Chloroquine Sulphate Research Articles

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198–0.096 μM, compared to IC50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

Artemisinin-based antimalarial combination therapy amongst healthcare professionals in a tertiary facility in south-south Nigeria: preferences, tolerability, and cost considerations

Background: Nigeria adopted the Artemisinin-Based Combination Therapy (ACT) as the mainstay of treating uncomplicated malaria in February 2005. However, the individual preferences for the use of these medicines by health care professionals (HCP) as distinct from their observed prescribing practices is largely unknown. This study determined the preferences, tolerability and cost of the ACTs among HCPin Benin-City.Methods: This descriptive cross-sectional study was conducted in the University of Benin Teaching Hospital, Benin-City, Nigeria. Consenting HCPs were recruited consecutively for the study. Semistructured questionnaires were administered to doctors, nurses and pharmacists in the hospital. Information obtained included demographics, treatment of malaria in the previous year, antimalarial medication preferences and tolerability as well as cost of ACT.Results: A total of 556 HCPs, 295 doctors (54.1%), nurses 200 (36.0%), pharmacists 61(11.0%) completed the questionnaire. In the previous year, 224 (75.9%) doctors, 153 (79.1%) nurses, and 48 (70.5%) pharmacists had treatment for malaria and self-medication was highest among doctors (228, 77.3%). Artemether-Lumenfantrine was the most preferred antimalarial used, 294 (52.8%); however, 1.6% used chloroquine sulphate and ACTs were perceived to be ineffective by 25.4%. Adverse effects were experienced by 167 (29.1%) resulting in 50 (9.0%) discontinuing their medication. Between 500 and 1500 Naira (~US$1-4) was expended on ACT by 66.3% of the staff, while 21.4% were concerned about the high cost of medications.Conclusion: This study highlights the use and preferences, self-medication practices, perceived lack of effectiveness and high cost of ACTs from a HCP perspective. There is an urgent need to address these concerns in view of adverse consequences as well as the likely possibility of its the impact on prescribingpractices.

Improved antimalarial activity of caprol-based nanostructured lipid carriers encapsulating artemether-lumefantrine for oral administration.

Artemether and lumefantrine display low aqueous solubility leading to poor release profile; hence the need for the use of lipid-based systems to improve their oral bioavailability so as to improve their therapeutic efficacy. The objective of this work was to utilize potentials of nanostructured lipid carriers (NLCs) for improvement of the oral bioavailability of artemether and lumefantrine combination and to evaluate its efficacy in the treatment of malaria. This study reports a method of formulation, characterization and evaluation of the therapeutic efficacies of caprol-based NLC delivery systems with artemether and lumefantrine. The artemether-lumefantrine co-loaded NLCs were prepared using the lipid matrix (5% w/w) (containing beeswax and Phospholipon® 90H and Caprol-PGE 860), artemether (0.1%w/w) and lumefantrine (0.6%w/w), sorbitol (4%w/w), Tween® 80(2%w/w as surfactant) and distilled water (q.s to 100%) by high shear homogenization and evaluated for physicochemical performance. The in vivo antimalarial activities of the NLC were tested in chloroquine-sensitive strains of Plasmodium berghei (NK-65) using Peter´s 4-day suppressive protocol in mice and compared with controls. Histopathological studies were also carried out on major organs implicated in malaria. The NLC showed fairly polydispersed nano-sized formulation (z-average:188.6 nm; polydispersity index, PDI=0.462) with no major interaction occurring between the components while the in vivo study showed a gradual but sustained drug release from the NLC compared with that seen with chloroquine sulphate and Coartem®. Results of histopathological investigations also revealed more organ damage with the untreated groups than groups treated with the formulations. This study has shown the potential of caprol-based NLCs for significant improvement in oral bioavailability and hence antimalarial activity of poorly soluble artemether and lumefantrine. Importantly, this would improve patient compliance due to decrease in dosing frequency as a sustained release formulation.

