Simple treatment for chronic female infections

A prospective, double-blind, placebo-controlled crossover study of the use of quinine for nocturnal leg cramps was carried out in 8 elderly volunteer patients. The patients were randomly assigned to receive either placebo or 200 mg of quinine sulfate by mouth at bedtime. After 4 weeks of treatment and after a one-week washout period, the group taking quinine switched to placebo and vice versa for another 4 weeks. The differences in the number, duration, and severity of cramps and the side effects were compared. All of the patients had fewer cramps and decreased severity and duration of attacks while receiving quinine. Mild side effects developed in only 2 patients, and these subsided without treatment or discontinuing the medication. We conclude that quinine was effective in relieving nocturnal leg cramps in a selected group of elderly patients.     

Meta-analysis of efficacy of quinine for treatment of nocturnal leg cramps in elderly people.

OBJECTIVE--To assess quantitatively the efficacy of quinine (as quinine sulphate) compared with placebo in the treatment of nocturnal leg cramps. DESIGN--A meta-analysis of six randomised, double blind, crossover trials. SETTING--Randomised trials that were available as of April 1994. SUBJECTS--A total of 107 general ambulatory patients who suffered from regular nocturnal leg cramps from six clinical trials. RESULTS--Data from individual patients were used to calculate point estimates and 95% confidence intervals for each of the outcome measures reported by these studies. Treatment with quinine resulted in a significant reduction in the number of cramps for a four week period compared with placebo (8.83 fewer cramps; 95% confidence interval 4.16 to 13.49). Treatment with quinine reduced the number of nights with cramps by 27.4% (24.0% to 30.8%) compared with placebo. Treatment did not produce a significant change in the severity or duration of individual nocturnal leg cramps. Side effects were uncommon. CONCLUSIONS--The results indicate that quinine can prevent nocturnal leg cramps in general ambulatory populations. Given the possible serious side effects of treatment with quinine, the benefits and risks in patients taking this drug should be closely monitored.     

Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.     

A quinine-activated cationic conductance in vertebrate taste receptor cells

The chincona alkaloid quinine is known to be a bitter tasting substance for various vertebrates. We examined the effects of quinine on isolated taste receptor cells from the bullfrog (Rana catesbeiana). Membrane currents were recorded by whole-cell recording, while quinine hydrochloride was applied extracellularly from a puffer pipette. At the resting potential (-77 +/- 9 mV, mean +/- SD, n = 49 cells), taste cells generated inward currents in response to quinine stimulation (> 1 mM), indicating a depolarizing response in the taste cells. Two types of current responses were observed; a newly found quinine-activated cationic conductance and a previously reported blocking effect of quinine on K+ conductances. The cationic current was isolated from the K+ current by using a Cs(+)-containing patch pipette. The relative permeabilities (Pion) of the quinine-activated cationic conductance were: PNa/PK/PCs = 1:0.5:0.42. The quinine dose-response relation was described by the Hill equation with the K1/2 of 3.6 mM and Hill coefficient of 5.3. When extracellular [Ca2+] (1.8 mM) was reduced to nominally free, the conductance was enhanced by about sixfold. This property is consistent with observations on quinine responses recorded from the gustatory nerve, in vivo. The quinine-induced cationic current was decreased with an application of 8-bromo-cAMP. We conclude that the bitter substance quinine activates a cation channel in taste receptor cells and this channel plays an important role in bitter taste transduction.     

