Administration Of Quinine Research Articles

Co-infection malaria and HIV/AIDS: Epidemiological and clinical aspects at the Communal Medical Center (CMC) Miniere, Guinea

Objectives: to calculate the frequency of malaria and HIV co-infections, to describe the socio-demographic characteristics, to describe the clinical signs and to plan treatment. Methodology: This was a retrospective descriptive study lasting 09 months from August 01, 2019 to April 31, 2020, conducted at CMC Minière (2nd level reference structure in Guinea). We carried out an exhaustive inventory of cases according to the inclusion and non-inclusion criteria. After applying the selection procedure (inclusion and non-inclusion criteria), we obtained a sample of size N = 68 cases. Results: we recorded 68 seropositive malaria patients out of a total of 1232, i.e. a frequency of 5.52%. The epidemiological profile was that of a person in the age group of 30-34 years (26.47%), Unemployed (47.06%), out of school (54.41%) and single (75%). The reasons for consultation are dominated by fever (69.11%) and physical asthenia (50%). Patients were from their homes (92.65%). The type of malaria was severe associated with HIV1 infection (55.88%). The majority of patients had an average parasite density (10,000-50000) or 54.41% and 22.06% had a CD4 count between 200-499 cells / mm3. The antimalarial and antiretroviral treatment consisted respectively of the administration of quinine 65% and AZT + 3TC + EFV or 54.41%. N.B: AZT = Zidovudine; 3TC = Lamivudine; EFV = Efavirenz; d4T = Stavudine Conclusion: Malaria contributes to an increase in the viral load in adults with positive retroviral serology, due to the lymphopenia caused during febrile attacks. This finding suggests an emphasis on malaria in people infected with HIV.

Comparative Effects of Intragastric and Intraduodenal Administration of Quinine on the Plasma Glucose Response to a Mixed-Nutrient Drink in Healthy Men: Relations with Glucoregulatory Hormones and Gastric Emptying.

In preclinical studies, bitter compounds, including quinine, stimulate secretion of glucoregulatory hormones [e.g., glucagon-like peptide-1 (GLP-1)] and slow gastric emptying, both key determinants of postprandial glycemia. A greater density of bitter-taste receptors has been reported in the duodenum than the stomach. Thus, intraduodenal (ID) delivery may be more effective in stimulating GI functions to lower postprandial glucose. We compared effects of intragastric (IG) and ID quinine [as quinine hydrochloride (QHCl)] administration on the plasma glucose response to a mixed-nutrient drink and relations with gastric emptying, plasma C-peptide (reflecting insulin secretion), and GLP-1. Fourteen healthy men [mean±SD age: 25±3y; BMI (in kg/m2): 22.5±0.5]received, on 4 separate occasions, in double-blind, randomly assigned order, 600 mgQHCl or control, IG or ID, 60min (IG conditions) or 30min (IG conditions) before a mixed-nutrient drink. Plasma glucose (primary outcome) and hormones were measured before, and for 2 h following, the drink. Gastric emptying of the drink was measured using a 13C-acetate breath test. Data were analyzed using repeated-measures 2-way ANOVAs (factors: treatment and route of administration) to evaluate effects of QHCl alone and 3-way ANOVAs (factors: treatment, route-of-administration, and time) for responses to the drink. After QHCl alone, there were effects of treatment, but not route of administration, on C-peptide, GLP-1, and glucose (P<0.05); QHCl stimulated C-peptide and GLP-1 and lowered glucose concentrations (IG control: 4.5±0.1; IG-QHCl: 3.9±0.1; ID-control: 4.6±0.1; ID-QHCl: 4.2±0.1 mmol/L)compared with control. Postdrink, there were treatment×time interactions for glucose, C-peptide, and gastric emptying, and a treatment effect for GLP-1 (all P<0.05), but no route-of-administration effects. QHCl stimulated C-peptide and GLP-1, slowed gastric emptying, and reduced glucose (IG control: 7.2±0.3; IG-QHCl: 6.2±0.3; ID-control: 7.2±0.3; ID-QHCl: 6.4±0.4 mmol/L) compared with control. In healthy men, IG and ID quinine administration similarly lowered plasma glucose, increased plasma insulin and GLP-1, and slowed gastric emptying. These findings have potential implications for lowering blood glucose in type 2 diabetes. This study was registered as a clinical trial with the Australian New Zealand Clinical Trials at www.anzctr.org.au as ACTRN12619001269123.