INTERACTION BETWEEN CHLOROQUINE SULPHATE AND COCONUT FRUIT WATER IN ADULT MALE RABBITS.

31May 2017 INTERACTION BETWEEN CHLOROQUINE SULPHATE AND COCONUT FRUIT WATER IN ADULT MALE RABBITS. Patience C. Nwonu , Reginald O. Obidike and Chukwunwike N. S. Nwonu. Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria. Department of Pharmacology and Therapeutics, Faculty of Basic and Allied Medical Sciences, College of Health Sciences, Benue State University, P.M.B. 102119, Makurdi, Nigeria. Lecturer, Department of Pharmacology and Therapeutics, Faculty of Basic and Allied Medical Sciences, College of Health Sciences, Benue State University, P.M.B. 102119, Makurdi, Nigeria.

Development and Validation of Reversed-Phase High Performance Liquid Chromatographic Method for Hydroxychloroquine Sulphate.

In the present work new, simple reversed-phase high performance liquid chromatographic method was developed and validated for the determination of hydroxychloroquine sulphate in blood plasma. Chloroquine sulphate was used as an internal standard. The chromatographic separation was achieved with octadecyl silane Hypersil C18 column (250×6 mm, 5 μm) using water and organic (acetonitrile:methanol: 50:50, v/v) mobile phase in 75:25 v/v ratio, with sodium 1-pentanesulfonate and phosphoric acid. This organic phase was maintained at pH 3.0 by orthophosphoric acid. The flow rate of 2.0 ml/min(.) with detection at 343 nm was used in the analysis. The calibration curve of standard hydroxychloroquine sulphate was linear in range 0.1-20.0 μg/ml. The method was validated with respected to linearity, range, precision, accuracy, specificity and robustness studies according to ICH guidelines. The method was found to be accurate and robust to analyze the hydroxychloroquine sulphate in plasma samples.

Chloroquine sulphate syrup has been discontinued

Chloroquine sulphate syrup has been discontinued

Hepatotoxicity Following Concurrent Administration of Aqueous Extract of Azadirachta Indica Leaf (Neem Leaf) and Chloroquine Sulphate in Rabbits

Background: Recently herbal medications have been introduced into modern health scheme for the treatment of diseases. Aqueous extract of A. indica is commonly used in treatment of malaria in combination with chloroquine, especially now that a combined therapy is said to be more effective. Objectves: This study is designed to investigate the effects of aqueous extract of A. indica leaf and concomitant administration of chloroquine sulphate+aqueous extract of A. indica leaf on the weight and liver cells of rabbit. Methods: Eight adult male rabbits with average weight range between 1.29 kg-1.52 kg obtained from department of Zoology University of Ekpoma, Edo state, Nigeria, were used for this study. They were weighed at intervals of five days before and after the experiment. They were randomly divided into four groups (A-D) of two rabbits each. The chloroquine and aqueous extract of A. indica leaf was administered to the animals orally via a cannula inserted through the oral cavity. They were treated as follows, group A received (15 mg/kg dry extract solution of aqueous extract of A. indica), Group B received (15 mg/kg of chloroquine sulphate), group C received (100 mg/mL dry extract solution of aqueous extract of A. indica+15 mg/kg of chloroquine sulphate and the control animals (group D) were given normal saline. Both treatment and control animals were sacrificed at the end of the experiment. The liver was carefully dissected out and immediately fixed in Bouin's fluid for histological studies. Results: Groups A-D animals showed normal liver histoarchitecture and increase in weight: 2.1% (group A), 1.4% (group B), 0.7%, (group C) and 1.4% (group D) respectively. When the average weight increase by the treated animals was compared to the average weight increase by the control animals, it was statistically not significant (p>0.6). Conclusions: Our findings revealed that aqueous extract of A. indica leaf has no effect on the histology of the liver and weight of adult male rabbits, even when it is administered concomitantly with chloroquine sulphate at a reported and recommended safe dose.

