Pharmaceutical analysis of the oral iron chelator deferiprone (DMHP, L1)

The oral iron chelator deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, DMHP, L1 or CP20) can be a useful drug in patients with transfusional hemosiderosis. From 1987 about 1000 patients in 16 countries have taken this drug on the base of clinical trials or compassionate use. Since this compound is only available as a raw substance, it is important to ascertain its purity before bringing the drug into a pharmaceutical formulation. Because deferiprone is administered chronically and in high doses, intake of potential toxic impurities can be substantial.In this article a proposal for the quality control of deferiprone is presented in the form of a pharmaceutical monograph. This includes the analytical methods required for identification, purity checking and assay. Furthermore the way we synthesized the drug to get hold of it in a pure form is described. This synthesis is also used in manufacturing the drug commercially. The monograph can be used as a guideline for standardization of the quality of deferiprone to be used for further study and treatment.     

Comparative efficacy and toxicity of desferrioxamine, deferiprone and other iron and aluminium chelating drugs

The efficacy and toxicity aspects of the iron and aluminium chelating drugs desferrioxamine and deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one), have been compared. Major emphasis was given in the use of these two and also of other chelators in conditions of iron overload, imbalance and toxicity, as well as the incidence and possible causes of toxic side effects in both animals and humans. The chemical basis of chelation and the interaction of these chelators with the iron pools are discussed within the context of clinical application in iron overload and other conditions such as renal dialysis, rheumatoid arthritis, cancer, heart disease, malaria, etc. The design and development of new orally active -ketohydroxypyridine and other chelators are considered and compared with 14 other chelators which have been previously tested in man for the removal of iron, most of which, however, were later abandoned because of low efficacy or major toxicity. The design of new therapeutic protocols based on the pharmacological, toxicological and metabolic transformation properties of the chelating drugs is also being considered, within the context of maximising their efficacy and minimising their toxicity. Overall, oral deferiprone appears to be as effective as s.c. desferrioxamine in the removal of iron and aluminium in man and to have a similar but different toxicity profile from desferrioxamine in both animals and man. The low cost and oral activity of deferiprone will make it the drug of choice for the vast majority of patients, who are not currently being chelated either because they cannot afford the high cost of desferrioxamine therapy or are not complying or have toxic side effects with its s.c. administration.     

UGT1A6 genotype-related pharmacokinetics of deferiprone (L1) in healthy volunteers

AIMS

To examine the effects of UGT1A6 polymorphisms on the pharmacokinetics of deferiprone in healthy volunteers.

METHODS

Twenty-two healthy volunteers were enrolled and grouped according to UGT1A6 genotype. After an overnight fast, the subjects received a single oral dose of 25 mg kg⁻¹ deferiprone. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after dosing. Urine output was collected at 0, 0–2, 2–4, 4–8, 8–12 and 12–24 h. Deferiprone (L1) and deferiprone-glucuronide (L1G) concentrations in serum and urine were determined using a validated high-performance liquid chromatography method. UGT1A6 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis.

RESULTS

No statistically significant differences in any pharmacokinetic parameters of either deferiprone or deferiprone-glucuronide among the genotype groups were noted. Likewise, there were no statistically significant differences in 24-h urinary deferiprone and deferiprone-glucuronide excretion among the genotype groups. Significant differences between men and women were found in AUC_0–∞, V_d/F, and CL/F of deferiprone. Gender differences in 24-h urinary deferiprone and its metabolite excretion, however, failed to reach statistical significance. The V_d/F of deferiprone was found to correlate significantly with serum ferritin (r_s = 0.665; P = 0.001).

CONCLUSION

The studied single nucleotide polymorphisms in UGT1A6 do not appear to exert statistically significant effects on the single-dose pharmacokinetics of deferiprone. Gender appears to influence the serum pharmacokinetics of deferiprone, but not urinary excretion of deferiprone and its metabolite. Body iron stores may have an influence on the extent of extravascular deferiprone distribution.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• UGT1A6 has been proposed as the predominant isoform responsible for the glucuronidation of deferiprone.
• UGT1A6*2 allele has been associated with the altered enzyme activity.

WHAT THIS STUDY ADDS

• There is no statistically significant effect of UGT1A6 genotype on the single-dose pharmacokinetics of deferiprone in healthy volunteers.
• Gender influences serum pharmacokinetics of deferiprone.
• Body iron stores reflected by serum ferritin levels may have an influence on the extent of extravascular deferiprone distribution.

