Course Of Quinine Research Articles

Efficacy of 3-day low dose quinine plus clindamycin versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children (CLINDAQUINE): an open-label randomized trial

BackgroundThe World Health Organization recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available. The efficacy of quinine plus clindamycin was compared with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age.MethodsAn open-label, phase 3, randomized trial was conducted in western Kenya. Children aged 6–59 months with uncomplicated falciparum malaria were randomly assigned (1:1) via a computer-generated randomization list to receive 3 days of twice a day treatment with either oral quinine (20 mg/kg/day) plus clindamycin (20 mg/kg/day) or artemether-lumefantrine (artemether 20 mg, lumefantrine 120 mg) as one (for those weighing 5–14 kg) or two (for those weighing 15–24 kg) tablets per dose. The primary outcome was a PCR-corrected rate of adequate clinical and parasitological response (ACPR) on day 28 in the per-protocol population.ResultsOf the 384 children enrolled, 182/192 (94.8%) receiving quinine plus clindamycin and 171/192 (89.1%) receiving artemether-lumefantrine completed the study. The PCR-corrected ACPR rate was 44.0% (80 children) in the quinine plus clindamycin group and 97.1% (166 children) in the artemether-lumefantrine group (treatment difference − 53.1%, 95% CI − 43.5% to − 62.7%). At 72 h after starting treatment, 50.3% (94 children) in the quinine plus clindamycin group were still parasitaemic compared with 0.5% (1 child) in the artemether-lumefantrine group. Three cases of severe malaria were recorded as serious adverse events in the quinine plus clindamycin group.ConclusionsThe study found no evidence to support the use of a 3-day low dose course of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective.Trial Registration: This trial is registered with the Pan-African Clinical Trials Registry, PACTR20129000419241.

Comparison of the efficacy of artesunate-amodiaquine with quinine ... clindamycin for treatment of uncomplicated falciparum malaria in children

Background Drug-resistant Plasmodium falciparum malaria is amajor contributor to increasing malaria-related morbidity andmortality. Artesunate-amodiaquine is a potential combinationtherapy that shows improved treatment efficacy. Clindamycin incombination with quinine is also a safe and effective treatmentfor multidrug-resistant P. falciparum malaria.Objectives To compare the efficacy of artesunate-amodiaquine andquinine-clindamycin combination therapies for the treatment ofuncomplicated falciparum malaria.Methods This randomized open label trial in 23 2 children agedbetween one month and 18 years old took place in MandailingNatal, North Sumatra, from August to September 2006. The AAgroup received a 3-day oral course of artesunate (4 mg/kg BWonce a day) plus amodiaquine (10 mg/kg BW once a day). TheQC group received a 3-day course of clindamycin (5 mg of base/kgBW twice a day) plus a 7-day course of quinine (10 mg of salt/kgBW orally for the first four days, then 5 mg of quinine salt/kg BWfor the next three days). We performed thin and thick peripheralblood smears on days 0, 2, 7, and 28.Results A total of 232 eligible children were enrolled but only22 7 completed the study (114 in group AA, 113 in group QC).The cure rates were lOOo/o in both groups by the second day, andthere was no recrudescence in either group. We found more sideeffects in AA group compared with in QC group, i.e., headacheand vomiting.Conclusion Artesunate-amodiaquine and quinine-clindamycincombinations showed similar efficacy for the treatment of uncomplicatedP. falciparum.

Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial

Objective To compare the effectiveness of oral quinine with that of artemether-lumefantrine in treating uncomplicated malaria in children.Design Randomised, open label effectiveness study.Setting Outpatient clinic of Uganda’s national referral hospital...

Severe Plasmodium falciparum malaria with peripheral gangrene

infection and intravenous quinine therapy was initiated (20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2–8 h three times a day, total dose 12 g). When the patient was referred to our hospital, he already had multi-organ failure: cerebral malaria, acute renal failure, respiratory failure, diff use intravascular coagulation with thrombocytopenia, and metabolic acidosis were noted. On day 3, acral discolourations of his toes (fi gure) were observed. Low fi brinogen concentration (120 mg/dL; normal 180–350 mg/dL), elevated D-dimers (3000 μg/L; normal <500 μg/L), prolonged prothrombin time (international normalised ratio value 1·3), and a persistently low platelet count (5–15×10³) suggested disseminated intravascular coagulation. Simultaneously, the patient received hydrocortisone (200 mg per day, perfusion pump) and high-dose catecholamines (norepinephrine 1 mg/h and phenylephrine 10 mg/h and fl uid) for hypovolemic shock. After a 7-day course of quinine followed by mefl oquine the patient was extubated and fully recovered from malarial disease. The tips of all toes remained gangrenous and were amputated 2 months later. Peripheral gangrene is a well described complication of severe

