Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new aralen research articles will be listed here shortly after becoming available to us.
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Medical research on aralen
Int J Infect Dis. 2008 Jun 21;
Plummer WB, Pereira LP
OBJECTIVES: This preliminary study sought to investigate the response of uncomplicated falciparum infections to semi-supervised drug administration with quinine and two adjunctive schizontocidal drugs in infected patients in Guyana. Quinine and chloroquine cross-sensitivity was also assessed in vitro. METHODS: Patients were treated with quinine 10mg/kg for 7 days followed by sulfadoxine/pyrimethamine 25mg/kg single dose (in children) or doxycycline 100mg daily for 7 days (in adults). Independently, falciparum-infected blood-medium mixtures were cultured in standardized pre-dosed quinine and chloroquine test plates, according to the protocol of the World Health Organization Mark III in vitro test system, for analysis. RESULTS: The quinine/doxycycline regimen (N=12) produced 100% clinical cure (12/12) at day 14 and 100% parasitological cure (11/11) at day 28. However, with the quinine/sulfadoxine/pyrimethamine scheme, 1/12 therapeutic failure (on day 14) and 2/9 parasitological failures (on day 28) were observed. In vitro, parasite development beyond the cut-off concentrations and high IC(50) values (geometric mean IC(50) quinine 504.65nM and IC(50) chloroquine 506.69nM), confirmed diminished Plasmodium falciparum sensitivity to both drugs. CONCLUSION: These findings suggest P. falciparum resistance to both quinine and chloroquine, and support either the use of antibiotics as adjuncts to quinine therapy or drugs with alternate pharmacodynamics as first-line therapy.
Int J Pharm. 2008 May 16;
Qiu L, Jing N, Jin Y
This study developed an active loading method for encapsulating chloroquine diphosphate (CQ) into liposomes. The effects of different formulation factors on the encapsulation efficiency (EE) and the size of CQ liposomes were investigated. These factors included the internal phase of liposomes, the external phase of liposomes, the ratio of drug to soybean phosphatidylcholine (drug/SPC), the ratio of cholesterol to soybean phosphatidylcholine (Chol/SPC), and the incubation temperature and time. The EE (93%) was obtained when using drug/SPC (1:50 mass ratio), SPC/Chol (1:5 mass ratio) at 0.10M citrate-sodium citrate buffer (pH 3.6). As 5mol% methoxypoly(ethylene glycol)(2000) cholesteryl succinate (CHS-PEG(2000)) or distearoyl phosphatidylethanolamine-poly (ethylene glycol)(2000) (DSPE-PEG(2000)) was added, the size of particle was reduced and the EE was improved. Freeze-drying with 5% trehalose as a cryoprotectant was carried out to achieve long-term stability. The drug release studies were performed in vitro simulating the desired application conditions, such as physiological fluids (pH 7.4), tumor tissues (pH 6.5) and endosomal compartments (pH 5.5). The release of CQ from the liposomes prepared via remote loading showed the significant pH-sensitivity and retention properties, which favored the application of liposomal CQ at tumor tissues and endosomal compartments.
Antiplasmodial and antitrypanosomal activities of aminobicyclo[2.2.2]octyl omega-aminoalkanoates.
Eur J Med Chem. 2008 May 10;
Schlapper C, Seebacher W, Faist J, Kaiser M, Brun R, Saf R, Weis R
Several 4-aminobicyclo[2.2.2]octyl esters of omega-dialkylamino acids were prepared. Their activities against the multidrug-resistant K(1) strain of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900) were determined using microplate assays and compared to those of formerly prepared analogues. The biological activity was influenced by the relative configuration in ring position 2, by the chain length of the acid moiety and by the amino substitution. The most active antiplasmodial ester was as active as chloroquine. One of the new compounds exhibited the highest antitrypanosomal activity and selectivity of all bicyclo-octane derivatives prepared so far.
Progress in malaria control in endemic areas.
Travel Med Infect Dis. 2008 Jul; 6(4): 173-6
Greenwood B
The international community is now making a serious effort to bring malaria under control. Funds for malaria control have become available on a scale not seen since the days of the eradication campaign 50 years ago. These new resources are being used largely to support a supply of artemisinin combination therapy to replace ineffective chloroquine and sulphadoxixne pyrimethamine for first line treatment of malaria and for the provision of long-lasting, insecticide treated bednets. There are early indications from several countries in Africa that this renewed effort at malaria control is beginning to have an effect but additional tools will probably be needed, including a highly effective vaccine, if the ultimate goal of malaria eradication is to be achieved.
Lysosomal trapping of amodiaquine: impact on transport across intestinal epithelia models.
Biopharm Drug Dispos. 2008 Jun 20;
Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell AL
The lipophilic weak base amodiaquine is an antimalarial drug that has been in use for over 40 years. Little is known of amodiaquine's mechanism of transport across membranes. Transport experiments of amodiaquine in Caco-2 cells showed a low recovery of 30% and rapid disappearance from the apical chamber. Compounds structurally similar to amodiaquine, and those affecting non-specific binding of amodiaquine or the pH of the system, were tested to unravel the mechanism behind these observations. Chloroquine and ammonium chloride increased the transmonolayer permeability of amodiaquine and decreased its accumulation in Caco-2 cells, whereas BSA had no effect. Chloroquine and BSA decreased plastic binding whereas ammonium chloride had no effect. This suggests that amodiaquine is trapped in acidic cell compartments such as lysosomes. Amodiaquine was also trapped in rat intestinal tissue. In addition, permeability from the apical to basolateral direction was significantly higher, suggesting an active uptake over the apical membrane of the rat tissue. It can be concluded that amodiaquine is trapped in acidic cell compartments due to its base properties and recovery may be improved by the use of ammonium chloride rather than BSA in transport experiments. Further studies are required to confirm whether amodiaquine is actively absorbed in the intestine. Copyright (c) 2008 John Wiley & Sons, Ltd.