     

居家药学服务在多重用药老年患者中效果的系统评价与Meta分析

目的:评价居家药学服务在多重用药老年患者中的效果.方法:采用Cochrane系统评价方法,以"多重用药"、"药师主导"和"老年患者"为检索词,检索Cochrane Library、PubMed、Web of Science数据库,对符合纳入标准的随机对照试验进行质量评价并提取有效信息进行Meta分析.结果:共纳入10项...     

The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.     

Meta-analytic review of the efficacy of smoking cessation interventions

A meta-analysis of randomized and controlled evaluations of the efficacy of smoking cessation interventions compared 146 estimates of the difference in abstinence rates between treated and control conditions (effect sizes) from 85 publications. Simple advice to quit and other brief intervention techniques, nicotine chewing gum and behavioural techniques were all found to be significantly better than relevant control conditions in promoting abstinence, although the results were not homogeneous. In five studies of acupuncture compared with control, consistent results were found showing no benefit for acupuncture.     

Tolerability of different oral iron supplements: a systematic review

Abstract

Objective:

A systematic review was conducted to analyze the tolerability of several oral iron supplements based on data obtained in available publications and to report the incidence of adverse effects (AEs) for each supplement both overall and gastrointestinal.     

Molecular factors affecting the complex formation between deferiprone (L1) and Cu(II). Possible implications on efficacy and toxicity.

Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, L1, CAS 30652-11-0) is a new chelating drug used worldwide for the treatment of iron overloading conditions. Spectrophotometric and potentiometric measurements were carried out to investigate the interaction of L1 with Cu(II) ions under different conditions. The complexation of Cu(II) ions with L1 in aqueous solution leads predominantly to the formation of the Cu(L1)2 species at a pH range of 4-9. The experimental results indicate that L1 has high affinity for Cu(II) with stability constants log beta 11 = 10.3 +/- 0.9 and log beta 12 = 19.2 +/- 0.6. The effect of Cu(II) ions on the affinity of L1 for Fe(III) ions by competition reactions in vitro indicate displacement of Fe(III) in a concentration dependent manner by Cu(II). Similarly, the presence of different buffers at various pH values resulted in the formation of different stoichiometry L1 complexes with Cu(II) and of mixed complexes with buffer anions. The strong interaction of L1 with Cu(II) may have implications on the therapeutic and toxicological properties of this chelating drug. In particular, L1 may be used in the treatment of copper overloading conditions, such as Wilson's disease or other conditions where copper toxicity is implicated.     

Cost effectiveness of oral terbinafine (Lamisil) compared with oral fluconazole (Diflucan) in the treatment of patients with toenail onychomycosis

OBJECTIVE: To determine the cost effectiveness of terbinafine (Lamisil) tablets compared with fluconazole (Diflucan) capsules in the treatment of patients with toenail onychomycosis. METHODS: Data from a randomised, double-blind, double-dummy, multicentre study were used as the basis for this study. Terbinafine 250 mg/day for 12 weeks (n = 48) was compared with fluconazole 150mg once weekly for 12 weeks (n = 45) or 24 weeks (n = 44) in patients with culture-confirmed toenail onychomycosis caused by dermatophyte infection. At the end of the study (week 60), complete clinical cure of the target toenail was achieved in 67% of patients in the terbinafine group, compared with 21 and 32%, respectively, in the 12- and 24-week fluconazole groups. We subsequently used these data to calculate the cost effectiveness of the three treatment regimens, defining cost effectiveness as the cost per complete clinical cure of the target toenail at week 60. RESULTS: The cost effectiveness of terbinafine for each complete clinical cure was superior to that of either of the fluconazole regimens. Costs per cure were Finnish markka (Fmk) 2824 ($US618) for terbinafine, compared with Fmk3748 ($US820) and Fmk4922 ($US1077), respectively, for the two fluconazole regimens. CONCLUSIONS: The clinical study showed that terbinafine was significantly more effective than fluconazole in the treatment of onychomycosis, achieving statistically higher rates of mycological and clinical cure. We have now shown that terbinafine is also more cost effective. These findings have important implications for both medical and social policy.     

