participants reported caffeine intake during the past week at each study visit.Correlation was assessed between viloxazine ER dose (mg/day) and weekly total caffeine consumption (mg) and between ADHD Investigator Symptom Rating Scale (AISRS) Total score and caffeine consumption. Fifteen AE preferred terms, known to be associated with caffeine consumption, were evaluated. For viloxazine ER-treated subjects (200–600 mg/day) who experienced a potentially caffeine-associated AE, the probability the AE occurred as a function of viloxazine ER dose and caffeine consumption during the DB or OLE trials was estimated using a logistic regression model for AEs with an incidence ≥5%.ResultsOf 372 enrolled subjects ~85% reported caffeine use during the DB trial; mean caffeine use was 1034 mg/week for the placebo group and 859 mg/week for the viloxazine ER group. There was no correlation between viloxazine ER dose and caffeine consumption (p=0.73), nor between AISRS total score and caffeine consumption (p=0.908). Of subjects reporting caffeine use, 44 (DB placebo), 79 (DB viloxazine ER), and 33 (OLE viloxazine ER) reported any of the pre-identified caffeine- associated AEs and were included in the regression analysis. For these subjects, insomnia-related AEs, fatigue, nausea, headache-related AEs, decreased appetite, and somnolence-related AEs occurred in ≥5% of viloxazine ER-treated subjects. Based on the regression analysis, caffeine consumption significantly increased the probability of experiencing insomnia-related AEs only (p=0.02).ConclusionsThis analysis suggests using caffeine concomitantly with viloxazine ER does not increase the likelihood of experiencing caffeine-related AEs except for insomnia. Still patients should be aware of the potential for viloxazine ER to augment caffeine exposure.FundingSupernus Pharmaceuticals, Inc.

Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.

This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments. Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants. Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Caffeine May Improve the Chemotherapeutic Effect of Docetaxel by Inducing UPR and Autophagy in Breast Cancer Cells

Breast cancer is the most frequently diagnosed cancer type among women. Chemotherapeutics are widely used for breast cancer treatment but acquired drug resistance is the main reason that limits their efficacy. Therefore, there is a continuing need for more effective treatment approaches with fewer side effects. One of the naturally occurring xanthine in coffee beans, caffeine is the most commonly used psychoactive substance worldwide. Numerous studies have drawn attention to the health benefits of coffee intake including decrement in risk of heart disease and risk of some cancers. Docetaxel is a second-generation antineoplastic agent of the taxane family and is widely used in the treatment of numerous cancers such as breast cancer. Herein, we evaluate the effect of caffeine and its combination with docetaxel on MCF-7 breast cancer cells. To test the effect of caffeine and its combination with docetaxel, we evaluate the autophagy, ubiquitin-proteasome system, unfolded protein response signaling and apoptosis-related protein levels were examined by immunoblotting. Cell viability was measured by WST-1 method. Morphological alterations in cells were evaluated in microscopical examinations. We found that caffeine remarkably induced UPR signaling, accelerated autophagic flux, and UPS-dependent protein turnover. Co-administration of caffeine and docetaxel strongly diminished the viability of MCF-7 cells by expanding the cytotoxic effect of docetaxel through accelerating the UPS-dependent protein turnover, induction of autophagy and apoptotic protein levels in a manner dose-dependently. Our results suggest that caffeine supplementation with docetaxel may expand the chemotherapeutic efficiency of docetaxel in breast cancer.

Effect of Black Pepper (Piper nigrum) Extract on Caffeine-Induced Sleep Disruption and Excitation in Mice

Sleep is one of the most essential factors required to maintain good health. However, the global prevalence of insomnia is increasing, and caffeine intake is a major trigger. The objective of this study was to investigate the inhibitory effect of black pepper, Piper nigrum extract (PE), on caffeine-induced sleep disruption and excitation in mice. Caffeine significantly decreased sleep duration in the pentobarbital-induced sleep test. It also resulted in a significant increase in sleep onset and a decrease in non-rapid eye movement sleep. Moreover, in an open-field test, caffeine-treated mice exhibited a significantly increased time in the center zone and total distance traveled. However, the co-administration of caffeine and PE did not result in similar arousal activities. Thus, our results suggest that PE can be used as a potential therapeutic agent to treat sleep problems and excitatory status associated with caffeine intake.

Simultaneous administration of coffee and rasagiline/l-dopa protects against paraquat-induced neurochemical and motor behavior impairments in vivo

BackgroundCaffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l-dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice.ResultsIn behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l-dopa + COF. l-Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l-dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l-dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l-dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ.ConclusionsOur findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l-dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.

Protective effect of co-administration of caffeine and piracetam on scopolamine-induced amnesia in Wistar rats

Alzheimer's disease is a cerebrovascular disorder characterized by progressive loss of the mental capabilities. The novel therapeutic agent piracetam is a cyclic derivative of γ-aminobutyric acid and one of the oldest recognized synthetic nootropics. Piracetam improves cognitive function without stimulation or sedation. Caffeine is a central nervous system stimulant with nootropic activity. Caffeine promotes the performance of tasks that involve working memory to a limited extent, and it also retards cognitive decline in healthy individuals. The present study aimed to determine the protective effect of co-administering piracetam and caffeine on scopolamine-induced amnesia in rats. Pre-treatment with caffeine and piracetam decreased scopolamine-induced cognitive damage and amnesia. The preventive response was demonstrated by an improved learning tendency. The mechanism responsible for these effects requires further investigation. The co-administration of caffeine and piracetam has potential as a novel therapeutic strategy for combating amnesia.

Caffeine Sensitizes U87-MG Human Glioblastoma Cells to Temozolomide through Mitotic Catastrophe by Impeding G2 Arrest.

Temozolomide (TMZ) is the first-line chemotherapeutic agent in the treatment of glioblastoma multiforme (GBM). Despite its cytotoxic effect, TMZ also induces cell cycle arrest that may lead to the development of chemoresistance and eventual tumor recurrence. Caffeine, a widely consumed neurostimulant, shows anticancer activities and is reported to work synergistically with cisplatin and camptothecin. The present study aimed to investigate the effects and the mechanisms of action of caffeine used in combination with TMZ in U87-MG GBM cells. As anticipated, TMZ caused DNA damage mediated by the ATM/p53/p21 signaling pathway and induced significant G2 delay. Concurrent treatment with caffeine repressed proliferation and lowered clonogenic capacity on MTT and colony formation assays, respectively. Mechanistic study showed that coadministration of caffeine and TMZ suppressed the phosphorylation of ATM and p53 and downregulated p21 expression, thus releasing DNA-damaged cells from G2 arrest into premature mitosis. Cell cycle analysis demonstrated that the proportion of cells arrested in G2 phase decreased when caffeine was administered together with TMZ; at the same time, the amount of cells with micronucleation and multipolar spindle poles increased, indicative of enhanced mitotic cell death. Pretreatment of cells with caffeine further enhanced mitotic catastrophe development in combined treatment and sensitized cells to apoptosis when followed by TMZ alone. In conclusion, our study demonstrated that caffeine enhanced the efficacy of TMZ through mitotic cell death by impeding ATM/p53/p21-mediated G2 arrest.

Caffeine Protects Dopaminergic Neurons From Dopamine-Induced Neurodegeneration via Synergistic Adenosine-Dopamine D2-Like Receptor Interactions in Transgenic Caenorhabditis elegans.

