Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases

Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.

Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

Inyecciones intravenosas de Quinina / Intravenous injections of Quinine

En el n ̇mero 30 de la Prensa Médica, correspondiente al 31 de mayo del corriente año, he leído un artículo de los doctores E. Jeanselme y A. Manaud con el mote: Técnica de las inyecciones intravenosas de quinina, en el cual demuestran, con algunas observaciones que publican, que las inyecciones intravenosas de clorhidrato básico de quinina, en soluciones al 2 por 100, son mal toleradas por las paredes venosas; provocan induraciones en ellas, dolores a lo largo de su trayecto y equimosis en los sitios correspondientes: verdaderas flebitis, resultado de la acción castica de las sales de quinina paralas paredes venosas. Aconsejan, como resumen de este importante trabajo y para evitar estos inconvenientes, diluir las soluciones al 1 por 100, emplearlas tibias e inyectarlas muy lentamente: de esta manera se atenuan estos inconvenientes, se producen menos induraciones venosas o ms tardías en su aparición y menos acentuadas, aunque es verdad que siempre se producen con el uso del clorhidrato básico, lo cual no acontece cuando se inyecta biclorhidrato de quinina y en soluciones al 1 por 100. Enfermos que habían pre-sentado induraciones consecutivas a inyecciones de clorhidrato de quinina básico al 1 por 100, se les ha puesto también inyecciones de biclorhidrato de quinina al mismo grado de concentración en las venas del otro brazo, sin haber presentado ninguna reacción flebÌtica. Pero si la solución de biclorhidrato de quinina se emplea en lugar del 1 por 100 al 1/50, se producen también induraciones venosas con esta otra sal de quinina, aunque menos marcadas, eso sí, que con las inyecciones de clorhidrato básico.

Relationship between plasma and red blood cell concentrations of quinine in Brazilian children with uncomplicated Plasmodium falciparum malaria on oral therapy / Relação entre as concentrações plasmáticas e eritrocitárias de quinina em crianças com malária por Plasmodium falciparum não complicada em terapia via oral

We determined the relationship between plasma and red blood cell concentrations of quinine in children with uncomplicated falciparum malaria from an endemic area of Amazonian region. Quinine was determined by high performance liquid chromatography with ultraviolet detection. In the steady state the ratio between plasma and red blood cell quinine concentration was 1.89 ± 1.25 ranging from 1.05 to 2.34. This result demonstrated that quinine do not concentrate in red blood cell of Brazilian children and characterize the absence of interracial difference in this relationship.

Neste estudo foi determinada a relação entre as concentrações plasmáticas e eritrocitárias de quinina em crianças com malária falciparum não complicada, oriundas de área endêmica da Região Amazônica. A quinina foi detrminada por cromatografia líquida de alta eficiência. No estado de equilíbrio, a relação foi 1,89 ± 1,25 variando de 1,05 a 2,34. Estes resultados demonstraram que a quinina não se concentra nos eritrócitos das crianças e caracterizaram a ausência de diferença racial nesta relação.

Symmetric peripheral gangrene of the lower limbs in a case of complicated falciparum malaria.

Association of symmetric peripheral gangrene (SPG) with falciparum malaria infection is a relatively uncommon clinical entity. Here we report a case of complicated falciparum malaria with SPG involving both lower limbs from the mid-calf downwards, probably due to antibody mediated vasculitis.

Purpura fulminans in a complicated Falciparum malaria.

A 19-year-old male presented with fever, oliguria and purpuric lesions involving both hands. The patient was diagnosed as a case of purpura fulminans with disseminated intravascular coagulation due to complicated Falciparum malaria. The case is presented to sensitize the physicians to keep malaria as a differential in cases of fever with purpura fulminans.

Quinine-induced arrhythmia in a patient with severe malaria.

It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases.

Acceptability of Praneem polyherbal vaginal tablet among HIV uninfected women & their male partners in Pune, India--Phase I study.

BACKGROUND & OBJECTIVE: The number of HIV infected women is steadily increasing worldwide and women controlled methods to prevent HIV are urgently needed. Vaginal microbicides are products for vaginal administration that can be used to prevent HIV infection and other sexually transmitted diseases (STDs). We conducted a Phase I safety and acceptability study of Praneem polyherbal tablet, a candidate microbicide, among HIV uninfected women in Pune, India. METHODS: Twenty eligible women were requested to use the product intravaginally once daily for 14 consecutive days between menses. Safety was assessed by clinical examination, laboratory monitoring and colposcopy. Acceptability was assessed after 14 days of product use through structured questionnaires, focus group discussions among participating women, and in-depth interviews with a subset of 5 randomly selected male partners. RESULTS: Praneem polyherbal tablet was found acceptable by the study participants with 90 per cent of the participants showing 80 per cent and more acceptability score. Discharge of the product residue was reported as a concern by 6 (30%) of participants. Nineteen (95%) female participants liked the smell and the same number reported that the product was easy to use and did not affect the usual sexual pleasure. However, men reported lack of sexual satisfaction. INTERPRETATION & CONCLUSION: Product characteristics received good acceptability score in women. However, studies of long-term safety and acceptability among at-risk population would provide more detailed information about its long term acceptability.

