Novel antimalarial drug targets: hope for new antimalarial drugs

Malaria is a major global threat, that results in more than 2 million deaths each year. The treatment of malaria is becoming extremely difficult due to the emergence of drug-resistant parasites, the absence of an effective vaccine, and the spread of insecticide-resistant vectors. Thus, malarial therapy needs new chemotherapeutic approaches leading to the search for new drug targets. Here, we discuss different approaches to identifying novel antimalarial drug targets. We have also given due attention to the existing validated targets with a view to develop novel, rationally designed lead molecules. Some of the important parasite proteins are claimed to be the targets; however, further in vitro or in vivo structure–function studies of such proteins are crucial to validate these proteins as suitable targets. The interactome analysis among apicoplast, mitochondrion and genomic DNA will also be useful in identifying vital pathways or proteins regulating critical pathways for parasite growth and survival, and could be attractive targets. Molecules responsible for parasite invasion to host erythrocytes and ion channels of infected erythrocytes, essential for intra-erythrocyte survival and stage progression of parasites are also becoming attractive targets. This review will discuss and highlight the current understanding regarding the potential antimalarial drug targets, which could be utilized to develop novel antimalarials.     

Novel antimalarial drug targets: hope for new antimalarial drugs

Malaria is a major global threat, that results in more than 2 million deaths each year. The treatment of malaria is becoming extremely difficult due to the emergence of drug-resistant parasites, the absence of an effective vaccine, and the spread of insecticide-resistant vectors. Thus, malarial therapy needs new chemotherapeutic approaches leading to the search for new drug targets. Here, we discuss different approaches to identifying novel antimalarial drug targets. We have also given due attention to the existing validated targets with a view to develop novel, rationally designed lead molecules. Some of the important parasite proteins are claimed to be the targets; however, further in vitro or in vivo structure-function studies of such proteins are crucial to validate these proteins as suitable targets. The interactome analysis among apicoplast, mitochondrion and genomic DNA will also be useful in identifying vital pathways or proteins regulating critical pathways for parasite growth and survival, and could be attractive targets. Molecules responsible for parasite invasion to host erythrocytes and ion channels of infected erythrocytes, essential for intra-erythrocyte survival and stage progression of parasites are also becoming attractive targets. This review will discuss and highlight the current understanding regarding the potential antimalarial drug targets, which could be utilized to develop novel antimalarials.     

Important drug interactions in dermatology

Drug interactions can occur at any step from absorption to elimination of a drug, and can induce adverse as well as beneficial effects. Since systemic drugs are increasingly available and important in the treatment of dermatological diseases, a variety of possible interactions between concomitantly administered drugs have to be considered by dermatologists. The xenobiotic-metabolising enzyme system cytochrome P450 (CYP) is involved in the metabolism of many drugs, regulating their plasma concentrations and activities. Furthermore, the adverse effects of many drugs depend on the basal activity and inducibility of particular CYP isoenzymes in an individual patient. Since drug therapy in dermatological practice is of increasing complexity, and an increasing number of potent systemic drugs have become commonly used therapeutic agents, this review focuses on the following topics with the aim of optimising dermatological drug therapy. In the first section, all the different types of drug interactions that can occur through pharmacokinetic and pharmacodynamic mechanisms are introduced briefly, and then discussed systematically with special reference to drugs important for dermatologists. Then, the network of drug interactions that may occur from absorption to elimination is presented. The most important drug interactions mediated by CYP isoenzymes are listed. Finally, the importance of pharmacogenetics for the development of new drugs and its potential impact on the optimisation of individual therapy regimens is discussed.     

Arteether, a new antimalarial drug: synthesis and antimalarial properties

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.     

Pharmacokinetic drug interactions with nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Drug interactions with this class of compounds are frequently reported and can be pharmacokinetic and/or pharmacodynamic in nature. The pharmacokinetic interactions can be divided into 3 classes: (1) drugs affecting the pharmacokinetics of an NSAID. (2) an NSAID interfering with the pharmacokinetics of another NSAID and (3) NSAIDs altering the pharmacokinetics of another drug. Although the pharmacokinetics of some NSAIDs may be significantly affected by the concurrent administration of certain other drugs (including other NSAIDs), this type of interaction only occasionally leads to serious complications. Concurrent administration of antacids or sucralfate may delay the rate of oral absorption of NSAIDs but generally has little effect on the extent. Use of antacids increases urinary pH, leading to increased renal excretion of unchanged salicylic acid and decreased plasma concentrations of this antirheumatic agent. The H2-receptor blocking agent cimetidine inhibits the oxidative metabolism of many concurrently administered drugs, including certain NSAIDs. Probenecid inhibits the renal secretion of drug glucuronides and this will lead to accumulation in plasma of those NSAIDs eliminated primarily by the formation of labile acyl glucuronides such as naproxen, ketoprofen, indomethacin, carprofen. Cholestyramine decreases the oral absorption of many concurrently administered drugs, including NSAIDs. It may also decrease plasma concentrations of those NSAIDs undergoing enterohepatic circulation (e.g. piroxicam, tenoxicam) by interrupting the enterohepatic cycle. Corticosteroids stimulate the clearance of salicylic acid, leading to low plasma salicylate concentrations. Plasma concentrations of many NSAIDs are significantly reduced when the NSAID is coadministered with aspirin. The clinical relevance of most of these interactions is not well established. However, in those cases where the interaction results in elevated plasma concentrations of the NSAID, special caution should be exercised to avoid excessive accumulation of the NSAID especially in elderly and/or very sick patients who may be more sensitive to the more serious gastroduodenal and renal side-effects of these agents. By virtue of their pharmacokinetic and pharmacodynamic properties, NSAIDs may significantly affect the disposition kinetics of a number of other drugs. They can displace other drugs from their plasma protein binding sites, inhibit their metabolism or interfere with their renal excretion. If the affected drug has a narrow therapeutic index, the interaction may be clinically significant. The pyrazole NSAIDs (phenylbutazone, oxyphenbutazone, azapropazone) inhibit the metabolism of many drugs such as the coumarin anticoagulants, oral antidiabetics and anticonvulsants such as phenytoin. Salicylates displace oral anticoagulants from their plasma protein binding sites.(ABSTRACT TRUNCATED AT 400 WORDS)     

Potential drug-drug interactions of immunosuppressants in kidney transplant recipients: comparison of drug interaction resources

International Journal of Clinical Pharmacy - Background Drug-drug interactions are frequently observed in kidney transplant recipients due to polypharmacy and use of immunosuppressants. However,...     

Comparative actions of immunosuppressants, glucocorticoids and non-steroidal anti-inflammatory drugs on various models of delayed hypersensitivity and on a non-immune inflammation in mice

Various models of delayed hypersensitivity (DH) were used in mice: contact hypersensitivity reactions to picryl chloride and oxazolone and reactions to methylated bovine serum albumin (MBSA) and sheep red blood cells (SRBC). Drugs of different classes were tested in these models by systemic treatment around the challenge period: non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors, and inhibitors of both cyclooxygenase and lipoxygenase); glucocorticoids and immunosuppressants (cyclosporin A. CsA; cyclophosphamide, Cy; methotrexate, Mtx; azathioprine, Aza). These compounds were also studied and compared for their effects on the 3-h and 24-h phase of the carrageenin mouse-paw edema (in which inflammation is maximal after 24 h). Non-steroidal anti-inflammatory drugs (including double inhibitors of cyclooxygenase and lipoxygenase) had little or no effect on DH models, except indometacin. Glucocorticoids inhibited all immune reactions except that to MBSA. Of the immunosuppressants, CsA reduced all the DH reactions while Aza mainly reduced the reaction to SRBC; Cy and Mtx were mainly active on SBRC and MBSA inflammations. On another hand CsA, Cy and Mtx were inactive on the 3-h phase but decreased the 24-h phase of carrageenin edema. At doses active on the DH models and on carrageenin inflammation, Cy induced a lasting blood leukopenia, but CsA and Mtx did not. This combination of tests in the mouse seems to be of interest to demonstrate any action on DH and any anti-inflammatory effect and to suggest whether these activities are related to a possible leukopenic effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effectiveness and tolerability of ketoprofen lysine, once a day, in patients with rheumatic disorders

Ketoprofen lysine (KL) at a dose of 160 mg b.i.d. has been shown to have favourable anti-inflammatory and analgesic properties in a large number of patients. In the present paper investigators describe their experience with a new therapeutic schedule of KL, 320 mg given once a day to patients with various rheumatic disorders. With this new schedule there was satisfactory clinical improvement of most of the clinical parameters and good tolerability, with a low incidence of gastric troubles. The favourable clinical effects and the patients' good compliance with once-a-day KL make it a useful drug for successful treatment of rheumatic disorders.     

伏立康唑与血液病患者常用药的药物相互作用研究

目的探讨伏立康唑与血液病患者常用药间的药物相互作用,指导伏立康唑个体化用药。方法收集2015-2017年天津市第一中心医院应用伏立康唑预防或治疗侵袭性真菌感染的血液病患者的血药浓度资料,应用非线性混合效应模型法,考察血液病患者常用药物与伏立康唑联用时的相互作用。结果伏立康唑清除率和表观分布容积的群体典型值分别为8.24 L·h^-1和163 L。群体药动学模型显示碱性磷酸酶对伏立康唑的清除率有显著影响(P<0.005)。联用兰索拉唑或环孢素时,伏立康唑的清除率分别降低33.4%、32.8%,而联用地塞米松使伏立康唑的清除率增加41.0%。结论临床上伏立康唑与兰索拉唑、环孢素或地塞米松联用时,需注意相互作用的产生,并合理调整用药剂量。     