Previous studies have suggested that caffeine reduces the risk of L-DOPA-induced dyskinesia. However, caffeine is also known to promote dopamine signaling, which seemingly contradicts this observed effect. To this end, the study aimed to clarify the mechanism of caffeine neuroprotection in vivo when excess dopamine is present. Transgenic Caenorhabditis elegans (UA57) overproducing dopamine was exposed to caffeine for 7 days and monitored by observing GFP-tagged dopaminergic (DA) neurons via fluorescence microscopy. Caffeine (10 mM) prevented neuronal cell loss in 96% of DA neurons, with a mean GFP intensity that is 40% higher than control (0.1% DMSO). To confirm if cAMP plays a role in the observed neuroprotection by caffeine, cAMP levels were elevated via forskolin (10 μM), an adenylyl cyclase activator. Forskolin (10 μM) exposure did not confer neuroprotection and was similar to control (0.1% DMSO) at the 7th day, suggesting that cAMP is not the sole secondary messenger utilized. Rotigotine (160 μM), a dopamine D2-like receptor (DOP2R) agonist, was not able to confer significant neuroprotection to the nematodes. This suggests that DOP2R activation is necessary but insufficient to mimic neuroprotection by caffeine. Lastly, co-administration of caffeine (10 mM) with olanzapine (160 μM), a DOP2R antagonist, eliminated neuroprotection. This suggests that the protective effect must involve both adenosine receptor antagonism and activation of DOP2Rs. Taken together, we show that caffeine protects DA neurons from dopamine-induced neurodegeneration and acts by modulating adenosine receptor-DOP2R interactions in C. elegans.

Caffeine Protects Against Anticonvulsant-Induced Impaired Neurogenesis in the Developing Rat Brain.

In preterm infants, phenobarbital is the first-line antiepileptic drug for neonatal seizures while caffeine is used for the treatment of apnea. Data from experimental animals suggest that phenobarbital and other anticonvulsants are toxic for the developing brain, while neuroprotective effects have been reported for caffeine both in newborn rodents and preterm human infants. To characterize the interaction of phenobarbital and caffeine in the hippocampus of the developing rodent brain, we examined the effects of both drugs given separately or together on postnatal neurogenesis after administration to neonatal rats throughout postnatal day (P) 4 to P6. Phenobarbital treatment (50mg/kg) resulted in a significant decrease of proliferative capacity in the dentate gyrus. Phenobarbital also reduced expression of neuronal markers (doublecortin (DCX), calretinin, NeuN), neuronal transcription factors (Pax6, Sox2, Tbr1/2, Prox1), and neurotrophins (NGF, BDNF, NT-3) up to 24h after the last administration. The phenobarbital-mediated impairment of neurogenesis was largely ameliorated by preconditioning with caffeine (10mg/kg). In contrast, caffeine alone reduced proliferative capacity and expression of the neuronal markers DCX and NeuN at 6h, but increased expression of neurotrophins and neuronal transcription factors at 6 and 12h. These results indicate that administration of phenobarbital during the vulnerable phase of brain development negatively interferes with neuronal development, which can be prevented in part by co-administration of caffeine.

Seizure vulnerability and anxiety responses following chronic co-administration and acute withdrawal of caffeine and ethanol in a rat model.

Caffeine antagonizes the intoxicating effects of alcohol. Consequently, there has been a dramatic global increase in the consumption of caffeinated drinks together with alcohol, especially among young adults. We assessed the seizure vulnerability and anxiety responses following the chronic co-administration of, and withdrawal from, caffeine and ethanol in male rats. The rats were randomly assigned to six groups consisting of 10 animals each: 10 mg/kg of caffeine, 20 mg/kg of caffeine, 4 g/kg of 20% ethanol, combined caffeine (20 mg/kg) and ethanol (4 g/kg of 20%), 4 mL/kg distilled water, and an untreated control group. The test substances were administered intragastrically twice daily for 29 days. On day 29, the rats were tested on the elevated plus maze to assess anxiety-related responses. On day 30, pentylenetetrazol (PTZ), a chemoconvulsant, was administered intraperitoneally at a dose of 40 mg/kg to the animals. Seizure responses and mortality up to 72 h were recorded. Compared with the control group, the rats that received chronic treatment with low-dose caffeine, ethanol alone, and combined caffeine and ethanol exhibited significant anxiogenic-like effects, unlike with high-dose caffeine. Both low- and high-dose caffeine significantly increased PTZ seizure latency. Ethanol alone and combined caffeine and ethanol both lowered PTZ seizure latency. No significant difference occurred between the controls and the untreated group for either anxiety or seizure expression. Combined caffeine and ethanol increased the seizure-induced mortality from withdrawal effects at 72 h. These findings suggest that the chronic co-administration of caffeine and ethanol and the acute withdrawal from these drugs lead to anxiogenic effects and increased seizure vulnerability.