The Effect of Some Anti-inflammatory Agents on Elastase Release From Neutrophils In-vitro

In view of the potential role of released polymorphonuclear leucocyte elastase in causing tissue damage, the effect of commonly used anti-inflammatory drugs on elastase release from neutrophils has been studied in-vitro. Elastase release from neutrophils exposed to the synthetic bacterial cell wall peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (10(-6) M) was quantitated using a radiometric immunoassay and a functional assay of elastase. Prednisolone and non-steroidal anti-inflammatory drugs inhibited elastase release at concentrations from 0.1 mM-0.1 nM. No inhibition by sulphosalicylic acid, D-penicillamine or chloroquine sulphate was observed. The clinical relevance of these findings is discussed.

The influence of spectral slit width on the absorption of visible or ultra-violet light by pharmacopoeial substances.

Abstract The importance of narrow slits in the spectrophotometric determination of extinction coefficients has been demonstrated. Care is needed in the B.P. 1958 spectrophotometric tests or assays of apomorphine hydrochloride, chloroquine phosphate, chloroquine sulphate, diiodohydroxyquinoline, naphazoline nitrate, papaverine hydrochloride and especially procyclidine hydrochloride, to avoid spuriously low results.

Discovery of new antimalarial compounds by use of molecular connectivity techniques.

Molecular connectivity has been applied to the search for new compounds with antimalarial activity. Linear discriminant analysis and connectivity functions were used to select several potentially suitable drugs which were tested for antimalarial properties by use of an in-vitro micro test which estimates parasite growth by measurement of incorporation of [3H]hypoxanthine. Hexetidine stands out among the compounds selected. Activity assays were performed with Plasmodium falciparum passou and 3CD7 strains, for which the IC50 values (doses resulting in 50% inhibition) were 320 and 400 ng mL(-1), respectively. These results are comparable with those obtained for quinine chlorhydrate (IC50 = 60 and 107.8 ng mL(-1)) and chloroquine sulphate (IC50 = 231 and 415 ng mL(-1)), the drugs used for reference. These results demonstrate the usefulness of our topological approach for the selection and design of new lead drugs active against Plasmodium falciparum.

The Schizonticidal responses to chloroquine sulfate quinine dihydrochloride and sulfadoxine/pyrimethamie combinations in malarial patients in Nnewi, Anambra State of Nigeria

The emergence of malaria resistant to one or more classes of anti-malarials constitutes a major problem in chemotherapy of this disease. Hence a study was carried out to monitor the degree of sensitivity of different schizonticidal response to chloroquine sulphate, quinine dihydrochloride and sulfadoxine+pyrimethamine (s/p) combination in malarial patients in Nnewi. From this study, we discovered that pyrimethamine+sulfadoxine has the highest sensitivity to P. falciparim species of malaria and this was closely followed by quinine dihydro-chloride and chloroquine sulphate running a distant third place. The study therefore suggests that pyrimethamine/sulfadoxine should be chosen as a drug of first choice in treatment of p.falciparum specie of malaria parasite in Nnewi Anambra State. Key Words: Chloroquine, Quinine, Sulphadoxine/Pyrimethamine, malarial patient. Journal of Biomedical Investigation Vol.1 2003: 28-32

The contributions of various chloroquine salts to the biliary and urinary execretion of hepatic paracetamol conjugation metabolites in the rat.

As an approach to explain the possible in vivo interaction of paracetamol (acetaminophen) with various chloroquine salts that are often administered during malaria tropica, the effects of these salts (chloroquine sulphate, chloroquine phosphate, chloroquine hydrochloride and ferrous sulphate) were examined in male rats. The coadministration of chloroquine salts with paracetamol for 7 days showed varied effects on urinary and biliary excretion of paracetamol sulphate and paracetamol glucuronide conjugates--the major metabolites of paracetamol metabolism. These findings suggest that chloroquine sulphate and ferrous sulphate may enhance the sulphation pathway in paracetamol metabolism and influence detoxification of paracetamol in the liver and thus protect the liver. Chloroquine sulphate is therefore a better choice compared to other chloroquine salts in the treatment of malaria with paracetamol as an antipyretic and analgesic.