Pharmacogenetics and individualized therapy in children: immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs

Pharmacogenetic polymorphisms that change the amino acid sequences in coding regions only account for part of the interindividual differences in disease susceptibility and drug response. Additional pharmacogenomic and epigenetic factors are also involved. In children, pharmacogenetic studies are limited, although it has been clear for many years that the interactions between developmental patterns of drug-metabolizing enzymes and transporters have a major impact on dose exposure with age-specific dosage requirements. This article will analyze the factors affecting variability in drug response in children and focus on the pharmacogenetic polymorphisms of immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. Additional pharmacogenetic and epigenetic studies should be performed to allow the individualization of therapy in children.     

Toxicodynamic therapeutic drug monitoring of immunosuppressants: promises, reality, and challenges

Although current immunosuppressive protocols have dramatically decreased acute rejection episodes, there has been less progress in terms of long-term graft survival after kidney transplantation over the last 2 decades. The key to reducing the damage to a transplanted organ as caused by chronic processes is early detection. Modern screening technologies in the fields of genetics, genomics, protein profiling (proteomics), and biochemical profiling (metabolomics) have opened new opportunities for the development of sensitive and specific diagnostic tools. Metabolic profiling appears to be a promising strategy because changes in the cell biochemistry are ultimately responsible for the histologic and pathophysiologic changes of the transplanted kidney and are most likely already detectable before histologic and pathophysiologic changes occur. Using truly no-targeted screening technologies as clinical diagnostic tools is not yet feasible, mostly because of the complexity of the data generated and the lack of algorithms to convert this information into clinically applicable information. A realistic and powerful targeted approach is the development of combinatorial biomarkers. These are biomarker patterns that typically consist of five or more individual parameters. Combined biomarker patterns confer significantly more information than a single measurement and, thus, can be expected to have better specificity and sensitivity. A series of studies in rats and healthy individuals evaluating the effects of immunosuppressants on urine metabolite patterns showed that immunosuppressant-induced changes of metabolite patterns in urine were associated with a combination of changes in glomerular filtration, changes in secretion/absorption by tubulus cells, and changes in kidney cell metabolism. These studies suggested that a combination of biomarkers that can be used for toxicodynamic therapeutic drug monitoring of immunosuppressants should include urine metabolites that constitute valid surrogate markers of these kidney functions.     

左甲状腺素钠的药物相互作用及机制初探

目的：对左甲状腺素钠的药物相互作用及机制作一综述，供临床用药时参考。方法：查阅国内外献，从影响左甲状腺素浓度的药物和左甲状腺素钠对其他药物的影响两个方面探讨了左甲状腺素与其他药物之间的相互作用及可能机制。结果：通过分折，对左甲状腺素与其有相互作用的其他药物合用时，提出了具体的用药建议。结论：左甲状腺素钠的药物相互作用值得关注，以减少可避免的不良后果。     

New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

Inhibition of drug metabolism by the antimalarial drugs chloroquine and primaquine in the rat

The effect of the antimalarial drugs chloroquine (CQ) and primaquine (PQ) on rat liver microsomal drug metabolism has been studied in vitro and in vivo. After acute administration, PQ increased pentobarbitone sleeping time in a dose-related manner [control, 94.0 ± 9.4 min; 10mg/kg, 137.0 ± 2.4 min; 20mg/kg, 197.0 ± 7.5 min; 50 mg/kg, 269.0 ± 2.9 min (means ± S.E.M.)], prolonged zoxazolamine paralysis time (control, 140.0 ± 10.0 min; 50 mg/kg, 341.5 ± 25.6 min) and decreased antipyrine blood clearance from 2.17 ± 0.19 to 0.86 ± 0.12 ml/min. CQ showed no effect on pentobarbitone sleeping time or zoxazolamine paralysis time, but decreased antipyrine clearance from 2.17 ± 0.19 to 1.11 ± 0.18 ml/min. Both drugs inhibited aminopyrine N-demethylase activity, although the concentration required to produce 50% inhibition was much greater for CQ (10 mM) than for PQ (approximately 0.1 mM). Lineweaver-Burk plots showed that CQ inhibited competitively whereas PQ inhibition was apparently non-competitive. Ethoxyresorufin O-deethylase activity decreased by about 40 and 50% in the presence of CQ and PQ respectively (250 nM, equimolar with substrate). There was no evidence of induction following chronic administration of CQ and PQ (50 mg/kg/day for 4 days). There was an apparent decrease in cytochrome P-450 content and aminopyrine N-demethylase activity was decreased. These results demonstrate that PQ and CQ inhibit hepatic drug metabolism both in vitro and in vivo and that PQ appears to be the more potent inhibitor.