Imported Malaria in Korea: a 13-Year Experience in a Single Center

The incidence of imported malaria has been increasing in Korea. We reviewed data retrospectively to evaluate the epidemiology, clinical features, and outcomes of imported malaria from 1995 to 2007 in a university hospital. All patients diagnosed with imported malaria were included. Imported malaria was defined as a positive smear for malaria that was acquired in a foreign country. A total of 49 patients (mean age, 35.7 year; M : F = 38 : 11) were enrolled. The predominant malarial species was Plasmodium falciparum (73.5%), and the most frequent area of acquisition was Africa (55.1%), followed by Southeast Asia (22.4%) and South Asia (18.4%). Fourteen-patients (30.6%) suffered from severe malaria caused by P. falciparum and 1 patient (2.0%) died of multiorgan failure. Most of the patients were treated with mefloquine (79.2%) or quinine (10.2%); other antimalarial agents had to be given in 13.2% treated with mefloquine and 44.4% with quinine due to adverse drug events (ADEs). P. falciparum was the most common cause of imported malaria, with the majority of cases acquired from Africa, and a significant number of patients had severe malaria. Alternative antimalarial agents with lower rates of ADEs might be considered for effective treatment instead of mefloquine and quinine.     

Antimalarial drug susceptibility testing of Plasmodium falciparum in Brazil using a radioisotope method

From March 1996 to August 1997, a study was carried out in a malaria endemic area of the Brazilian Amazon region. In vivo sensitivity evaluation to antimalarial drugs was performed in 129 patients. Blood samples (0.5 ml) were drawn from each patient and cryopreserved to proceed to in vitro studies. In vitro sensitivity evaluation performed using a radioisotope method was carried out with the cryopreserved samples from September to December 1997. Thirty-one samples were tested for chloroquine, mefloquine, halofantrine, quinine, arteether and atovaquone. Resistance was evidenced in 96.6% (29/30) of the samples tested for chloroquine, 3. 3% (1/30) for quinine, none (0/30) for mefloquine and none for halofantrine (0/30). Overall low sensitivity was evidenced in 10% of the samples tested for quinine, 22.5% tested for halofantrine and in 20% tested for mefloquine. Means of IC 50 values were 132.2 (SD: 46. 5) ng/ml for chloroquine, 130.6 (SD: 49.6) ng/ml for quinine, 3.4 (SD: 1.3) ng/ml for mefloquine, 0.7 (SD: 0.3) ng/ml for halofantrine, 1 (SD: 0.6) ng/ml for arteether and 0.4 (SD: 0.2) ng/ml for atovaquone. Means of chloroquine IC 50 of the tested samples were comparable to that of the chloroquine-resistant strain W2 (137.57 ng/ml) and nearly nine times higher than that of the chloroquine-sensitive strain D6 (15.09 ng/ml). Means of quinine IC 50 of the tested samples were 1.7 times higher than that of the low sensitivity strain W2 (74.84 ng/ml) and nearly five times higher than that of the quinine-sensitive strain D6 (27.53 ng/ml). These results disclose in vitro high resistance levels to chloroquine, low sensitivity to quinine and evidence of decreasing sensitivity to mefloquine and halofantrine in the area under evaluation.     

Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria.

Patients with falciparum malaria were studied in Thailand, an area of known chloroquine resistance. The patients were unselected and some had severe malaria, and they were randomly assigned to one of two sequential regimes. A short course of quinine (average 4 doses, equivalent to 2 g base) followed by a single dose of pyrimethamine-sulfadoxine (Fansidar) cured 92% of patients (36 out of 39), while a short course of quinine followed by a single 1-5-dose of mefloquine cured all of the 35 patients who could be followed up. Gastrointestinal side effects were minimal if at least 12 hours elapsed between the last dose of quinine and the mefloquine. Sequential quinine and mefloquine is the most effective treatment for patients with chloroquine-resistant falciparum malaria, including those with severe or complicated disease. Mefloquine, however, is not commercially available, and the similar regimen using Fansidar is almost as effective.     

Synthesis and biological activity of fatty acid derivatives of quinine

Derivatives of quinine with fatty acids including polyunsaturated fatty acids were prepared. They showed moderate antimalarial activity as compared with quinine itself using Plasmodium falciparum. The activities were not dependent on whether the fatty acyl group was saturated or unsaturated. On the other hand, the derivatives showed significantly higher cytotoxicity against a mammary tumor cell line FM3A than quinine itself. Calculating from these data, an acetyl derivative of quinine with the shortest acyl group was found to give the highest selectivity.     