Lipophilicity of kinetically labile metal complexes through the example of antidiabetic Zn(II) and VO(IV) compounds

The lipophilic character of several carrier ligands of antidiabetic Zn(II) and VO(IV) metal complexes were characterized by the traditional saturation shake flask method based on n-octanol/water partitioning. The transfer of the neutral ligand species to the organic phase was followed by UV spectrophotometry at various pH and the partition and distribution coefficients were calculated with the help of the proton dissociation constants and the spectra of the individual ligand species. Partition and distribution coefficients of the Zn(II) and VO(IV) complexes were determined by analysis of the metal ion content of the aqueous phases before and after separation by ICP-AES, their UV spectra and the corresponding concentration distribution curves. Results revealed the fairly hydrophilic character both the carrier ligands and their neutral Zn(II) and VO(IV) complexes. A quasi-linear relationship was found between logP of the ligands and that of the metal species in the case of the ligands studied with the exception of the picolinates. Importance of the knowledge of the chemical speciation (i.e. stoichiometry and stability constants) was also highlighted for the characterization of the lipophilic character of the kinetically labile metal complexes.     

Effectiveness and cost effectiveness of pharmacist input at the ward level: a systematic review and meta-analysis

BackgroundPharmacists play important role in ensuring timely care delivery at the ward level. The optimal level of pharmacist input, however, is not clearly defined.ObjectiveTo systematically review the evidence that assessed the outcomes of ward pharmacist input for people admitted with acute or emergent illness.MethodsThe protocol and search strategies were developed with input from clinicians. Medline, EMBASE, Centre for Reviews and Dissemination, The Cochrane Library, NHS Economic Evaluations, Health Technology Assessment and Health Economic Evaluations databases were searched.Inclusion criteria specified the population as adults and young people (age >16 years) who are admitted to hospital with suspected or confirmed acute or emergent illness. Only randomised controlled trials (RCTs) published in English were eligible for inclusion in the effectiveness review. Economic studies were limited to full economic evaluations and comparative cost analysis. Included studies were quality-assessed. Data were extracted, summarised. and meta-analysed, where appropriate.ResultsEighteen RCTs and 7 economic studies were included. The RCTs were from USA (n = 3), Sweden (n = 2), Belgium (n = 2), China (n = 2), Australia (n = 2), Denmark (n = 2), Northern Ireland, Norway, Canada, UK and Netherlands. The economic studies were from UK (n = 2), Sweden (n = 2), Belgium and Netherlands. The results showed that regular pharmacist input was most cost effective. It reduced length-of-stay (mean = −1.74 days [95% CI: 2.76, −0.72], and increased patient and/or carer satisfaction (Relative Risk (RR) = 1.49 [1.09, 2.03] at discharge). At £20,000 per quality-adjusted life-year (QALY)-gained cost-effectiveness threshold, it was either cost-saving or cost-effective (Incremental Cost Effectiveness Ratio (ICER) = £632/QALY-gained). No evidence was found for 7-day pharmacist presence.ConclusionsPharmacist inclusion in the ward multidisciplinary team improves patient safety and satisfaction and is cost-effective when regularly provided throughout the ward stay. Research is needed to determine whether the provision of 7-day service is cost-effective.     

The fenton activity of iron(III) in the presence of deferiprone

Hydroxyl radical production from a range of clinically relevant iron chelators in the presence of hydrogen peroxide was measured using the deoxyribose oxidation assay. Hydroxyl radical production from an iron complex is dependent on whether the ligand is able to completely surround the iron, thereby preventing access of reductants to the coordinated iron cation. The partially coordinated [(deferiprone)(2)Fe(III)](+) complex is able to generate hydroxyl radicals in the presence of oxidants, whereas the fully coordinated [(deferiprone)(3)Fe(III)](0) complex is not. Hydroxyl radical production from iron(III)deferiprone complexes is dependent on the molar ratio of iron to deferiprone, which, in turn, affects the speciation of the complex. Mass spectrometry data have confirmed the presence of the [(deferiprone)(2)Fe(III)](+) complex in aqueous solution. Hydroxyl radical production from the [(deferiprone)(2)Fe(III)](+) complex is maximal in the presence of equimolar ascorbate and hydrogen peroxide and is abolished in the absence of hydrogen peroxide. Under biological conditions, any [(deferiprone)(2)Fe(III)](+) complex formed intracellularly will be rapidly reduced by ascorbate. The resulting unstable iron(II) complex will dissociate to hexa-aquo iron(II), a major component of the endogenous intracellular labile iron pool.     

Effects on Mycobacterium avium replication in normal human macrophages by deferiprone (L1) and other iron chelators. Possible implications on toxicity

Mycobacterium avium growth in cultured human macrophages is influenced by serum lipids, transferrin and iron levels. Iron-saturated transferrin enhances M. avium growth, whereas apotransferrin inhibits mycobacterial replication. The ability of iron chelators to mimic the effects of transferrin on intracellular and extracellular M. avium growth was examined. Smooth, transparent, AIDS patient derived M. avium 7497 scrovar 4 was used to infect 7-day cultured human macrophages. Growth was measured by determining the colony-forming units (CFU) after infected macrophages were lysed 0 to 7 days after infection. The new iron chelating drug deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one or L1, CAS 30652-11-0), 1-ethyl-2-methyl-3-hydroxypyrid-4-one (L1NEt), 1-propyl-2-methyl-3-hydroxypyrid-4-one (L1NPr), 1-allyl-2-methyl-3-hyproxypyrid-4-one (L1NAll), and 3,4-dihydroxycinnamic acid enhanced intracellular and extracellular mycobacterial replication at concentrations of 0.1-2.5 micrograms/ml. 2-Pyridinecarboxaldehyde-2-quinolylhydrazone (PCQH) inhibited intracellular replication from 0.1-1.0 microgram/ml. Most, but not all of the PCQH-induced intracellular inhibition could be eliminated using iron at concentrations greater than 1.0 microgram/ml. Iron also suppressed the effects of PCQH on extracellular M. avium replication. These results indicate that iron chelators may have variable effects at different concentrations and can significantly alter both intracellular and extracellular M. avium replication. It is suggested that at low concentrations deferiprone and other aketohydroxypyridine chelators could enhance the growth of M. avium but at high concentrations may function as adjunct therapy with other antimicrobials against infections with M. avium. These findings are important for therapeutic considerations and dose protocol design in relation to the new iron chelating drug deferiprone, which is currently used in thalassaemia and other iron loaded patients, some of whom are suffering from AIDS.     

Prognostic factors for the clinical effectiveness of fluconazole in the treatment of oral candidiasis in HIV-1-infected individuals.

OBJECTIVE: To identify prognostic factors for the clinical effectiveness of fluconazole in HIV-1-infected patients with oropharyngeal candidiasis.DESIGN AND SETTING: The study was designed as a prospective, open label, non-comparative, dose escalating, single centre trial.PATIENTS AND METHODS: Thirty-four HIV-1-infected patients with oropharyngeal Candida infection were treated with 50 or 100mg fluconazoleday(-1), depending on the clinical manifestation (erythematous or pseudomembranous). The dose was doubled weekly until clinical cure. The predictive value of potential prognostic factors for the duration of treatment and cumulative fluconazole dose until cure was studied: exposure to fluconazole, previous use of fluconazole, the use of antiretroviral drugs, the CD4(+) cell count, erythematous or pseudomembranous appearance, the minimum inhibitory concentration (MIC) for fluconazole of the isolated Candida strain, and xerostomia.RESULTS: Twenty-eight patients (with 30 episodes of oropharyngeal candidiasis) were evaluated. Twenty-five episodes were cured within 1-week of treatment, the remaining five episodes were cured within 2 weeks. No predictive value for any of the studied factors on the duration of fluconazole treatment or the cumulative fluconazole dose until cure was demonstrated.CONCLUSION: Because of the high susceptibility to fluconazole and the positive clinical outcome, the variation in outcome measurements was too modest to establish a significant relationship between any of the investigated potentially prognostic factors and the cumulative fluconazole dose and the duration of treatment to reach cure. On the other hand it can be concluded, that fluconazole is very effective in patients with advanced HIV infection and low CD4(+) cell counts, even if they are not using antiretroviral agents.     