Short course of quinine plus a single dose of sulfadoxine/pyrimethamine for Plasmodium falciparum malaria

Quinine remains the treatment of choice in hospitalized malaria cases; however, adverse reactions and the long treatment duration of 7 days often hamper its adequate use. Shortening the treatment by adding sulfadoxine/pyrimethamine may enhance compliance and reduce side effects. We aimed to assess the efficacy of a 3-day course of quinine plus a single dose of sulfadoxine/pyrimethamine for the treatment of non-severe hospitalized malaria cases in Lambaréné, Gabon. Fifty children aged between 2 and 7 years received quinine dihydrochloride (12 mg/kg every 12 hours for 72 hours), and then a single dose of oral SP (500 mg/25 mg tablet) was given according to weight category. The children were hospitalized for the duration of the treatment and until two consecutive blood smears were negative for malaria parasites. The follow-up period lasted 28 days. Parasites were cleared after 66 hours (SD: 15 hours) and the fever after 46 hours (SD: 24 hours). All patients evaluable by day 28 were negative for malaria parasites (100% efficacy rate, 95% CI: 0.92-1). Only two patients out of 49 had gametocytemia on days 7 and 14. There was no adverse event probably or possibly attributable to the study drugs. A very high efficacy can be reached using a 3-day course of quinine plus a single dose of sulfadoxine/pyrimethamine for the treatment of non-severe hospitalized malaria cases in our study area.

Clinical-parasitological response and in-vitro sensitivity of Plasmodium vivax to chloroquine and quinine on the western border of Thailand

This study was conducted during 2002-2004 at Mae Sot District, on the Thai-Myanmar border, an area of multidrug-resistant Plasmodium falciparum malaria. Sixty-two patients with P. vivax malaria were included in the study. All were randomized into two groups to receive a 3-day regimen of chloroquine or a 3-day regimen of quinine. Primaquine was given to patients in both groups for the elimination of hepatic stages. Results from the present study suggest that the standard regimen of chloroquine and a 3-day course of quinine at the dose regimens under investigation were very effective and well tolerated for the treatment of P. vivax malaria in this area. All patients responded well to both drug regimens; the cure rates with chloroquine or quinine, when given concurrently with the tissue schizontocidal drug primaquine, were virtually 100% within 28 days of follow-up. No significant correlations between parasite clearance time (PCT) or fever clearance time (FCT) and inhibitory concentration 50 (IC50) were found. Patients who had PCT < or = 24 h and those with PCT >24 h had comparable IC50 to chloroquine (alone and plus primaquine) and quinine, as well as similar concentrations of chloroquine/desethylchloroquine (in blood) or quinine (in plasma) at the investigated time points.

EFFECTIVENESS OF QUININE MONOTHERAPY FOR THE TREATMENT OF PLASMODIUM FALCIPARUM INFECTION IN PREGNANT WOMEN IN LAMBARÉNÉ, GABON

Pregnant women participating in a longitudinal immuno-epidemiologic survey in Lambaréné, Gabon, and presenting with Plasmodium falciparum parasitemia at monthly blood smear examinations were offered treatment with oral 7-day quinine monotherapy according to national health guidelines. A total of 50 pregnant women were offered 7-day oral quinine sulfate 10 mg/kg thrice daily. Clinical examinations and laboratory tests were performed on Days 28 and 56 to assess the effectiveness of this standard regimen. By Day 28, the effectiveness of the 7-day quinine regimen was 60% (95% confidence interval: 46-72%). We conclude that a 7-day course of quinine has a poor effectiveness and that alternative treatment regimens for malaria in pregnant women should be assessed.