Effect of oral or intragastric delivery of the bitter tastant quinine on food intake and appetite sensations: a randomised crossover trial.

Stimulation of gastrointestinal taste receptors affects eating behaviour. Intraduodenal infusion of tastants leads to increased satiation and reduced food intake, whereas intraileal infusion of tastants does not affect eating behaviour. Currently, it is unknown whether oral- or intragastric administration of tastants induces a larger effect on eating behaviour. This study investigated the effects of oral- and/or intragastric administration of quinine on food intake, appetite sensations and heart rate variability (HRV). In a blinded randomised crossover trial, thirty-two healthy volunteers participated in four interventions with a 1-week washout: oral placebo and intragastric placebo (OPGP), oral quinine and intragastric placebo (OQGP), oral placebo and intragastric quinine (OPGQ) and oral quinine and intragastric quinine (OQGQ). On test days, 150 min after a standardised breakfast, subjects ingested a capsule containing quinine or placebo and were sham-fed a mixture of quinine or placebo orally. At 50 min after intervention, subjects received an ad libitum meal to measure food intake. Visual analogue scales for appetite sensations were collected, and HRV measurements were performed at regular intervals. Oral and/or intragastric delivery of the bitter tastant quinine did not affect food intake (OPGP: 3273·6 (sem 131·8) kJ, OQGP: 3072·7 (sem 132·2) kJ, OPGQ: 3289·0 (sem 132·6) kJ and OQGQ: 3204·1 (sem 133·1) kJ, P = 0·069). Desire to eat and hunger decreased after OQGP and OPGQ compared with OPGP (P < 0·001 and P < 0·05, respectively), whereas satiation, fullness and HRV did not differ between interventions. In conclusion, sole oral sham feeding with and sole intragastric delivery of quinine decreased desire to eat and hunger, without affecting food intake, satiation, fullness or HRV.

AJP-Regulatory, Integrative and Comparative Physiology: Looking Toward the Future

<i>AJP-Regulatory, Integrative and Comparative Physiology</i>: Looking Toward the Future

Intragastric administration of the bitter tastant quinine lowers the glycemic response to a nutrient drink without slowing gastric emptying in healthy men.

The rate of gastric emptying and the release of gastrointestinal (GI) hormones are major determinants of postprandial blood-glucose concentrations and energy intake. Preclinical studies suggest that activation of GI bitter-taste receptors potently stimulates GI hormones, including glucagon-like peptide-1 (GLP-1), and thus may reduce postprandial glucose and energy intake. We evaluated the effects of intragastric quinine on the glycemic response to, and the gastric emptying of, a mixed-nutrient drink and the effects on subsequent energy intake in healthy men. The study consisted of 2 parts: part A included 15 lean men, and part B included 12 lean men (aged 26 ± 2 yr). In each part, participants received, on 3 separate occasions, in double-blind, randomized fashion, intragastric quinine (275 or 600 mg) or control, 30 min before a mixed-nutrient drink (part A) or before a buffet meal (part B). In part A, plasma glucose, insulin, glucagon, and GLP-1 concentrations were measured at baseline, after quinine alone, and for 2 h following the drink. Gastric emptying of the drink was also measured. In part B, energy intake at the buffet meal was quantified. Quinine in 600 mg (Q600) and 275 mg (Q275) doses alone stimulated insulin modestly (P < 0.05). After the drink, Q600 and Q275 reduced plasma glucose and stimulated insulin (P < 0.05), Q275 stimulated GLP-1 (P < 0.05), and Q600 tended to stimulate GLP-1 (P = 0.066) and glucagon (P = 0.073) compared with control. Quinine did not affect gastric emptying of the drink or energy intake. In conclusion, in healthy men, intragastric quinine reduces postprandial blood glucose and stimulates insulin and GLP-1 but does not slow gastric emptying or reduce energy intake under our experimental conditions.

Ingesting a Bitter Solution: The Sweet Touch to Increasing Short-Term Cycling Performance

Purpose: The authors investigated the potential benefit of ingesting 2mM of quinine (bitter tastant) on a 3000-m cycling time-trial (TT) performance. Methods: Nine well-trained male cyclists (maximal aerobic power: 386 [38]W) performed a maximal incremental cycling ergometer test, three 3000-m familiarization TTs, and four 3000-m intervention TTs (∼4min) on consecutive days. The 4 interventions were (1)25mL of placebo, (2)a 25-mL sweet solution, and (3) and (4)repeat 25mL of 2-mM quinine solutions (Bitter1 and Bitter2), 30 s before each trial. Participants self-selected their gears and were only aware of distance covered. Results: Overall mean power output for the full 3000m was similar for all 4 conditions: placebo, 348 (45)W; sweet, 355 (47)W; Bitter1, 354 (47)W; and Bitter2, 355 (48)W. However, quinine administration in Bitter1 and Bitter2 increased power output during the first kilometer by 15 ± 11W and 21 ± 10W (mean ± 90% confidence limits), respectively, over placebo, followed by a decay of 34 ± 32W during Bitter1 and Bitter2 during the second kilometer. Bitter2 also induced a 11 ± 13-W increase during the first kilometer compared with the sweet condition. Conclusions: Ingesting 2mM of quinine can improve cycling performance during the first one-third of a 3000-m TT and could be used for sporting events lasting ∼80s to potentially improve overall performance.

Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach

The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans. Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes. Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm. All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients. The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.

Intragastric quinine administration decreases hedonic eating in healthy women through peptide-mediated gut-brain signaling mechanisms

Objectives: Intragastric bitter tastants may decrease appetite and food intake. We aimed to investigate the gut-brain signaling and brain mechanisms underlying these effects.Methods: Brain responses to intragastric quinine-hydrochloride (QHCl, 10 µmol/kg) or placebo infusion were recorded using functional magnetic resonance imaging in 15 healthy women. Appetite-related sensations, plasma levels of gastrointestinal hormones and hedonic food intake (ad libitum drink test) were assessed.Results: Lower octanoylated ghrelin (P<0.04), total ghrelin (P<0.01), and motilin (P<0.01) plasma levels were found after QHCl administration, along with lower prospective food consumption ratings (P<0.02) and hedonic food intake (P<0.05). QHCl increased neural activity in the hypothalamus and hedonic (anterior insula, putamen, caudate, pallidum, amygdala, anterior cingulate cortex, orbitofrontal cortex, midbrain) regions, but decreased activity in the homeostatic medulla (all pFWE-corrected<0.05). Differential brain responses to QHCl versus placebo covaried with subjective and hormonal responses and predicted differences in hedonic food intake.Discussion: Intragastric QHCl decreases prospective and actual food intake in healthy women by interfering with homeostatic and hedonic brain circuits in a ghrelin- and motilin-mediated fashion. These findings suggest a potential of bitter tastants to reduce appetite and food intake, through the gut-brain axis.

PSIDIUM GUAJAVA L. EXTRACT INCREASES PLATELET COUNT THROUGH ENHANCEMENT OF STEM CELL FACTOR EXPRESSION IN THROMBOCYTOPENIC MICE MODEL

Objective: The purpose of this study was to determine the mechanism through which guava extract increases platelet count.Methods: Twenty male Swiss webster mice were divided into 4 group. Group I received 2.8 mg/20 g body weight of quinine and 1 ml of distilled water. Group II received 2.8 mg/20 grBW of quinine and 0.785 mg/20 grBW of guava extract. Group III received 1 ml distilled water and 0.785 mg/20 grBW of guava extract and Group IV only received 1 ml distilled water. After 14 days** treatment, platelet count was measured using Raas-Ecker method. SCF and TPO mRNA expressions in mice liver were assessed using qRT-PCR.Results: The data showed that quinine administration reduced platelet count significantly (P&lt;0.05). Psidium guajava L. extraction significantly enhanced platelet count in mice that were treated with quinine compared with quinine group (p&lt;0.05). The mechanism was analysed further and our RT PCR data showed that stem cell factor mRNA expression significant increased (p&lt;0.05) in quinine plus guava extract group compared to quinine group.Conclusion: It indicated guava extract role in increasing megakaryopoiesis which resulted in an increase of platelet count.