Cancer Invest. 2008 Jun; 26(5): 448-55
Ren T, Wen ZK, Liu ZM, Qian C, Liang YJ, Jin ML, Cai YY, Xu L
CpG-oligonucleotides (CpG-ODN), which induce signaling through Toll-like receptor 9 (TLR9), are currently under investigation as adjuvants in therapy against infections and cancer. However, whether the CpG-ODN alone could enhance the anti-tumor immunity and the underlying mechanisms remains unclear. Here, we investigated that stimulation of peripheral blood mononuclear cells (PBMCs) from human lung cancer patients with CpG-ODN induced proliferation responses of the PBMCs, accompanied by the elevated cytokine secretion, including IFN-alpha, IL-12 and TNF-alpha. In addition, after treatment with CpG-ODN, the cytotoxic activity of the PBMCs and the production of IFN-gamma in CD8(+) T cells were dramatically enhanced. Furthermore, we found that adoptive transfer of CpG-ODN treated PBMCs significantly inhibited the tumor progression in nude mice, which were challenged with the autologuous tumor cells from human lung cancer patients. Finally, we demonstrated that the inhibitory CpG ODN or chloroquine could dramatically abrogate the enhanced anti-tumor responses of the CpG ODN treated PBMCs. Our findings suggest that the CpG-ODN is promising as a preventive and therapeutic anti-tumor measure against pulmonary carcinoma.
J Parasitol. 2008 Apr; 94(2): 473-80
Porter H, Gamette MJ, Cortes-Hernandez DG, Jensen JB
It has been shown by others that after cultures of Plasmodium falciparum were exposed to a febrile temperature of 40 C, parasitemia was reduced in the subsequent generation, suggesting a temperature-induced inhibition of trophozoites and schizonts. In the current study, influences unique to cultivation were ruled out, demonstrating that 40 C impacted the parasites directly. Metabolic profiling of DNA synthesis, protein synthesis, and glucose utilization clearly indicated that febrile temperatures had a direct effect on parasite development, beginning 20-24 hr after erythrocyte invasion. The mechanism of parasite death was investigated for evidence of temperature-induced apoptosis. Lack of typical physiological hallmarks, namely, caspase activation, characteristic mitochondrial membrane potential changes, and DNA degradation as indicated by DNA laddering, eliminated 'classical' apoptosis as a mechanism of parasite death. Parasites dying under the influence of heat, staurosporine, and chloroquine initially appeared pyknotic by light and electron microscopy (as in apoptosis), but eventual swelling and lysis of the food vacuole membrane led to secondary necrosis. Chloroquine did induce DNA laddering, but it was later attributed to occult white blood cell contaminants. While not apoptosis, the results do not rule out other forms of temperature-induced programmed cell death.
PLoS Med. 2008 Jun 17; 5(6): e128
Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, Lampah DA, Price RN
BACKGROUND: Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. METHODS AND FINDINGS: Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08-1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). CONCLUSIONS: In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.
Investigation of the Redox Behavior of Ferroquine, a New Antimalarial.
Mol Pharm. 2008 Jun 19;
Chavain N, Vezin H, Dive D, Touati N, Paul JF, Buisine E, Biot C
Ferroquine (FQ or SR97193) is a unique ferrocene antimalarial drug candidate which just entered phase IIb clinical trials in autumn 2007. FQ is able to overcome the chloroquine (CQ) resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. However, as for other therapeutic agents such as chloroquine (CQ) and artemisin, its mechanism of action remains partially unknown. Most investigations have so far focused on comparing the activity of FQ to that of CQ in order to understand how the ferrocene core contributes to a stronger antiplasmodial activity. Studies have already shown that the ferrocene altered the shape, volume, lipophilicity, basicity and also electronic profile of the parent molecule and, hence, its pharmacodynamic behavior. However, few investigations have been undertaken to probe the real contribution of redox properties of the ferrocene (iron(II))/ferricinium (iron(III)) system in FQ as reported in this article. In our experimental and theoretical approach, we considered the redox profile of the ferrocene core of FQ in the specific conditions (acidic and oxidizing) of the parasitic digestive vacuole as a possible discriminating property from CQ in the antimalarial activity.
Arch Pharm Res. 2008 Jun; 31(6): 688-97
Weis R, Berger H, Kaiser M, Brun R, Saf R, Seebacher W
New alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the antitrypanosomal and antiplasmodial activities. They were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K ( 1 ) (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. 4-Aminobicyclo[2.2.2]oct-2-enes and 3-azatricyclo[3.2.2.0(2,4)]nonylamines exhibit similar antiprotozoal activities as 4-aminobicyclo[2.2.2] octanes. 4-Aminobicyclo[2.2.2]oct-2-ylamines and their N-benzyl derivatives showed decreased antiplasmodial but enhanced antitrypanosomal (IC(50) = 0.22-0.41 muM) activities compared to their parent oximes and to formerly synthesized 4-amino-2-azabicyclo[3.2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei.