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Lobaplatin combined floxuridine/pirarubicin-based transcatheter hepatic arterial chemoembolization for unresectable primary hepatocellular carcinoma. Zhao Chang,Wang Xu-Jie,Wang Song,Feng Wei-Hua,Shi Lei,Yu Chun-Peng Asian Pacific journal of cancer prevention : APJCP PURPOSE:To assess the effect and safety of lobaplatin combinated floxuridine /pirarubicin in transcatheter hepatic arterial chemoembolization(TACE) of unresectable primary liver cancer. PATIENTS AND METHODS:TACE combined with the chemotherapy regimen was used to treat 34 unresectable primary liver cancer patients. DSA/ MRI/CT/blood routine examinations were used to evaluate short term activity and toxicity after 4-5 weeks, the process being repeated if necessary. RESULTS:Among the 34 cases, 1 (2.9%) showed a complete response, 21 (61.7%) a partial response, 8 (23.5%) stable disease, and 4 progressive disease, with a total effective rate of 67.6%. The content of alpha fetoprotein dropped by over 50% in 20 cases (58.8%). The rate of recovery was hepatalgia (88.2%), ascites (47.1%), appetite (55.9%), Performance Status(30.4%). The median follow-up time (MFT) was 281 days (63-558 days), and median progression-free survival was 118.5 days (95%, CI:88.8-148.2 days). Adverse reactions (III-IV grade) were not common, with only 4 cases of vomiting and 2 cases of thrombocytopenia (III grade). CONCLUSIONS:Lobaplatin-based TACE is an effective and safe treatment for primary liver cancer. 10.7314/apjcp.2014.15.5.2057
Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells. Wu Qiong,Qin Shu-Kui,Teng Feng-Meng,Chen Chang-Jie,Wang Rui Journal of hematology & oncology BACKGROUND:Hepatocellular carcinoma (HCC) still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored. METHODS:Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR) and protein (Western blot) levels. The phosphorylation status of cyclin-dependent kinases (CDKs) and retinoblastoma (Rb) protein was also examined using Western blot analysis. RESULTS:Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G1 and G2/M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1), pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27. CONCLUSION:Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC. 10.1186/1756-8722-3-43
Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer. Zhang Hongming,Chen Runzhe,Wang Xiyong,Zhang Haijun,Zhu Xiaoli,Chen Jibei Frontiers in oncology Platinum-based chemotherapy is recommended as the first-line treatment regimen for patients with advanced non-small-cell lung cancer (NSCLC). Lobaplatin (LBP), a third-generation platinum anti-neoplastic agent, has shown an improved efficacy. This study is aimed to investigate the mechanisms of LBP-induced apoptosis in the A549 p53 wild-type cell line. The Cell Counting Kit-8 assay (CCK-8), flow cytometry (FCM), Western blot, xenograft tumor models, terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), and RNA interference were used in this study. Our results showed that the proliferation of A549 cells could be inhibited by LBP. At lower concentrations, LBP triggered cell cycle arrest at the G1 phase in A549 cells. LBP could also induce apoptosis of A549 cells. LBP also increased the expression of PARP and Bax and the cleavage of caspase-3, caspase-8, and caspase-9 and reduced Bcl-2 expression. experiment confirmed that LBP could inhibit tumor growth in the A549 xenograft models and induce apoptosis. Apoptosis of A549 cells was decreased after transfected with p53 shRNA or treated with reactive oxygen species inhibitor NAC and p38MAPK inhibitor SB203580, suggesting that the p53/ROS/p38MAPK pathway appeared to mediate the LBP-induced apoptosis of A549 cells. Our data demonstrate that LBP could be a promising candidate for the treatment of NSCLC with wild-type p53. 10.3389/fonc.2019.00538
Lobaplatin-TACE combined with radioactive 125I seed implantation for treatment of primary hepatocellular carcinoma. Peng Sheng,Yang Qiu-Xia,Zhang Tao,Lu Ming-Jian,Yang Guang,Liu Zhen-Yin,Zhang Rong,Zhang Fu-Jun Asian Pacific journal of cancer prevention : APJCP AIM:To investigate the efficacy and safety of lobaplatin-transcatheter arterial chemoembolization (TACE) combined with radioactive 125I seed implantation in treatment of primary hepatocellular carcinoma (HCC). METHODS:75 patients with primary HCC were enrolled in the study, among them 43 receiving lobaplatin- TACE (TACE group) and 32 lobaplatin-TACE combined with 125I seed implantation (TACE+125I group). After treatment, the local remission rates and postoperative complications of two groups were compared using the Pearson Chi-square test. Overall survival in the two groups was calculated using Kaplan-Meier survival curves and the differences were tested using Log-rank test. RESULTS:There were 7 cases of complete response (CR), 13 of partial response (PR), 6 of stable disease (SD) and 17 of progressive disease (PD) in the TACE group, with 13 cases of CR, 9 of PR, 5 of SD and 5 of PD in the TACE+125I group. The disease control rates of TACE and TACE+125I group were 60.5% (26/43) and 84.4% (27/32), respectively, with a significant difference between them (P < 0.05). The survival rates at 6, 12 and 18 months in the TACE group were 100.0%, 81.8% and 50.0%, respectively, and those in TACE+125I group were 100.0%, 93.8% and 65.6%. The mean survival times in the TACE and TACE+125I groups were 19.5 and 22.9 months, respectively. There was a significant difference in the overall survival rate between two groups (P < 0.05). No serious complications were encountered in either group. CONCLUSION:Lobaplatin-TACE combined with 125I seed implantation is favorable and safe for treatment of primary HCC. 10.7314/apjcp.2014.15.13.5155
Application of lobaplatin in trans-catheter arterial chemoembolization for primary hepatic carcinoma. Wang Nan,Lv Yin-Zhang,Xu An-Hui,Huang Yan-Rong,Peng Ling,Li Jia-Rui Asian Pacific journal of cancer prevention : APJCP OBJECTIVE:To explore the efficiency of single application of lobaplatin in tran-scatheter arterial chemoembolization (TACE) for patients with a primary hepatic carcinoma who were unable or unwilling to undergo surgery. METHODS:173 patients with primary hepatic carcinoma diagnosed by imaging or pathology were randomly divided into experimental and control groups and respectively treated with lobaplatin and pirarubicin hydrochloride as chemotherapeutic drugs for TACE. The amount of iodipin was regulated according to the tumor number and size, and then gelatin sponge or polyvinyl alcohol particles were applied for embolisms. The efficiency of treatment in the two groups was compared with reference to survival time and therapeutic response. RESULTS:The experimental group (single lobaplatin as chemotherapy drug) was superior to control group (single pirarubicin hydrochloride as chemotherapy drug) in the aspects of survival time and therapeutic response, with statistical significance. CONCLUSIONS:Single lobaplatin can be as a chemotherapy drug in TACE and has better efficiency in the aspects of mean survival time and therapeutic response, deserving to be popularized in the clinic. 10.7314/apjcp.2014.15.2.647
Lobaplatin promotes I-induced apoptosis and inhibition of proliferation in hepatocellular carcinoma by upregulating PERK-eIF2α-ATF4-CHOP pathway. Li Dong,Wang Wu-Jie,Wang Yong-Zheng,Wang Yi-Biao,Li Yu-Liang Cell death & disease We investigated the mechanism underlying the effect of a combination treatment of I radioactive seed implantation and lobaplatin (LBP) in hepatocellular carcinoma. The effects of administration of HCC cells and subcutaneous tumor model of mice with different doses of I or a sensitizing concentration of LBP alone, or in combination, on cellular apoptosis and proliferation were analyzed and it was confirmed that LBP promotes I-induced apoptosis and inhibition of proliferation of HCC. Furthermore, isobaric tag for relative and absolute quantification labeling analyses suggested that I promoted the apoptosis and inhibition of proliferation of HCC cells by upregulating the expression of PERK-eIF2α-ATF4-CHOP pathway, a well-known apoptosis-related pathway. Moreover, LBP was found to boost the I-induced upregulation of this pathway and increase the apoptosis. Our data indicate that LBP promotes the apoptotic and anti-proliferative effects of I and provide a firm foundation for better clinical application of this combination therapy. 10.1038/s41419-019-1918-1
Lobaplatin: a new antitumour platinum drug. McKeage M J Expert opinion on investigational drugs Lobaplatin (D-19466) is a diastereometric mixture of platinum(II) complexes containing a 1,2-bis(aminomethyl)cyclobutane stable ligand and lactic acid as the leaving group. Its antitumour activity results from the formation of DNA-drug adducts, mainly as GG and AG intra-strand cross-links. Lobaplatin influences the expression of the c-myc gene, which is involved in oncogenesis, apoptosis and cell proliferation. Lobaplatin has activity in a wide range of preclinical tumour models and appears to overcome tumour resistance to cisplatin and carboplatin in some of these models. In the body, lobaplatin remains largely intact until removed by glomerular filtration. Exposure of the body to lobaplatin (AUC) correlates with dose, creatinine clearance and the degree of thrombocytopoenia. Phase I clinical trials of three quite different administration schedules found the same dose-limiting toxicity (thrombocytopoenia) and similar maximum tolerated doses (60 mg/m(2) per 3 - 4 weeks). In Phase II trials, lobaplatin showed activity in patients with a variety of tumour types. Many of the patients who responded to lobaplatin may also have responded to cisplatin and carboplatin because they had had no prior chemotherapy or had a prolonged remission after earlier treatment. In conclusion, lobaplatin is a new platinum drug, which overcomes some forms of cisplatin resistance in preclinical tumour models. Several potential clinical applications remain unexplored, such as its use in relapsed testicular cancer and in combination with other cancer chemotherapeutic agents and ionising radiation. 10.1517/13543784.10.1.119
Lobaplatin: D 19466. Drugs in R&D Lobaplatin [D 19466] is a platinum complex with DNA alkylating activity that was developed by ASTA Medica (Degussa) for the treatment of cancer. ASTA Medica discontinued development of lobaplatin, and subsequent development of the compound became the responsibility of Zentaris AG (AEterna Laboratories), which was formed in 2001 from the biopharmaceutical, inhalation technology and gene therapy activities of ASTA Medica. On 30 December 2002, Zentaris was acquired by AEterna Laboratories. Cisplatin, one of the original platinum compounds, has had a major impact on the treatment of solid tumours such as germ cell cancer, ovarian cancer, bladder cancer and bronchial carcinoma, but its clinical usefulness is limited by renal, neurological and gastrointestinal toxicity. This has led to the development of second- and third-generation platinum analogues, such as lobaplatin, with reduced toxicity and a better therapeutic index. In January 2003, Zentaris AG and Hainan Tianwang International Pharmaceutical signed a contract for the manufacture and marketing of lobaplatin in China. The technology transfer agreement provides for Zentaris to receive a one-time payment to the amount of 4.5 million Canadian dollars. In addition, the contract foresees for Tianwang to manufacture and deliver lobaplatin to Zentaris or its partners for marketing in all other countries worldwide. Lobaplatin has been approved in China for the treatment of chronic myelogenous leukaemia (CML) and inoperable, metastatic breast and small cell lung cancer. However, it has not yet been launched there. In June 2003, AEterna reported that it expects lobaplatin to be launched in China by the end of 2003 at the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003). Lobaplatin has also completed phase II clinical trials in the US, Australia, EU, Brazil and South Africa for the treatment of various cancers, including breast, oesophageal, lung and ovarian cancers as well as CML. 10.2165/00126839-200304060-00008
Chemoembolization with lobaplatin mixed with iodized oil for unresectable recurrent hepatocellular carcinoma after orthotopic liver transplantation. Zhou Bin,Shan Hong,Zhu Kang-Shun,Jiang Zai-Bo,Guan Shou-Hai,Meng Xiao-Chun,Zeng Xian-Cheng Journal of vascular and interventional radiology : JVIR PURPOSE:To determine whether chemoembolization can benefit patients with unresectable recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). MATERIALS AND METHODS:Twenty-eight of 71 patients (39%) with unresectable recurrent HCC following OLT and without contradictions to chemoembolization were included: 14 patients received chemoembolization after OLT (chemoembolization group) and 14 matched control subjects who did not receive chemoembolization (non-chemoembolization group). Tumor response was determined with follow-up computed tomography after each chemoembolization procedure and classified into four grades according to Response Evaluation Criteria in Solid Tumors. Overall survival was evaluated from OLT and from the diagnosis of recurrent HCC. RESULTS:Within a median follow-up of 14.5-months, 12 of the 14 patients in the chemoembolization group (86%) and 13 of the 14 in the non-chemoembolization group (93%) developed new recurrences. Eight of the 14 patients in the chemoembolization group (57%) showed partial tumor response (>30% reduction in the size of target lesions). Moreover, patients who underwent chemoembolization had a significantly longer overall survival after OLT (P = .0133) and after the diagnosis of HCC recurrence (P = .0338) compared to those who did not. No severe complications developed in patients receiving chemoembolization during follow-up. CONCLUSIONS:Lobaplatin-based chemoembolization may elicit effective tumor response for recurrent HCCs and improve the overall survival of patients with unresectable HCC recurrence following OLT. 10.1016/j.jvir.2009.11.006
The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents. Zhou Jiabei,Kang Yu,Chen Lu,Wang Hua,Liu Junqing,Zeng Su,Yu Lushan Frontiers in pharmacology Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely. 10.3389/fphar.2020.00343