&lt;i&gt;In vitro&lt;/i&gt; study of interaction between quinine and &lt;i&gt;Garcinia kola&lt;/i&gt;

Purpose : To investigate the interaction between quinine and Garcinia kola using an in vitro adsorption study. Methods : In vitro interaction between quinine and G. kola was conducted at 37 ± 0.1 °C. Adsorption of quinine (2.5 - 40 μg/ml) to 2.5 % w/v G. kola suspension was studied. Thereafter, quinine desorption process was investigated. The amount of quinine adsorbed and desorbed was quantified using HPLC. A Freundlich isotherm was constructed to describe the resulting data and percentage of quinine desorbed was determined from the desorption data. Results : An adsorption isotherm of the data gave a Freundlich constant (K) of 52.66 μg/g, with a slope of 0.69 indicating a high capacity and affinity of G. kola to adsorb quinine at a concentration smaller than 2.41 μg/g of G. kola. However the adsorptive capacity of G. kola for quinine at 37 ± 0.1 °C appears to be a saturable process as observed from the isotherm. Quinine desorption from G. kola peaked at 1 hour (37.51 %) and decreased to a constant amount (about 35 %) over the remaining sampling time. Conclusion : Quinine is adsorbed on G. kola in vitro. This suggests that concurrent administration of quinine and G. kola should be avoided, to prevent potential drug interaction and decreased drug bioavailability. Keywords: Quinine, Garcinia kola, Adsorption, Desorption, Drug interaction

Modulation of cytochrome P450 3A4 mediated quinine metabolism in healthy volunteers by two honey samples from different floral and geographical sources

Background: Honey is widely used both for its nutritional and medicinal benefits and reports exist to suggest it may alter the disposition of conventional drugs whose metabolism is mediated by CYP3A4. The study aimed at investigating the effect of multiple dose administration of honey sourced from two different geographical zones in Nigeria, on an antimalarial, quinine and its CYP3A4 mediated metabolism. Methods: In a randomized cross-over study, twenty healthy volunteers divided into two groups A and B [A used honey (HA) from Northern and B used honey (HB) from Eastern Nigeria; n=10 respectively] received single oral doses of 600 mg quinine sulphate tablet alone and after 7 days administration of 10 ml of honey (HA or HB) twice daily. Blood samples collected at the 16 th hour following quinine administration were subjected to HPLC analysis. Results: Compared to baseline, 10 ml of honey HA significantly increased (0.86±0.22 versus 1.36±0.43) (p 0.05) (0.84±0.19 versus. 0.69±0.34) of the metabolic ratio of quinine in group B volunteers. Also, the geometric mean [95% CI: 0.63(0.45, 0.91)] of quinine metabolic ratio in the presence of honey HA alone was significantly increased (p=0.02, t-test). Conclusions: Honey sample from Northern Nigeria significantly stimulated CYP3A4-mediated quinine metabolism as reflected by an increased metabolic ratio of quinine. In conclusion some honey samples may have the potential to significantly modulate CYP3A4 activity, thus honey effects cannot be generalized.

Association between HRP-2/pLDH rapid diagnostic test band positivity and malaria-related anemia at a peripheral health facility in Western Uganda.