Chloroquine Therapy in Patients with Recent-Onset Rheumatoid Arthritis: The Clinical Response can be Predicted by the Low Level of Acute-Phase Reaction at Baseline

If rheumatoid arthritis (RA) patients with a mild disease course could be identified early in the phase of the disease, therapy with less aggressive and probably less toxic antirheumatic drugs seems to be rational. The aim of this study was to investigate which factors at baseline could predict a clinical response (American College of Rheumatology preliminary response criteria) after treatment with chloroquine for 16 weeks. Two hundred and three early RA patients with active disease were treated with oral chloroquine sulphate (Nivaquine) at a daily dose of 300 mg during the first 4 weeks, 200 mg during the second 4 weeks and 100 mg thereafter. One hundred and eighty-three patients (90%) completed the study and 20 patients prematurely discontinued treatment. Of all the patients, 43 patients (21%) met the response criteria. A low level of C-reactive protein (CRP) was the only independent predictor for clinical response [relative risk: 0.97 (95% confidence interval: 0.95-0.98)]. It was concluded that a clinical response to chloroquine therapy in early RA patients can be predicted by a low CRP level at baseline.

Membrane Based Lipid-Drug Interaction

The action of drugs an living systems is a membrane-based process. Their interaction at the membrane surface/interior and transport through it induces a change in the physical properties of the membrane, of which fluidity is among the most important ones. The lipophilic drugs can affect this fluidity directly through their incorporation into the lipid matrix, whereas the action of the hydrophilic drugs is confined mostly at the membrane-water interface. Using the liposomal membranes of dipalmitoyl phosphatidyl choline, a comparative study of the effect of a hydrophilic drug, chloroquine sulphate, and a lipophilic drug, hydrocortisone, on the membrane fluidity, measured in terms of anisotropy, is presented. From the membrane anisotropy-temperature curve, the associated enthalpy change has been calculated. Results show that the two drugs affect the membrane order in two different ways, indicating that there is a difference in the interaction of these two drugs with the liposomal membrane at the molecular level.

Prevalence of malaria parasitaemia in transfused donor blood in Benin City, Nigeria.

In view of the problem of transfusional malaria, the prevalence of malaria parasitaemia in transfused donor blood was assessed. Blood film examination for malaria parasites on Giemsa-stained donor blood which was used for transfusion to neonates in Benin City, Nigeria was carried out over a 6-month period. Blood group O was the dominant blood type (17%). A high malarial parasite prevalence rate of 40% was noted in the transfused donor blood and Plasmodium falciparum was the dominant infecting species. All blood groups and rhesus factor types were infected with malarial parasites. There was no significantly increased malarial infection rate in any particular blood group type. The neonate, who is known to be immunologically naive, is at high risk of symptomatic malaria acquired through blood transfusion. All neonates who require blood transfusion should be given chloroquine sulphate soon after transfusion, at a dose of 5 mg/kg/day for 3 days, when the parasites are chloroquine-sensitive. In cases of chloroquine resistance, quinine sulphate or halofantrine hydrochloride is an acceptable alternative. Where feasible, donor blood screening for malaria should be carried out before transfusion to any neonate.

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.

Lipid perturbation of liposomal membrane of dipalmitoyl phosphatidylcholine by chloroquine sulphate — a fluorescence anisotropic study

Chloroquine sulphate (CQS) is a water-soluble anti-malarial drug having blood schizontocidal activity against Plasmodium falciparum, P. ovale, P. vivax and P. malarine. It has been reported that the lipid-soluble chloroquine base, which has similar anti-malarial and other biochemical effects, rigidifies (orders) the liposomal membrane in vivo. Here, in order to examine the lipid perturbation mechanism of CQS, we have studied the effect of incorporation of this drug into the liposomal membrane of dipalmitoyl phosphatidylcholine as measured by the fluorescence polarization of the membrane-embedded probe, 1,6-diphenyl-1,3,5-hexatriene. Our results show that the drug CQS also rigidifies the liposomal membrane even though the mechanism of the drug metabolism in vivo plays an important role. Probably the anti-malarial and other biochemical effects of CQS are exercised through this membrane rigidification.