Management of severe falciparum malaria.

Plasmodium falciparum is the most common cause of severe and life-threatening malaria. Falciparum malaria causes over one million deaths every year. In Africa, a vast majority of these deaths occur in children under five years of age. The presentation of severe malaria varies with age and geographical distribution. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. The management of severe malaria includes prompt administration of appropriate parenteral anti-malarial agents and early recognition and treatment of the complications. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure. In adults, renal failure and pulmonary oedema are more common causes of death. In contrast, concomitant bacterial infections occur more frequently in children and are associated with mortality in children. Admission to critical or intensive care units may help reduce the mortality, and the frequency and severity of sequelae related to severe malaria.

Low-dose quinine for treatment of chloroquine-resistant falciparum malaria in Sudanese pregnant women

Pregnant Sudanese women who presented at a hospital in eastern Sudan with chloroquine-resistant falciparum malaria were randomly allocated to one of two quinine regimens: low-dose [10 mg/kg 2 times/day] [18 patients] or st and ard [10 mg/kg 3 times/day] [24 patients]. Treatment was for 7 days and follow-up for 28 days. Significantly fewer patients in the low-dose group reported vomiting and abdominal pain than the st and ard regimen group. Hypoglycaemia, preterm labour and recrudescence were slightly but not significantly higher in patients in the st and ard group than low-dose group. There were no significant differences between the groups in the mean time from admission to remission of fever and parasite clearance. We tentatively advocate the use of quinine 2 times/day to reduce side-effects and improve compliance

Clinical experience with intravenous quinine, intramuscular artemether and intravenous artesunate for the treatment of severe malaria in Thailand.

We prospectively studied 803 Thai patients admitted to the Bangkok Hospital for Tropical Diseases to assess the safety, tolerability and effectiveness of treatments for strictly defined P. falciparum malaria. Patients were assigned to one of five treatment groups: (i) a 5-day course of intravenous artesunate in a total dose of 600 mg, Group Aiv; (ii) intravenous artesunate as in Group Aiv followed by mefloquine, 25 mg/kg, Group Aiv+M; (iii) a 3-day course of intramuscular artemether in a total dose of 480 mg, Group Aim; (iv) intramuscular artemether as in Group Aim followed by mefloquine, 25 mg/kg, Group Aim+M, and (v) intravenous quinine, 200 mg/kg given in divided doses over seven days followed by oral tetracylcine, 10 mg/kg, for 7 days. When patients could take oral medications, the parenteral antimalarials were administered as oral agents. There were no major adverse effects observed with any of the five treatment regimens. With all regimens, 95 to 100% of the patients survived. Mean parasite clearance times were more rapid with the artemisinin regimens (53 to 62 hours) than with quinine (92 hours). The mean fever clearance times with intravenous artesunate (80 to 82 hours) were about a day shorter than those with intramuscular artemether (108 hours) or intravenous quinine (107 hours). Mefloquine reduced the recrudescence rate from 24 to 5% with intravenous artesunate but from 45 to 20% with intramuscular artemether; recrudescence was 4% with quinine and tetracycline. A dose and duration of therapy greater than those in this study are needed for optimal therapy with intramuscular artemether. Effective therapy for severe falciparum malaria can be provided by either intravenous artesunate followed by mefloquine or by intravenous quinine followed by tetracycline.

Concomitant acral necrosis and haemolytic uraemic syndrome following ingestion of quinine.

Thrombotic microangiopathy, which broadly includes thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS), is a multisystemic disorder that is characterised by thrombocytopaenia, microangiopathic haemolytic anemia and ischaemic manifestations, resulting from platelet agglutination in the arterial microvasculature. Acral necrosis (distal necrosis of fingers and toes) occurs usually as a sequel to severe Raynaud's phenomenon, a vasculospastic disorder frequently related to endothelial cell dysfunction. We report a case of quinine induced TTP-HUS and acral necrosis, two distinct clinical abnormalities which have not yet been reported together in association with quinine. Both of these conditions in this case resolved promptly to treatment with corticosteroids.

Randomized trial of artesunate and mefloquine in comparison with quinine sulfate to treat P. falciparum malaria pregnant women.