The detection of severe malaria in resource–constrained settings is often difficult because of requirements for laboratory infrastructure and/or clinical expertise. The aim of this study, therefore, was to explore the utility of a multiple antigen (HRP–2/pLDH) rapid diagnostic test (RDT) as a low–cost, surrogate marker of patients at high risk for complications of severe malaria. We reviewed programmatic data at a peripheral health center in Western Uganda. Available demographic and clinical data on all individuals presenting to the center who underwent an RDT for suspected malaria infection were reviewed. We fit logistic regression models to identify correlates of two outcomes of interest: 1) severe malaria–related anemia, defined here as hemoglobin ≤7g/dL and 2) receipt of parenteral quinine. 1509 patients underwent malaria testing with an SD FK60 RDT during the observation period. A total of 637 (42%) RDTs were positive for at least one species of malaria, of which 326 (51%) exhibited a single HRP–2 band and 307 (48%) exhibited both HRP–2 and pLDH bands, while 4 exhibited only a single pLDH band. There was a trend towards more severe anemia in patients with a HRP–2/pLDH positive RDT compared to a HRP–2 only RDT (β = –0.99 g/dl, 95% CI –1.99 to 0.02, P = 0.055). A HRP–2/pLDH positive RDT was associated with an increased risk of severe malaria–related anemia compared to a negative RDT (adjusted odds ratio (AOR) 18.8, 95% CI 4.32 to 82.0, P < 0.001) and to a HRP–2 only RDT (AOR 2.46, 95% CI 0.75 to 8.04, P = 0.14). There was no significant association between RDT result and the administration of parenteral quinine. These results offer preliminary evidence that specific patterns of antigen positivity on RDTs could be utilized to identify patients at an increased risk for complications of severe malaria.

Influence of a Nigerian honey on CYP3A4 biotransformation of quinine in healthy volunteers.

Some studies, howbeit with conflicting reports, have suggested that consumption of honey has a potential to modulate drug metabolizing enzymes which may result in a honey-drug interaction. Numerous studies have established that honey varies in composition, influenced by the dominant floral, processing and environmental factors. Thus, variation in honey composition may be a contributing factor to the controversial results obtained. No previous drug interaction study has been carried out with any honey from Africa. CYP 3A4 is an important enzyme in drug metabolism studies as it is involved in the metabolism of over 50% of drugs in clinical use and quinine remains very relevant in malaria treatment in the tropics, and we therefore determined whether there is potential drug interaction between a Nigerian honey and quinine, a drug whose metabolism to 3-hydroxyquinine is mediated majorly by CYP3A4. In a three-phase randomized crossover study with a washout period of 2weeks between each treatment phase, ten (10) healthy volunteers received quinine sulphate tablet (600mg single dose) alone (phase 1) or after administration of 10ml of honey (Phase 2) and 20mL of honey (Phase 3) twice daily for seven (7) days. Blood samples were collected at the 16th hour post-quinine administration in each phase, and quinine and its major metabolite, 3-hydroxyquinine, were analysed using a validated HPLC method. After scheduled doses of honey, the mean metabolic ratios of quinine (3-hydroxyquinine/quinine) increased by 24·4% (with 10mL of honey) and reduced by 23·9% (with 20mL of honey) when compared to baseline. These magnitudes of alteration in the mean metabolic ratios were not significant (P>0·05; Friedman test). The geometric mean (95% CI) for the metabolic ratio of quinine before and after honey intake at the two dose levels studied was 0·82 (0·54, 1·23) and 1·29 (0·96, 1·72), respectively, and were also not significant (P=0·296 and 0·081 respectively; Student's t-test). This is a pioneer study on the effect of Nigerian/African honey on quinine metabolism. Thefindings indicated that low and high doses of honey did not significantly affect metabolism of quinine to 3-hydroxyquinine. This suggests that CYP3A4 activity is not significantly altered following low or high dose of honey, as CYP3A4 has been reported to be responsible for the conversion of quinine to 3-hydroxyquinine. In conclusion, the outcome of this study suggests that there may be no potential significant metabolic interaction between Nigerian honey and quinine administration.

Mouth rinsing and ingestion of a bitter-tasting solution increases corticomotor excitability in male competitive cyclists.

Recently, we have shown that the combination of mouth rinsing and ingesting a bitter-tasting quinine solution immediately prior to the performance of a maximal 30-s cycling sprint significantly improves mean and peak power output. This ergogenic effect was proposed to be related to the activation of the corticomotor pathway by afferent taste signals originating from bitter taste receptors in the oral cavity. The aim of the present study was to use single-pulse transcranial magnetic stimulation to investigate whether mouth rinsing and ingestion of a bitter quinine solution increases corticomotor excitability. A series of 10 motor-evoked potentials (MEPs) were recorded from the relaxed first dorsal interosseus muscle in 16 male competitive cyclists immediately before and after they rinsed their mouth for 10 s and then ingested either a 2 mM bitter quinine solution or plain water. Mean MEP amplitude was significantly increased in response to quinine administration by 16% (p < 0.05), with no evidence of a time-dependent effect over the 10 pulses. Mean MEP amplitude also increased by 10% in response to water administration (p < 0.05), though this increase was significantly smaller than the response to quinine (p < 0.05). We conclude that the activation of bitter taste receptors in the oral cavity and upper gastrointestinal tract has the capacity to increase corticomotor excitability in male competitive cyclists.