The role of sequential administration of sulphadoxine/pyrimethamine following quinine in the treatment of severe falciparum malaria in children

Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe falciparum malaria to shorten the course of quinine. The efficacy of SP alone in the treatment of non-severe malaria has been declining rapidly in East Africa, raising concerns of the usefulness of a shortened course of quinine followed SP. We audited the efficacy of quinine/SP in the treatment of severe malaria in Kenyan children. Children with severe falciparum malaria were treated with parenteral quinine followed by a single oral dose of SP. A clinical evaluation was performed 3 weeks later in which a blood sample was obtained for full haemogram, blood slide and analysis of the parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) codons, mutations of which are associated with resistance to SP. A total of 452 children were enrolled, of whom 374 completed the study. Fifty-two (13.9%) children were parasitaemic by 3 weeks of whom 17 (4.5%) had fever as well. The treatment failure group had a significantly higher parasitaemia (129 061 vs. 43 339; P<0.001) and haemoglobin on admission, but only admission parasitaemia independently predicted treatment failure. Those with treatment failure had a significantly lower rise in haemoglobin at 3 weeks compared with treatment successes (9.0 vs. 10.0 g/dl). Of the 76 parasite isolates collected before treatment, 40 (53%) were triple mutant DHFR-double DHPS (Tp-Db), the genotype most associated with SP resistance. Three weeks after SP treatment, the proportion of Tp-Db increased to 72% (31/43). The high treatment failure rate and proportion of parasites with Tp-Db negate the use of SP to shorten the course of quinine treatment in East Africa.

Rapid reappearance of Plasmodium falciparum after drug treatment among Senegalese adults exposed to moderate seasonal transmission.

To investigate the relationship between the entomologic inoculation rate (EIR) and time to reappearance of malaria parasites after radical treatment under moderate seasonal transmission conditions, a study was undertaken in a mesoendemic area of Senegal where malaria transmission is concentrated over an annual three-month period and averages 12 infective bites per person per year. A three-day course of quinine was administered to 48 asymptomatic adults between 19 and 66 years of age. Malaria transmission and parasitemia were monitored every week for two months and cases of fever or symptoms were investigated as part of a daily clinical surveillance. The proportion of persons reinfected at Days 28, 35, and 56 was 25%, 38%, and 54%, respectively. Adults less than 40 years of age had a shorter time to reinfection. In this age group, the median Plasmodium falciparum reappearance time was 28 days, and it was estimated that only one infected mosquito bite was able to induce a patent infection among half of the subjects. Only 8% (2 of 26) of the reinfections caused a clinical attack. These data are discussed in the light of previous studies conducted among adults naturally exposed to intense perennial transmission or among naive volunteers receiving artificial challenges. Rapid reinfection occurs at very low EIRs and dramatic differences in actual and cumulated exposure to infected mosquito bites poorly affect the median time to reappearance of malaria parasites in endemic populations.

Clinical Characteristics of Neonatal Malaria

The clinical characteristics of 16 neonates with malaria parasitaemia diagnosed on Giemsa stained smears were documented during a 3-month rainy season period in a tropical African city. The prevalence of neonatal malaria was 8 per cent. Seventy-five per cent of these neonates had congenital malaria, 13 per cent transfusional malaria, and 13 per cent had acquired malaria. Plasmodium falciparum was found in all positive smears. Bacterial cultures of blood, urine, and cerebrospinal fluid were sterile. The predominant clinical features were those of fever (88 per cent), respiratory distress (57 per cent), pallor and anaemia (38 per cent each), hepatomegaly (31 per cent), and jaundice and diarrhoea (25 per cent each). Twenty-five per cent of the neonates were resistant to chloroquine sulphate; 19 per cent of the chloroquine resistant babies were also resistant to quinine sulphate 13 per cent of whom responded to halofantrine hydrochloride. One died a day after completing a full course of quinine, with a post-mortem blood smear showing no change in the density of parasitaemia.

Drug susceptibility of Plasmodium falciparum in the western Amazon region, state of Acre, Brazil

Field studies in the western Amazon region (state of Acre, Brazil) indicate that the 4-aminoquinolines, as well as the combined regimen with sulfadoxine-pyrimethamine, can no longer be recommended for the treatment and prophylaxis of P. falciparum infections in this region. Quinine remains an effective drug when used correctly. However, compliance problems arise due to the often occurring side-effects during a ten day regimen. Prospects of overcoming these constraints by combining a short course of quinine with other drugs are limited, because of the lack of suitable partner compounds. For this reason quinine/clindamycin appears to be a more practical therapy of P. falciparum malaria. In vitro data from this study suggest that mefloquine is another effective alternative for the treatment of falciparum malaria in this Amazon region.

Changes in the H-reflex during a preparatory brain potential in hemiparetics with a focal ischaemic brain lesion

1.One hundred and five cases of general paralysis were inoculated subcutaneously (very rarely intravenously) with malaria—ninety-eight with simple tertian, six with quartan, and one with malignant tertian. Information is given regarding the incubation period and character of the fever, and the mode and result of treatment.2.During the last twenty months a strain of P. vivax has been transmitted by direct subcutaneous inoculation through twenty-three passages involving seventy cases. This procedure has apparently not been attended by any change in the parasite.3.Forty-one cases of general paralysis were infected with P. vivax by the bites of infective Anopheles. Information is given regarding the incubation period, and the mode and result of treatment.4.Both A. maculipennis and A. bifurcatus were used for this purpose and proved equally susceptible to infection with P. vivax, and equally capable of transmitting the parasite to man.5.Evidence is adduced which, in our opinion, renders the unicity hypothesis of the malaria parasites of man untenable.6.The malaria infections, whether induced by inoculation of virulent blood or by the mosquito, proved extraordinarily susceptible to treatment, a short course of quinine, grs. 30 for three consecutive days, being sufficient to sterilise the infection in sixty of sixty-one inoculated cases and in twenty-seven of thirty-one mosquito-infected cases. These successes are contrasted with the frequent failures obtained in the treatment of simple tertian malaria during the war and in ordinary practice.7.Various hypotheses which have been advanced to explain the susceptibility of the induced malaria to treatment are considered, and found to be unsatisfactory.8.Evidence is produced to show that the susceptibility to treatment in the induced malaria is bound up with the fact that in these cases one is concerned with the treatment of primary infections.9.The mechanism by which a cure is obtained in malaria is considered at length, and the conclusion reached that the essential factor for the production of cures is the capacity of the host to produce immune-body in response to antigen formation, resulting from the destruction of a considerable number of parasites by a medicament. If, for any reason, the immune-body formation is insufficient, the infection is not sterilised and a relapse occurs.10.The failure of treatment in chronic relapse cases is explicable on the same hypothesis; the parasites in such cases are not quinine resistant, but immune-body resistant.11.Observations on the value of quinine prophylaxis showed that administration of the drug before infection is useless; that its administration must be continued for at least ten days after the infecting feed, to prevent infection from developing; and that the daily dose given has but little influence apart from the fact that with very large doses (30 grains) the period for which the drug has to be given to prevent development of infection is a little shortened. It is concluded from these observations that quinine has little, if any, action on sporozoites, and that the mechanism by which development of infection is prevented is similar to that by which a cure is effected.12.So far as can be judged at present, the results obtained with the malaria treatment of general paralysis are most satisfactory. Of the eighty-four paretics, who have been observed for a sufficient time after treatment to warrant any conclusion, twenty-three (27·4 per cent.) have been, or are about to be, discharged as provisionally cured, seventeen (20·2 per cent.) have showed distinct mental and great physical improvement, and many of the remainder have improved physically.

QUINIDINE IN FALCIPARUM MALARIA

Fourteen patients with falciparum malaria were successfully treated with oral quinidine. Twelve of these patients were followed for 35 days without recrudescence. In six patients the infection had already recrudesced after antimalarial treatment, which in two cases had included a full course of quinine. Quinidine caused no cardiotoxicity, although the electrocardiogram QTc interval was prolonged by more than 25% in four patients. In-vitro cultures from nine of these patients and a further seven patients with falciparum malaria showed that the minimum inhibitory concentration was consistently lower for quinidine than for quinine. Quinidine is an effective antimalarial drug for Plasmodium falciparum infections and may be more potent than quinine.

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.

Tetracycline Treatment of Chloroquine-Resistant Falciparum Malaria in Thailand

Tetracycline hydrochloride was evaluated in asymptomatic and acutely ill subjects naturally infected with chloroquine resistant strains of<i>Plasmodium falciparum</i>. Sixteen asymptomatic subjects of whom eight had recently experienced chloroquine treatment failures received 250 mg of tetracycline hydrochloride, four times daily for ten days. A presumptive radical cure was demonstrated in 12. In the other four, treatment was discontinued within 72 hours because of symptomatic development. Acutely ill subjects were assigned to one of two treatment groups. One group received 640 mg of quinine sulfate, three times daily for three days, followed by 250 mg of tetracycline hydrochloride, four times daily for ten days. The other group received a similar course of quinine followed by a conventional course of chloroquine. A presumptive radical cure was demonstrated in 29 of 30 treated with the quinine-tetracycline regimen, and in 15 of 36 treated with the quinine-chloroquine regimen.

Minocycline and tetracycline treatment of acute falciparum malaria in Thailand.

Abstract The purpose of this study was to evalute the antimalarial action of a new tetracycline analogue, minocycline, which is more potent and has a broader antibacterial spectrum than tetracycline. The study was conducted in an area endemic for chloroquine-resistant falciparum malaria. Acutely ill residents infected with P. falciparum were alternately assigned to one of two treatment groups. Subjects in one group were given 540 mg of quinine base, thrice daily for 3 days followed by 100 mg of minocycline, twice daily for 7 days. Subjects in the other group were given a similar course of quinine followed by 250 mg of tetracycline, 4 times daily for 10 days. Presumptive radical cures were achieved in all 29 patients treated with quinine-tetracycline and in 27 of 28 treated with quinine-minocycline. No significant toxic side-effects were observed. Although both treatments were highly effective, further studies are warranted to determine the optimal duration and dosage of minocycline and its potential human toxicity.

Quinine, pyrimethamine, and sulphorthodimethoxine: clinical response, plasma levels, and urinary excretion during the initial attack of naturally acquired falciparum malaria.

Plasma concentrations and urinary excretion rates of antimalarial drugs were studied during acute illness in 15 patients with naturally acquired falciparum malaria despite chloroquine‐primaquine prophylaxis. The therapeutic regimen included single oral doses of sulphorthodimethoxine and pyrimethamine in combination with a 14 day course of quinine. The plasma half‐life of a 1 Gm. dose of sulphorthodimethoxine was 200 hours with levels exceeding 8 mg. per 100 ml. for 4 days. Plasma‐pyrimethamine concentrations remained relatively stable during the 14 day study. For both drugs a slow rate of urinary elimination accounts for sustained plasma levels following single doses. Doses of 650 mg. of quinine every 8 hours produced mean plasma levels in excess of 11 mg. per liter during the first 5 days. Thereafter the concentration gradually declined to levels observed in patients receiving quinine during relapse and experimental infections. Transient hepatic dysfunction during the acute phase of the illness may account for the initial elevation and subsequent decline during continued administration. In all patients the clinical illness was promptly controlled and no toxicity developed. There were no relapses. The advantages of single‐dose oral therapy, the promising clinical results, and low incidence of toxicity suggest that sulphorthodimethoxine may be an important antimalarial drug and that further clinical and pharmacological investigation is warranted.

Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine.

Summary The first of two patients with Plasmodium falciparum infections which failed to respond to chloroquine therapy administered in Colombia, South America, received three further courses of 1.5 g of chloroquine and experienced clinical and parasitic relapses 12 and 8 days, respectively, after the first two courses. Upon the completion of the third course the drug was continued for 14 more days at a dosage of 0.3 g daily. Blood smears remained positive during this period. A 3-day course of quinine sulphate (90 grains) produced negative blood smears, but a parasitic relapse occurred after 17 days. An apparent cure was effected by a 10-day course of quinine. The second patient experienced a clinical and parasitic relapse approximately 20 days after a first course of chloroquine; and after a second course (2.1 g) followed by a 14-day course of primaquine, a recurrence of parasitemia accompanied by minor symptoms approximately 21 days after the completion of the chloroquine therapy was observed. A 10-day course of quinine produced an apparent cure.

Clinico-Pathological Conference

Dr. Smith (reading the clinical summary): A fifty-one-year-old white grocery salesman was admitted because of fever of six weeks' duration. The patient's general health had been good until the present illness. He had Cuban fever in 1899, which lasted for two or three weeks. He had two penile sores at the age of seventeen, with bilateral enlargement of the inguinal nodes. Concomitantly he had pain on urination and urethral discharge. He was treated with iodides, mercurials, and intraurethral medication, and recovered in a few weeks without sequelae. Blood Wassermann tests made thirty and fifteen years before admission were reported negative. Four months before entry the patient began to feel generally below par and slightly feverish, with a few chilly sensations. Thinking he had malaria, he gave himself a course of atabrine, following which his skin turned yellow. Subsequently he visited his physician, who gave him a course of quinine, without improvement in his symptoms. About six weeks before admission, ...

RECURRENCE OF INOCULATION MALARIA

It is generally thought that tertian malaria transmitted by direct blood inoculation is easily cured by quinine. According to James,1clinically there is a striking difference between the two classes in that true (long interval) relapses and recurrences are not observed (so far as we can ascertain) in inoculated cases, while they occur in 50 per cent of mosquito infected cases. He adds that blood inoculated cases are cured by a single short course of quinine. Yorke2concurs in this view, saying it is an established fact that two or three doses of quinine almost invariably suffice definitely to cure the inoculated case. Wagner-Jauregg3relates that in Vienna, where more than 6,000 patients have been treated, no case of recidivation has been noted. He considers 5 Gm. of quinine, given in the course of a week, sufficient to cure the disease. Although few in number, recurrences have