To compare the effectiveness and safety of quinine sulfate and artesunate with mefloquine for treating second trimester pregnancy in women who suffered from Plasmodium falciparum malaria. The prospective study was done in Srisangwal Hospital, Mae Hong Son, Thailand. Sixty, second to third trimester pregnant patients with P. falciparum infection, were recruited at random. They received either quinine sulfate 10 mg/kg/day for at least 7 days, 29 women (group I), or oral artesunate 2 mg/kg as the first dose, 1 mg/kg every 12 hours orally for at least 5 days together with split doses of mefloquine, 15 mg/kg and 6 hours later 10 mg/kg orally 1 day after artesunate was stopped, 28 women (group II). Three cases (5%) were lost to follow-up before delivery, one case in group I and two cases in group II. After treatment, the mean hematocrit of group I was significantly less than group II (p = 0.000). The PCT (parasite clearance time) and FCT (fever clearance time) of group II were significantly shorter than group I (p = 0.000). None of the patients in both groups had recrudescences within 28 days. Group I had more adverse effects than group II. No adverse neurological effects in pregnancy were found in both groups. The calcification of placenta and IUGR (Intrauterine growth retard) were not different between the two groups (p = 0.964, 0.363 respectively). The PCT was not different between the calcified placenta group and normal placenta group (p = 0.058), but the TTPP (Total time of parasite presentation) was (p = 0.000). TTPP related to low birth weight and low apgar score at 1 minute might be the cause (p = 0.000, 0.000 F = 5.261, 21.627 respectively). TTPP and PCT related to neonatal blood pH and caused low neonatal blood pH (p = 0.000, 0.001 F = 24.351, 11.162 respectively). The physical and neurological development of the babies at 2, 4, 6 and 12 months follow-up, were normal and there were no congenital abnormalities in either group. TTPP relating to fetal outcome, the longer the TTPP, the worse the fetal outcome, so we should diagnose early and treat P. falciparum malaria in pregnancy to prevent fetal jeopardy. Artesunate with mefloquine could shorten the PCT more than quinine sulfate in pregnancy, so the fetal outcome was better than that of quinine sulfate. In cases of prolonged infection before treatment, artesunate might be the alternative treatment of P. falciparum malaria in pregnancy. However, its safety should be carefully studied further with a larger sample size.

Effect of intravenous quinine on capillary glucose levels in malaria.

OBJECTIVE: Hypoglycemia occurring during management in patients of severe malaria is often overlooked, which can be associated with higher morbidity and mortality rates. METHOD: Capillary glucose was estimated in 32 patients of malaria before, at one hour and at six hours of quinine administration. Quinine was given in saline solution intravenously. RESULTS: Pretreatment capillary glucose was found to be lower (71-80 mg/dl) in 12.5% cases. After one hour of intravenous quinine administration, capillary glucose levels fell by 11.84% in all the cases. A further fall of 20.50% was observed in 75% of cases after six hour. Two patients died and both were suffering from cerebral malaria. Statistically, fall in capillary glucose was highly significant at one hour (t=9.4, p < 0.001) and at six hours. (t=3.87, p < 0.001) CONCLUSION: Statistically significant fall in capillary glucose levels has been observed in patients of malaria with quinine administration.

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 percent (29/30) of the samples tested for chloroquine, 3.3 percent (1/30) for quinine, none (0/30) for mefloquine and none for halofantrine (0/30). Overall low sensitivity was evidenced in 10 percent of the samples tested for quinine, 22.5 percent tested for halofantrine and in 20 percent 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

Experience with quinine in falciparum malaria.

During a period of 1 year from July 95 to June 96, 60 patients with falciparum malaria were treated with quinine at Kasturba Medical College Hospital, Mangalore. Of these, 24 patients developed adverse effects to quinine. They were cinchonism (15) cardiotoxicity (10) hypoglycemia (9) hyperventilation (3) hypersensitivity reactions (3) and hypokalemia (1). Cardiotoxicity was noted in 4 of the 7 patients who received intravenous quinine and all four had renal and hepatic failure and prolonged Q-Tc on electrocardiogram. All 4 died of cardiac arrhythmias, 2 had broad QRS tachycardia and 2 had sinus bradycardia. We conclude that: 1. Quinine should be used cautiously in patients with impaired hepatic or renal function and in those with prolonged QTc as it can lead to cardiotoxicity in the form of I0 AV block, prolonged Q-Tc, broad QRS tachycardai or fatal bradyarrhythmia. Dosage reduction to 5 mg/kg body weight in the patients seem to be safer. 2. Hypoglycemia is a very frequent complication of quinine therapy and special care and frequent blood sugar estimations are required especially if the patient has vomiting. 3. Parenteral quinine is more likely to cause toxicity than oral quinine as earlier described.