Effect of dehusked Garcinia kola seeds on the overall pharmacokinetics of quinine in healthy Nigerian volunteers.

We investigated the effect of concurrent ingestion of Garcinia kola seed on the pharmacokinetics of quinine. In a randomized crossover study, 24 healthy Nigerian volunteers were assigned into 2 groups (A and B; n = 12 per group) on the basis of G. kola dose orally ingested. Each subject received 600 mg quinine sulfate before and after ingesting 12.5 g of G. kola once daily for 7 days (group A) or 12.5 g twice daily for 6 days and once on the seventh day (group B). Blood samples were collected and analyzed for plasma quinine and its metabolite (3-hydroxyquinine) using a validated high performance liquid chromatography method. Concurrent administration of quinine with G. kola reduced quinine tmax by 48% (group A), mean Cmax by 19% and 26% in groups A and B, respectively, and slight reduction in mean AUC0- ∞ of quinine in both groups. 3-hydroxyquinine Cmax also reduced by 29% and 32%; AUC0-∞ by 13% and 9%, respectively. The point estimates of the T/R ratio of the geometric means for all Cmax obtained and only the AUC0-∞ at a higher dose of G. kola were outside the 80%-125% bioequivalence range. In conclusion, an herb-drug interaction was noted with concurrent quinine and G. kola administration.

Perinatal administration of a bitter tastant influences gene expression in chicken palate and duodenum.

Bitter taste receptors (Tas2rs) and downstream effectors are responsible for mediating bitterness perception and regulation of food choice in mammals. Using RT-PCR, we demonstrated the expression of three Tas2rs and taste signal transduction molecules, α-gustducin, PLCβ2, and TRPM5, in the palate, tongue, and gastrointestinal tract sections in chicken. The bitter tastant quinine activates all three chicken Tas2rs in vitro as shown using calcium-imaging assays of transfected cells. Administration of quinine postnatally or perinatally (both pre- and posthatch) to chickens increased the expression of Tas2r genes in the palate by 6.45-fold (ggTas2r1 postnatal treatment), 4.86-fold (ggTas2r1 perinatal treatment), and 4.48-fold (ggTas2r7 postnatal treatment) compared to the genes' expression in the naı̈ve group respectively, and affected taste related gene expression in the duodenum. Whereas no-choice intake of quinine solution was not significantly lower than that of water in naı̈ve chicks, the treatment groups postnatal, prenatal, and perinatal showed significantly lower intake of quinine by 56.1, 47.7, and 50.2%, respectively, suggesting a possible trend toward sensitization. These results open new venues toward unraveling the formative stages shaping food intake and nutrition in chicken.

Aversive Stimuli Drive Drug Seeking in a State of Low Dopamine Tone

BackgroundStressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). MethodsCombining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). ResultsWe found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. ConclusionsThese data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity.

China rubra for side-effects of quinine: a prospective, randomised study in pregnant women with malaria in Cotonou, Benin