Efficacy of quinine against ichthyophthiriasis in common carp Cyprinus carpio

Ichthyophthiriasis, caused by Ichthyophthirius multifiliis, is an economically important worldwide parasitic disease that infects all freshwater fish. Since the banning of malachite green for use in food fish, there has been a great need for alternative therapeutants. The goal of this study was to investigate the efficacy of quinine against I. multifiliis. Parasite developmental stages from our laboratory-established life cycle in rainbow trout Oncorhynchus mykiss were exposed to quinine in vitro, and a dual fluorescent staining technique was used to allow a clear distinction between viable and damaged parasites. Furthermore, the effect of quinine was assessed in vivo by oral administration and intraperitoneal injections in common carp Cyprinus carpio. The results of the in vitro experiments proved quinine to be effective against the parasite. Quinine injected at a dosage of 60 mg kg(-1) body weight resulted in a significantly lower number of trophonts. In contrast, in-feed trials did not show a significant reduction of trophonts after treatment commencing 1 d after infection with concentrations of up to 20 g quinine kg(-1) feed for 3 d. After a 14-d treatment at concentrations of up to 10 g quinine kg(-1) feed prior to theront exposure, there was also no significant difference in parasite numbers between treated and control groups. The results of oral versus parenteral application of quinine indicate that the substance is not completely absorbed from the intestinal tract of common carp. However, medicated feed containing higher concentrations of quinine was less readily accepted by the fish, presumably due to the bitter taste.     

Synthesis and Biological Activity of Fatty Acid Derivatives of Quinine

Derivatives of quinine with fatty acids including polyunsaturated fatty acids were prepared. They showed moderate antimalarial activity as compared with quinine itself using Plasmodium falciparum. The activities were not dependent on whether the fatty acyl group was saturated or unsaturated. On the other hand, the derivatives showed significantly higher cytotoxicity against a mammary tumor cell line FM3A than quinine itself. Calculating from these data, an acetyl derivative of quinine with the shortest acyl group was found to give the highest selectivity.     

Citric acid and quinine share perceived chemosensory features making oral discrimination difficult in C57BL/6J mice

Evidence in the literature shows that in rodents, some taste-responsive neurons respond to both quinine and acid stimuli. Also, under certain circumstances, rodents display some degree of difficulty in discriminating quinine and acid stimuli. Here, C57BL/6J mice were trained and tested in a 2-response operant discrimination task. Mice had severe difficulty discriminating citric acid from quinine and 6-n-propylthiouracil (PROP) with performance slightly, but significantly, above chance. In contrast, mice were able to competently discriminate sucrose from citric acid, NaCl, quinine, and PROP. In another experiment, mice that were conditioned to avoid quinine by pairings with LiCl injections subsequently suppressed licking responses to quinine and citric acid but not to NaCl or sucrose in a brief-access test, relative to NaCl-injected control animals. However, mice that were conditioned to avoid citric acid did not display cross-generalization to quinine. These mice significantly suppressed licking only to citric acid, and to a much lesser extent NaCl, compared with controls. Collectively, the findings from these experiments suggest that in mice, citric acid and quinine share chemosensory features making discrimination difficult but are not perceptually identical.     

High incidence of hypoglycaemia in African patients treated with intravenous quinine for severe malaria.

Changes in plasma glucose and insulin concentrations were monitored over 24 hours in 28 African patients receiving quinine intravenously in an average dose of 8.5 mg base/kg over one hour eight hourly for severe malaria. The patients (nine children and 19 adults) were moderately undernourished; none was pregnant or had renal insufficiency. Plasma insulin concentrations rose during the infusion and then declined. Plasma glucose concentrations were decreased at two, three, and four hours after the start of the infusion. Insulin: glucose ratios were raised between half an hour and two hours after the start of the infusion. The three infusions of quinine increased plasma insulin concentrations in a similar way. In nine patients, including four children, plasma glucose concentrations fell below 2.8 mmol/l on one or two occasions. At the time of the hypoglycaemia plasma insulin concentrations were inappropriately high as shown by a consistent and often considerable increase in the insulin:glucose ratio. Hypoglycaemia that may pass unnoticed in comatose patients is thus a common complication of treating severe malaria with quinine, in particular in children. Its high incidence calls for attentive monitoring and preventive measures.     