Novel approach to accurately predict bond strength and ligand lability in platinum-based anticancer drugs. Ponce-Vargas Miguel,Klein Johanna,Hénon Eric Dalton transactions (Cambridge, England : 2003) Prompted by the antineoplastic properties of cisplatin, a plethora of platinum(ii)-based complexes have been synthesized in the past decades. At present, their rational design is based on a number of structure-activity relationships involving the nature of the ligands initially coordinated to platinum(ii): either non-labile (acting as a carrier) or labile (undergoing substitution). The coordinate bond strength of the labile ligand plays a key role in the first step of the drug mechanism of action, i.e., the hydrolysis process, which is associated to the retention time of the medicine in the body. Therefore, an accurate determination of the metal-ligand bond strength becomes highly relevant as it will help the rational design of novel chemotherapeutic agents. Herein, we challenge the recently developed intrinsic bond strength index (IBSI) as a rapid and practical tool to assess the ligand lability in Pt(ii) complexes. In a first stage, given the importance of the trans-effect in synthetic strategies of cisplatin-based drugs, the effect of eleven trans-directing ligands T is quantified in two sets of complexes [Pt(NH3)2(H2O)T]n+ and [PtCl2(NH3)T]m+ where T = H2O, F-, NH3, Cl-, Br-, I-, SO32-, CH3-, CN-, CO, and H-. An essential outcome of this work is a novel index IBSItrans = IBSIσ + IBSIπ able to rank the directing ligands by their trans-effect according to their σ-donation and π-backbonding electronic contributions. In a second stage, we apply the IBSI score to a panel of eleven case studies, comprising mostly antineoplastic agents, such as cisplatin, carboplatin, lobaplatin etc., in order to quantify the coordinate bond strength of the ligands, providing insights about the hydrolysis process. The obtained results, in good agreement with experimental data and reported theoretical studies, demonstrate that the IBSI score is able to deliver a rapid and reliable picture of the coordinate bond strength, representing a chemically intuitive tool helpful for the development of novel anticancer agents prior to synthetic efforts. 10.1039/d0dt02552f
The current status of new platinum analogs. Christian M C Seminars in oncology Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance.
D-19466, a new cyclobutane-platinum complex with antitumor activity. Voegeli R,Schumacher W,Engel J,Respondek J,Hilgard P Journal of cancer research and clinical oncology D-19466, a new platinum complex, was characterized. It showed no nephrotoxic side-effects as determined by the measurement of blood urea. It was cytotoxic in vitro for tumor cells in concentrations comparable to or lower than cytotoxic concentrations of cisplatin. It had excellent anticancer activity in vivo against a number of murine experimental tumors, including a cisplatin-resistant P388 line. Clinical evaluation of this compound has therefore been initiated.
New cisplatin analogues in development. A review. Weiss Raymond B,Christian Michaele C Drugs Cisplatin was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Since the early seminal work in the preclinical and clinical development of this drug, several thousand analogues have been synthesised and tested for properties that would enhance the therapeutic index of cisplatin. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. However, carboplatin has afforded benefit only in reducing some cisplatin toxicities; it has not enlarged the spectrum of platinum-sensitive cancers, nor has it proved active in cisplatin-resistant cancers. The major obstacle to the efficacy of cisplatin or carboplatin is platinum resistance, either innate or acquired. The mechanisms of this resistance have been under intense study, and many of the cisplatin analogues synthesised in the past decade have been designed specifically with the hope of overcoming platinum resistance. The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life. Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS) 10.2165/00003495-199346030-00003
Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function. Welink J,Boven E,Vermorken J B,Gall H E,van der Vijgh W J Clinical cancer research : an official journal of the American Association for Cancer Research The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplatin in cancer patients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable) platinum, intact lobaplatin, creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable platinum and intact lobaplatin revealed almost identical patterns. The elimination of ultrafilterable platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. The calculated creatinine Cl was linearly correlated with the total body clearance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated well with the creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.