CK2 Oppositely Modulates l-DOPA-Induced Dyskinesia via Striatal Projection Neurons Expressing D1 or D2 Receptors.

We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A2A receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A2A antagonist, caffeine. Because both, D1 and A2A receptors, play major roles in the cellular responses to l-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects of l-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson's disease. We report here that knock-out of CK2 in striatonigral neurons reduces the severity of l-DOPA-induced dyskinesia (LID), a finding that correlates with lowered pERK but unchanged pPKA substrate levels in D1 medium spiny neurons as well as in cholinergic interneurons. In contrast, lack of CK2 in striatopallidal neurons enhances LID and ERK phosphorylation. Coadministration of caffeine with a low dose of l-DOPA reduces dyskinesia in animals with striatopallidal knock-out to wild-type levels, suggesting a dependence on adenosine receptor activity. We also detect reduced Golf levels in the striatonigral but not in the striatopallidal knock-out in response to l-DOPA treatment.Our work shows, in a rodent model of PD, that treatment-induced dyskinesia and striatal ERK activation are bidirectionally modulated by ablating CK2 in D1- or D2-positive projection neurons, in male and female mice. The results reveal that CK2 regulates signaling events critical to LID in each of the two main populations of striatal neurons.SIGNIFICANCE STATEMENT To date, l-DOPA is the most effective treatment for PD. Over time, however, its efficacy decreases, and side effects including l-DOPA-induced dyskinesia (LID) increase, affecting up to 78% of patients within 10 years of therapy (Hauser et al., 2007). It is understood that supersensitivity of the striatonigral pathway underlies LID, however, D2 agonists were also shown to induce LID (Bezard et al., 2001; Delfino et al., 2004). Our work implicates a novel player in the expression of LID, the kinase CK2: knock-out of CK2 in striatonigral and striatopallidal neurons has opposing effects on LID. The bidirectional modulation of dyskinesia reveals a central role for CK2 in striatal physiology and indicates that both pathways contribute to LID.

Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans.

Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine® (25 or 125 mg), caffeine (150 mg), or a combination of theacrine (125 mg) and caffeine (150 mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered.

Co-administration of caffeine and caffeic acid alters some key enzymes linked with reproductive function in male rats.

This study assessed the effects of caffeine combined with caffeic acid on some biomarkers of male reproductive function using normal albino Wistar rats. Rats were divided into four groups (n=6) and treated for seven successive days; group 1 represents the control rats; group 2 rats were treated with 50mg/kg body weight (BW) of caffeine only; group 3 rats were treated with 50mg/kg BW of caffeic acid, while the rats in group 4 were cotreated with an equal combination of caffeine and caffeic acid. The results revealed significant increase in reproductive hormone, testicular and epididymal nitric oxide levels of the rats. Moreover, decreased oxidative stress in the testes and epididymides of the treated rats was evidenced by significant increase in total and nonprotein thiol levels, catalase and superoxide dismutase activities. Similarly, decreased testicular cholesterol level with concomitant elevation in testicular steroidogenic enzyme activities, glycogen and zinc levels were observed in the treated rats. No morphological changes were observed as revealed by the photomicrographs from light microscopy in treated rats. Nevertheless, the combination therapy exhibited additive/synergistic effect on these biochemical indices than when they were administered singly. This study suggests the combination therapy of caffeine and caffeic acid at the dose tested for improving male reproductive function.

Effect of Taurine and Caffeine on Spatial Memory in Adult Male Wistar Rats

There is an increase in the production and consumption of caffeine and taurine beverages tagged as energy drinks. This study was therefore undertaken to investigate the effect of co-administration of caffeine and taurine on memory in Wistar rats. Fifty-four adult Wistar rats were divided into nine groups of six animals and treatments were as follows: Group 1 (10 ml/kg normal saline), Group 2 (100 mg/kg taurine), Group 3 (200 mg/kg taurine), Group 4 (taurine plus furosemide; 20 mg/kg), Group 5 (taurine plus nifedipine; 10 mg/kg), Group 6 (taurine plus caffeine), Group 7 (7.5 mg/kg caffeine), Group 8 (15 mg/kg caffeine) and Group 9 (taurine plus nifedipine plus furosemide plus caffeine). Treatment was once daily for 21 days, after which long term spatial memory of pretreatment training in Morris Water Maze was tested. Histological study was done using haematoxylin and eosin stains on hippocampus tissues harvested from the brain of one animal in each group. The results showed that there was a significant (p<0.05) decrease in time taken to find and mount the escape platform compared with the control. This was with the exception of the group co-treated with caffeine and taurine. Histological studies showed normal cell morphology, arrangement and distribution in the hippocampus. There was increased in the number of cells in the hippocampus of the animals given taurine (200 mg/kg) plus caffeine (15 mg/kg), and caffeine (15 mg/kg). In conclusion, at the doses used, co-administration of caffeine and taurine has no significant effects on spatial memory, however the separate use of caffeine or taurine proved to have capacity to enhance spatial memory.

Effect of Caffeine Co-Ingested with Carnitine on Weight, Body- Fat Percent, Serum Leptin and Lipid Profile Changes in Male Teen Soccer Players: a Randomized Clinical Trial

Background: Weight loss and decreasing the Body fat percentage (BF%) is motivated to optimize performance. In order to achieve these, many supplements are used by athletes, however the possible negative or synergic effects have not been fully described in the literature, specifically in humans. The present study was conducted to investigate the co-administration effects of two common used supplements in body weight and BF% management to recommend athletes for safe weight and BF% reduction. Materials and Methods: In the present double-blind, randomized, parallel, placebo-controlled study, the effect of six-week co-administration of caffeine and carnitine was determined on changes in body weight (BW), BF%, serum leptin concentration and lipid profile (triglyceride, HDL Cholesterol, LDL Cholesterol and Total Cholesterol), fasting blood glucose (FBG), and free fatty acid (FFA) changes. Twenty eight male teen soccer players from Ahvaz-Iran, were divided in three groups (group CafPlc, caffeine (6 mg/kg/day) + dextrose; group CafCar, caffeine (6 mg/kg/day) + carnitine (2g); and group Plc, dextrose). Results: Caffeine-carnitine had a lowering effect on BW (P=0.02) and BF% (P=0.03), compared to caffeine alone and placebo in male teen soccer players (mean age of 16.92 ± 0.76 years). TG was significantly decreased in CafCar (P=0.04). FFA levels were increased in CafCar (P=0.04) and there was significant differences between CafCar and Plc groups (P=0.01). FBG was increased in both CafPlc and CafCar (P=0.01 and P=0.02, respectively), with no significant differences between groups. Conclusion: The synergistic effect of caffeine-carnitine might be suggested to decrease the BF% and BW, besides it may prevent the increment of FFA levels; however it should be prescribed cautiously since it increased FBG levels.

Potential Role of Caffeine in the Treatment of Parkinson's Disease.

Parkinson’s disease [PD] is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from both in vivo and in vitro studies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2A receptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.

Effect of caffeine and retinoic acid on skeleton of mice embryos

The present study was conducted to evaluate the effect of caffeine and retinoic acid either separately or in combination on the skeleton of the developing embryos of mice. Pregnant females were treated with either caffeine or retinoic acid at the onset of organogenesis (7th day of gestation). At morphological level no abnormalities in either caffeine or retinoic acid in the developing embryos at 14th day of gestation whose mothers’ were administered caffeine (2mg/100g b.w.) or those of the mothers’ treated with retinoic acid up to 4mg/kg b.w. during the onset of the second trimester of pregnancy were observed. However, dose-dependent retinoic acid treatment initiates chondrocyte vacuolation, depression of PAS+ve intracellular inclusions and depression of nuclear fluorescence that were concomitant with downregulation of TGFβ2 expression in the perichondrium of the developing vertebrae. Co-administration of caffeine was found to ameliorate the effects of 2mg/kg b.w. rather than 4mg/kg b.w. of retinoic acid treatment. At the 18th day of gestation the uterine horns appeared normal without any signs of fetoresorption in all treatments. However, the effect of both caffeine (2mg/100g b.w) and retinoic acid at both doses (2, 4mg/kg b.w) in Alizarin Red stain of wholemount revealed minor phalange deformation of the developing limbs either separately or in combined treatments.

Co-administration of caffeine and hydromethanolic fraction of Citrullus lanatus seeds improved testicular functions in alloxan-induced diabetic male Wistar rats

Abstract Objective To investigate the effect of Citrillus lanatus ( C. lanatus ) seeds and caffeine on blood glucose levels and testicular functions of alloxan-induced diabetic male Wistar rats. Methods Alloxan was administered at a single dose of 150 mg/kg BW to induce diabetes. A dose of either 200 mg/kg C. lanatus or 100 mg/kg caffeine or both was administered daily to alloxan-induced diabetic rats for three weeks, after which results were compared with a normal control group and a positive control group that received both alloxan and glybenclamide. Results C. lanatus seeds extract significantly decreases ( P P C. lanatus seed extract and caffeine. Conclusions The present study showed that co-administration of caffeine and hydromethanolic fraction of C. lanatus seed extract have hypoglycemic effect and may consequently ameliorate the impaired testicular general architecture and inhibits sperm death or testicular damage caused by alloxan-induced diabetes.

Co-administration of Caffeine and Hydromethanolic Fraction of Citrullus lanatus Seeds Extract Improved Heamatological and Lipid Profile of Wistar Albino Rats

Co-administration of Caffeine and Hydromethanolic Fraction of Citrullus lanatus Seeds Extract Improved Heamatological and Lipid Profile of Wistar Albino Rats

Caffeine Alters Diurnal Variation in Ethanol-Induced Ataxia in Mice

It is common among American youth to mix alcohol (ethanol) with caffeine, which is associated with high dose/ high frequency drinking patterns and much greater health risks than alcohol alone. However, few studies to date have investigated the neurobiology of drugs used in combination. Growing evidence suggests that disruption of circadian (daily, 24 h) rhythms is key to the pathophysiology of addiction, yet the underlying mechanisms are poorly understood. Several key determinants of vulnerability to alcohol addiction, such as sensitivity to intoxication, reward responsiveness, and even drinking itself, vary diurnally. Here, we investigated the effect of caffeine on ethanolinduced ataxia in mice at six 4 h intervals over the 24 h photocycle. We observed a distinct diurnal variation in ataxia caused by ethanol (1.5 g/kg), with a nadir in sensitivity occurring early in the daytime (rest-phase). Co-administration of caffeine (7.5 mg/kg) advanced this diurnal pattern and surprisingly, abolished the nadir (e.g. increased sensitivity to ethanol early in the day). Our data support the notion that there may be a circadian rhythm in ethanol-induced motor incoordination and demonstrate that the effect of caffeine on this measure is dependent upon the time of day the two drugs are administered.