RELATIONSHIP BETWEEN TASTE AND CHEWING PATTERNS OF VISCO-ELASTIC MODEL FOODS

The jaw movements and muscular activity of masticatory muscles of five assessors, having bitterness thresholds about 8 μM quinine in water, were monitored throughout chewing of similar strength gelatin gels containing 0, 40, 70 or 100 μM quinine. Gel bitterness ratings were not related to sensory texture which was 78kN/m² by shear test. On average, 100 μM quinine gels were as bitter as 7 to 30 μM quinine in water, depending on the assessor. Chewing patterns were not affected by concentration of quinine in the gels. During mastication of acceptable gels, there appears to be no feedback from taste to the motor control of mastication. In gels of the same consistency and the same concentration of quinine, assessors who chewed more rated higher for bitterness. The implications for mimicking mastication by machine and the training of assessors for solid foods are discussed.     

Diazepam-binding inhibitor-like activity in rat cerebrospinal fluid after stimulation by an aversive quinine taste

Cerebrospinal fluid (CSF) taken from rats after stimulation by an aversive quinine taste (hereafter called quinine CSF) administered into the fourth ventricle of mice suppressed their intake of 5% sucrose solution. We examined the effects of CSF on glutathione-induced tentacle ball formation (TBF) of hydra to determine the change in CSF components associated with aversive taste stimuli. The suppressive activity of quinine CSF on TBF in the presence of 3 microM S:-methyl-glutathione (GSM) was markedly lower than that of CSF obtained from control rats (control CSF). Pronase-treated quinine CSF had suppressive activity similar to that of control CSF. The active principle passed through an ultrafiltration membrane, with a molecular weight cut-off of 30 kDa, but not through one with a cut-off of 3 kDa. A peptide fragment of diazepam-binding inhibitor (DBI) nullified the suppression of TBF at 3 microM GSM by control CSF. The nullifying activity of quinine CSF was not observed after treatment with a benzodiazepine receptor preparation that was able to bind DBI. When flumazenil, a benzodiazepine receptor antagonist, was given to mice, the suppression of the intake of 5% sucrose solution by quinine CSF was partially reversed. It is suggested that quinine CSF contains a DBI-like substance.     

A novel action of quinine and quinidine on the membrane conductance of neurons from the vertebrate retina

The cinchona alkaloids quinine and quinidine have been shown to block a broad range of voltage-gated membrane conductances in a variety of excitable tissues. Using the whole-cell version of the patch clamp technique, we examined the effects of these compounds on voltage- dependent currents from horizontal cells dissociated enzymatically from the all-rod retina of the skate. We report here a novel and unexpected action of quinine and quinidine on isolated horizontal cells. In addition to blocking several of the voltage-activated currents of these cells, the introduction of the alkaloids evoked a large outward current when the cells were held at depolarized potentials. Using tail current analysis, the reversal potential of the outward current was close to O mV, and the current was markedly suppressed by extracellularly applied cobalt, acetate, and halothane. Depolarization in the presence of quinine also permitted entry into the cells of extracellularly applied Lucifer yellow (MW = 443 D), whereas a 3-kD fluorescein-dextran complex was excluded. These findings suggest that the large, apparently nonselective conductance induced by quinine and quinidine results from the opening of hemi-gap junctional channels.     

A comparison of the actions of 4-aminopyridine, caffeine and quinine on the toad isolated rectus abdominis muscle

1. 4-Aminopyridine (4-AP)-induced contractures have been compared with those evoked by caffeine and quinine on the toad rectus abdominis muscle. 2. All three compounds produced slowly-developing sustained contractures. The time to half maximal contracture and relaxation was significantly longer for 4-AP than for caffeine or quinine. 3. Verapamil and manganese inhibited 4-AP, caffeine and quinine-induced contractures. 4. Ca2+-free-EGTA Ringer and procaine severely inhibited caffeine and quinine responses, but 4-AP contractures were relatively unaffected. 5. In depolarizing (100 mM K+) Ringer solution, caffeine and quinine responses were reduced to 6-9% of their controls. 4-AP responses were reduced by about 25%. 6. It is concluded that in the toad rectus muscle, 4-AP-induced contractures differ from those produced by caffeine and quinine, and appear to rely mainly on the release of intracellular located Ca2+, while caffeine and quinine are considered to act predominantly on plasma membrane sites.     