鼻饲患者不同口腔护理方法效果的临床观察

目的针埘长期鼻饲患者寻找一种患者更加舒适、更加有效的口腔护理方法。方法随机对86例患者进行VI腔护理,按随机分成两组,双数者为实验组（44例）,单数为对照组（42例）,实验组用3cm×3cm8层棉纱块对口腔进行清洁护理,对照组用棉球口腔清洁护理,并进行舒适度、口腔清洁度评价及观察口臭、恶心等情况。两组性别、年龄、病情比较差异无统计学意义（P〉0．05）。结果新的口腔护理方法通过自行设计的问卷调查患者的主观感觉、护士的评估和口腔分泌物细菌培养3个方面进行比较,用纱块做口腔护理明显优于棉球作口腔护理,两组比较差异有统计学意义。（P〈0．05）。结论新的口腔护理方法的清洁效果明显优于传统的清洁效果,更适合长期鼻饲的患者。     

Bioavailability of iron and cyanide from oral potassium ferric hexacyanoferrate(II) in humans

After oral administration of 500 mg KFe[Fe(CN)₆] labelled with⁵⁹Fe either in the ferric or ferrous position and with¹⁴C in the cyanide group only 0.22% of the Fe^II and <0.04% of the Fe^III were absorbed in three male volunteers. Only 2 mg non-complex bound relabelled cyanide (0.03 mg CN-/kg body wt) were absorbed from 500 mg [¹⁴C]KFeHCF, which is about a factor of 20–100 below the lethal dose in humans (0.5–3.5 mg CN-/kg body wt). Therefore, iron(III) hexacyanoferrates(II) can be considered as safe antidotes, i.e. for inhibiting the intestinal absorption of radiocaesium or for accelerating the excretion of already absorbed^134/137Cs in the case of a severe nuclear accident.     

A meta-analysis of apremilast on psoriatic arthritis long-term assessment of clinical efficacy (PALACE)

The aim of this article was to assess the efficacy and safety of apremilast in treatment of psoriatic arthritis (PsA) with meta-analysis method. We included four randomized clinical trials identified from MEDLINE, EMBASE, Cochrane Library, “ISRCTN Register” and “ClinicalTrials.gov” which compared apremilast with placebo. The meta-analysis was performed by the software of Review Manager, version 5.2. Apremilast was associated with significantly higher proportion of patients who achieved ACR20 at week 16 (in apremilast 20 mg subgroup, odds ratio [OR]= 2.04, 95% confidence interval [Cl] 1.58-2.63, P<0.00001; in apremilast 30 mg subgroup, OR=2.53, 95%Cl 1.96-3.25, P<0.00001) and significantly higher scores of Health Assessment Questionnaire-Disability Index (in apremilast 20 mg subgroup, WMD=-0.11, 95%Cl -0.16~-0.06, P<0.0001; in apremilast 30 mg subgroup, WMD=-0.16, 95%Cl -0.21~-0.11, P<0.00001). Apremilast was as safe as placebo in terms of serious adverse events (AEs). The AEs occurred in participants with apremilast were mild and well tolerated during treatment. Apremilast can be used in treatment of PsA with lower costs, oral availability and well tolerated. But the long-term benefit and safety of apremilast should be further investigated.     

胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂联用二甲双胍治疗2型糖尿病的疗效与安全性对比的系统评价

目的：比较胰高血糖素样肽-1（GLP-1）受体激动剂和二肽基肽酶-4（DPP-4）抑制剂联用二甲双胍治疗2型糖尿病的疗效和安全性。方法：计算机检索Pubmed,Embase,Cochrane Library,CNKI,WanFang,VIP,CBM数据库,纳入GLP-1受体激动剂和DPP-4抑制剂联用二甲双胍比较治疗2型糖尿病的随机对照试验（RCT）,检索时间截止至2016年6月1日。由两位研究者根据纳入排除标准筛选文献、提取资料以及对文献质量进行评价,采用Rev-Man 5.3.5软件对数据进行分析。结果：共纳入14篇RCT。Meta分析结果显示：GLP-1受体激动剂+二甲双胍在降低糖化血红蛋白,降低空腹血糖,减轻体重,降低收缩压方面均优于DPP-4抑制剂+二甲双胍,差异具有统计学意义;在降低舒张压方面,2组并无差别;DPP-4抑制剂+二甲双胍组不良反应发生率更低,差异具有统计学意义;在低血糖方面,2组发生率相当,没有统计学差异。结论：GLP-1受体激动剂+二甲双胍在降低2型糖尿病患者的血糖,体质量控制以及降低收缩压方面优于DPP-4抑制剂+二甲双胍,但是不良反应发生率更高。