In endemic areas, gestational malaria is responsible for low birth weight and maternal anaemia. Quinine is the reference treatment for acute malaria in pregnant women, irrespective of term. However, quinine administration is associated with various side-effects. We evaluated the impact of the homeopathic medicine China rubra 7CH on the side-effects of quinine used as treatment for acute malaria in pregnant women in Cotonou, Benin. This prospective, comparative, randomised study was carried out between June and December 2007 in the Saint Jean-Baptiste Medical Centre, Cotonou. Women were included if they were >3 months pregnant and had a clinical diagnosis of malaria confirmed by a positive thick blood smear. The study population was divided into two groups: (i) patients who presented between the 1st and 15th of each month and who received China rubra 7CH plus quinine (China group); and (ii) patients who presented from the 16th to the end of each month and who received treatment with quinine only (Standard group). The aim was to compare the frequency of side-effects of quinine in the two groups until day 6 after the start of treatment. Neither the patients nor the care givers were blinded to study treatment. Statistical comparison of the two groups was carried out with an alpha risk fixed at 5%. 211 women were recruited: 105 received quinine plus China rubra 7CH (China group) and 106 received quinine only (Standard group). A decrease in proportion of patients presenting with side-effects was observed in the China group from day 0 to day 6 of follow-up (53.9%-23.3%) whereas the proportion of patients with side-effects in the Standard group did not change significantly (85.9% on day 0 vs. 82.5% on day 6). Ninety-six (72.4%) patients in the China group and 103 (97.2%) in the Standard group reported at least one side-effect during follow-up (p < 0.0001). The most frequently reported side-effects were tinnitus, dizziness and asthenia. This preliminary study shows the interest of China rubra 7CH in limiting the side-effects of quinine used for the treatment of acute malaria in pregnant women.

Decreased fast ripples in the hippocampus of rats with spontaneous recurrent seizures treated with carbenoxolone and quinine.

Background. In models of temporal lobe epilepsy and in patients with this pathology, high frequency oscillations called fast ripples (FRs, 250–600 Hz) can be observed. FRs are considered potential biomarkers for epilepsy and, in the light of many in vitro and in silico studies, we thought that electrical synapses mediated by gap junctions might possibly modulate FRs in vivo. Methods. Animals with spontaneous recurrent seizures induced by pilocarpine administration were implanted with movable microelectrodes in the right anterior and posterior hippocampus to evaluate the effects of gap junction blockers administered in the entorhinal cortex. The effects of carbenoxolone (50 nmoles) and quinine (35 pmoles) on the mean number of spontaneous FR events (occurrence of FRs), as well as on the mean number of oscillation cycles per FR event and their frequency, were assessed using a specific algorithm to analyze FRs in intracranial EEG recordings. Results. We found that these gap junction blockers decreased the mean number of FRs and the mean number of oscillation cycles per FR event in the hippocampus, both during and at different times after carbenoxolone and quinine administration. Conclusion. These data suggest that FRs may be modulated by gap junctions, although additional experiments in vivo will be necessary to determine the precise role of gap junctions in this pathological activity associated with epileptogenesis.

In vitro and in vivo evaluation of quinine in gilthead sea bream, Sparus aurata naturally infected with the ciliate Cryptocaryon irritans

The use of quinine as a potential antiparasitic compound was evaluated at cellular level and in naturally infected gilthead sea bream, Sparus aurata with the ciliate Cryptocaryon irritans. Quinine concentrations up to 10μg/ml (30μΜ) did not exhibit any in vitro hemolytic or pro-apoptotic effects on red blood cells or head kidney macrophages, respectively. Dietary administration of quinine in gilthead sea bream at a concentration of 100mg/kg fish for 10days was incomplete due to palatability problems after the fifth day post treatment. A decreasing distribution profile of quinine was evident in the analyzed tissues even during the period where quinine consumption was supposedly ensured. The highest concentrations were measured on day 1 reaching 8.98±3.85μg/ml (27μΜ), 1.33±0.45μg/g and 0.75±0.48μg/g in plasma, skin and gills respectively. Quinine was rapidly removed from the tissue compartment while it remained at low concentration in fish circulation after therapy. A 100% C. irritans prevalence was accompanied with no mortalities during the experiment. Parasitic intensity, measured as trophont number, was significantly reduced in quinine-treated fish at the first sampling point (3rd day: 8±0.8 vs 11±2.6), while no statistical differences were observed thereafter. A significant reduction in plasma glucose level was also observed at the same time point. Organoleptic evaluation in fillets, showed no difference in the flesh bitterness between quinine-treated and control fish.In conclusion, quinine has no cytotoxic effect on the assessed fish cells and is adequately absorbed in circulation, affecting the glycemic level but its distribution to the targeted tissues by the ciliate tissues is relatively small. Quinine significantly reduced C. irritans' intensity in lightly-infected gilthead sea bream. The sensory attributes of quinine-treated fish are not affected by the treatment.