Differential effects of the K+ channel blockers apamin and quinine on glucose-induced electrical activity in pancreatic beta-cells from a strain of ob/ob (obese) mice

The effects of apamin and quinine on glucose-induced electrical activity in pancreatic islets from ob/ob mice (Norwich colony) were compared. Apamin (40-400 nM) increased the duration of the bursts of electrical activity, whereas quinine (50-100 microM) affected only slightly the steady-state electrical response to glucose. This sensitivity to apamin and poor response to quinine contrast with the resistance to apamin and sensitivity to quinine previously reported for pancreatic islets from albino mice. The results give further support to the idea that pancreatic beta-cells from ob/ob mice have a modified Ca2+-activated K+ permeability.     

Bitter taste stimuli induce differential neural codes in mouse brain

A growing literature suggests taste stimuli commonly classified as "bitter" induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes) was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total), including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA), presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5) were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05) to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05) from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among "bitter" stimuli, data that challenge a strict monoguesia model for the bitter quality.     

Riboflavin-binding protein is a novel bitter inhibitor

Riboflavin-binding protein (RBP) from chicken egg, which was recently reported to be a selective sweet inhibitor for protein sweeteners, was also found to be a bitter inhibitor. RBP elicited broadly tuned inhibition of various bitter substances including quinine-HCl, naringin, theobromine, caffeine, glycyl-L-phenylalanine (Gly-Phe), and denatonium benzoate, whereas several other proteins, such as ovalbumin (OVA) and beta-lactoglobulin, were ineffective in reducing bitterness of these same compounds. Both the bitter tastes of quinine and caffeine were reduced following an oral prerinse with RBP. It was found that RBP binds to quinine but not to caffeine, theobromine, naringin, and Gly-Phe. However, the binding of RBP to quinine was probably not responsible for the bitter inhibition because OVA bound to quinine as well as RBP. Based on these results, it is suggested that the bitter inhibitory effect of RBP is the consequence of its ability to interact with taste receptors rather than because it interacts with the bitter tastants themselves. RBP may have practical uses in reducing bitterness of foods and pharmaceuticals. It may also prove a useful tool in studies of mechanisms of bitter taste.     

Reduction of saltiness and bitterness after a chlorhexidine rinse

Chronic rinsing with chlorhexidine, an oral-antiseptic, has been shown to decrease the saltiness of NaCl and the bitterness of quinine. The effect of acute chlorhexidine on taste has not been investigated. The purpose of the present study was to examine the effect of acute chlorhexidine rinses on taste intensity and quality of 11 stimuli representing sweet, salt, sour, bitter and savory. All stimuli were first matched for overall intensity so the effects of chlorhexidine would be directly comparable across compounds. As a control treatment, the bitter taste of chlorhexidine digluconate (0.12%) was matched in intensity to quinine HCl, which was found to cross-adapt the bitterness of chlorhexidine. Subjects participated in four experimental conditions: a pre-test, a quinine treatment, a chlorhexidine treatment, and a post-test condition, while rating total taste intensity and taste qualities in separate test sessions. Relative to the quinine treatment, chlorhexidine was found to decrease the salty taste of NaCl, KCl and NH4Cl, and not to significantly affect the tastes of sucrose, monosodium glutamate (MSG), citric acid, HCl and the taste of water. The bitter taste of urea, sucrose octa-acetate and quinine were suppressed after chlorhexidine rinses relative to water rinses, but were only marginally suppressed relative to quinine rinses. Potential mechanisms are discussed.