Chloroquine reduces blood pressure and forearm vascular resistance and increases forearm blood flow in healthy young adults

The effects of chloroquine on resting blood pressure, forearm blood flow (FBF), and forearm vascular resistance (FVR) and on the responses to cold stimulation were studied in healthy young adults. Chloroquine sulphate (800 mg) reduced systolic pressure and increased FBF (P < 0.05) but had no effect on resting FVR. Cold immersion increased systolic pressure (from 108.8 +/- 1.7 mmHg to 127.8 +/- 6.9 mmHg; P < 0.05) diastolic pressure (from 73.4 +/- 2.7 to 95.2 +/- 6.2 mmHg; P < 0.01) and FVR (from 5.9 +/- 0.9 to 13.0 +/- 1.9 a.u.; P < 0.001) but reduced FBF (from 14.3 +/- 1.64 to 10.1 +/- 1.29 ml min-1; P < 0.05). Chloroquine reduced the increase in FVR reduced by cold stimulation (P < 0.01), but had little effect on the BF and FBF responses to cold stimulation. The hypotensive effect of chloroquine could be attributed, at least in part, to the observed fall in vascular resistance.

Use of cryopreserved animal and human hepatocytes for cytotoxicity studies

To evaluate the potential use of cryopreserved hepatocytes for toxicological studies, rat, dog and human hepatocytes were frozen in Leibovitz medium containing 20% foetal calf serum and various concentrations of dimethylsulphoxide and stored in liquid nitrogen. 50% or more of the hepatocytes that attached and survived immediately after isolation still possessed these properties after freezing/thawing. Thawed hepatocytes from the three species showed only a slight reduction in their ability to metabolize phenacetin or to conjugate paracetamol with glucuronic acid. Sensitivity to the toxic effects of erythromycin was not affected by the MTT and neutral red assays. Similar observations were made with rat hepatocytes for five other toxic agents—chloramphenicol, chlorpromazine, acrylamide, chloroquine sulphate and p-chloromercuribenzoic acid. These results suggest that, after cryopreservation, isolated hepatocytes represent a suitable model for drug metabolism and toxicity screening studies.

Chloroquine disposition in hypersensitive and non-hypersensitive subjects and its significance in chloroquine-induced pruritus.

Twenty-one healthy Nigerian volunteers distributed into four groups participated in a study to determine the significance of chloroquine disposition in chloroquine-induced pruritus. It involved the administration of chloroquine with or without promethazine pre-administration to the subjects. Group I consisted of 8 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate (300 mg base); Group II consisted of 5 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate 30 minutes after 25 mg promethazine tablet pre-administration; Group III consisted of 5 chloroquine hypersensitive subjects treated as in Group II; Group IV consisted of 3 hypersensitive subjects treated as in Group I. Blood (5 ml) and urine samples were collected periodically for up to 6 days post-dose. The samples were analysed for chloroquine and some of its oxidation metabolites by a specific HPLC method. Probit plots of cumulative drug/metabolite ratios were done to determine if there is polymorphism in chloroquine metabolism. There was bimodality only in the distribution of chloroquine/monodesethylchloroquine ratios, suggesting polymorphism in the metabolic oxidation of chloroquine in these subjects. Higher levels of monodesethylchloroquine were obtained in Group IV subjects when compared with any of the other groups. The oral clearance rate, elimination half-life, and volume distribution at steady state of chloroquine in the study groups were not significantly different (P greater than 0.05). In the absence of promethazine there appears to be an extensive metabolism of chloroquine in hypersensitive individuals to produce monodesethylchloroquine which probably determines the degree of pruritus experienced by an individual.