Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma

Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-na?ve and cytokine-pretreated patients. Among treatment-na?ve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-α. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted therapy. Future studies will further clarify the comparative efficacy of pazopanib with other agents as well as optimal sequencing with other agents. If similar efficacy is seen among the TKIs, it is likely that varying incidences of adverse effects may be analysed to tailor therapy according to the patient's individual co-morbidities and preferences.     

Pazopanib,a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.     

Pazopanib for the treatment of breast cancer

INTRODUCTION: Several clinical trials have shown clinical benefit of angiogenesis inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyrosine kinase inhibitor that is currently approved for the treatment of patients with advanced renal cell carcinoma (RCC). AREAS COVERED: In this article, the clinical development of pazopanib as it relates to breast cancer is reviewed including its evaluation in clinical trials and side effect profile. Preclinical data show the anti-tumor activity of pazopanib in animal models. Several trials of pazopanib monotherapy and combination therapy in breast cancer have been completed or are underway. EXPERT OPINION: The development of biomarkers predictive of response and toxicity to angiogenesis inhibitors remains a challenging endeavor and is necessary to help guide treatment decision.     

Pazopanib for the treatment of renal cancer

INTRODUCTION: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors. AREAS COVERED: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed. EXPERT OPINION: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents - sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) - have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.

Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.

Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

Pazopanib. Kidney cancer: many risks, but is there a benefit for patients?

Chemotherapy has little impact on renal carcinoma. Interferon alfa is the standard treatment, in the absence of a better alternative, but the median survival time is less than a year among patients with advanced-stage or metastatic disease. Pazopanib inhibits multiple receptor tyrosine kinases, including the tyrosine kinase coupled to the vascular endothelial growth factor receptor (VEGFR), thus inhibiting angiogenesis. It is authorised in the European Union for the treatment of advanced-stage renal carcinoma. Clinical evaluation of pazopanib is based on a double-blind placebo-controlled trial in 435 patients. Follow-up is currently too short to determine whether pazopanib improves overall survival. The median progression-free survival time, based on radiological criteria, was 5 months longer with pazopanib: 9.2 months versus 4.2 months with placebo. This is similar to the efficacy obtained in trials of other cytotoxic drugs such as sunitinib. The adverse-effect profile of pazopanib is unfavourable: it includes disorders linked to its antiangiogenic activity (hypertension, arterial thrombosis, myocardial infarction, haemorrhage, etc.), as well as gastrointestinal disorders and hand-foot syndrome. In clinical trials including a total of 593 patients, 2 patients receiving pazopanib developed torsades de pointes and 3 other patients died of liver failure. Numerous pharmacokinetic interactions are likely, notably involving cytochrome P450 isoenzyme CYP 3A4. The risk-benefit balance of pazopanib is currently too unfavourable to justify its use in patients with advanced-stage or metastatic kidney cancer.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development. Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib . It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC. Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

Emerging therapies targeting tumor vasculature in multiple myeloma and other hematologic and solid malignancies

Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies.     

Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines

Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse‐XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady‐state plasma concentrations in humans. In HepaRG cells, pretreatment with rifampicin decreased membrane toxicity (measured as adenylate kinase release) and dissipation of adenosine triphosphate stores, indicating that toxicity was associated mainly with the parent drugs. Ponatinib strongly impaired oxidative metabolism but only weakly glycolysis, and induced apoptosis of HepG2 cells at concentrations higher than steady‐state plasma concentrations in humans. Crizotinib and dasatinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis of HepG2 cells. Pazopanib was associated with a weak increase in mitochondrial reactive oxygen species accumulation and inhibition of glycolysis without being cytotoxic. In conclusion, regorafenib and sorafenib are strong mitochondrial toxicants and inhibitors of glycolysis at clinically relevant concentrations. Ponatinib affects mitochondria and glycolysis at higher concentrations than reached in plasma (but possibly in liver), whereas crizotinib, dasatinib and pazopanib showed no relevant toxicity. Mitochondrial toxicity and inhibition of glycolysis most likely explain hepatotoxicity associated with regorafenib, sorafenib and possibly pazopanib, but not for the other compounds investigated.     

Sulfonamides: a patent review (2008 - 2012)

INTRODUCTION: The primary sulfonamide moiety is present in many clinically used drugs, such as diuretics (furosemide, indapamide, chlorthalidone, thiazides); carbonic anhydrase (CA) inhibitors (CAIs) (including acetazolamide, dichlorophenamide, dorzolamide and brinzolamide); antiepileptics (zonisamide and sulthiame); the antipsychotic sulpiride and the cycloxygenase 2 (COX2) inhibitors celecoxib and valdecoxib. Recently, novel drugs have been launched, such as apricoxib and pazopanib, which also incorporate this group. AREAS COVERED: The article presents the main classes of sulfonamides investigated between 2008 and 2012. Specifically, the authors review the scientific and patent literature on CAIs, COX2 inhibitors, pazopanib and its congeners, which are multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. EXPERT OPINION: Most patents deal with sulfonamide CAIs incorporating NO-donating moieties as antiglaucoma agents, or with compounds targeting the tumor-associated isoforms CA IX/XII. The antidandruff actions of sulphonamides, which inhibit yeast CAs, were also claimed. Apricoxib (a COX2 inhibitor) and pazopanib, a tyrosine kinase inhibitor, show significant antitumor activity and several patents deal with these drugs. There is a constant need of novel sulfonamides to act as selective antiglaucoma drugs (targeting CA II), as antitumor agents/diagnostic tools (targeting CA IX/XII), and to treat and diagnose other disease. This privileged structural motif is likely to be present in other drugs in the future.     

Pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma

Introduction: Liposarcomas (LPS) are a heterogeneous group of adipocytic soft tissue sarcomas with limited treatment options in the advanced/metastatic setting. Pazopanib is a multi-target tyrosine kinase inhibitor (TKI) with anti-angiogenic and antitumorigenic properties. Whilst targeted agents including TKIs have been extensively studied in other solid tumors and the sarcoma subtype gastrointestinal stromal tumor (GIST), we currently lack effective treatments for the liposarcoma subtype. Several phase II and III studies of oral TKIs in soft tissue sarcomas have excluded liposarcoma because of a reported lack of activity following the EORTC 62043 study.

Areas: We review the use of pazopanib in advanced intermediate and high-grade liposarcomas where complete surgical resection is not possible.

Expert opinion: The current clinical and pharmacological data demonstrate the efficacy of pazopanib in soft tissue sarcomas, but new data suggest that anti-angiogenic agents may have limited activity in liposarcoma. Anti-angiogenic TKIs are generally well tolerated and liposarcomas vary in their response to systemic chemotherapy; hence, there is a role for further exploration of the efficacy of this treatment amongst the histological subtypes of liposarcoma. This affords further understanding of biomarkers which may be associated with response to pazopanib and other anti-angiogenic TKI treatments.     

伊马替尼耐药胃肠间质瘤治疗药物的研究进展

胃肠间质瘤是胃肠道发生频率最高的间质来源的恶性肿瘤,彻底手术切除是其获得根治的唯一方法,但术后复发和转移的频率较高。伊马替尼在2002年被美国食品药品管理局(FDA)批准用于胃肠间质瘤的治疗,但治疗失败的病例依然不可避免。原发耐药和继发耐药是伊马替尼治疗胃肠间质瘤失败的主要耐药机制。相关指南推荐已获批准的用于伊马替尼治疗失败后的酪氨酸激酶抑制剂舒尼替尼和瑞戈非尼作为二、三线药物治疗,同时ATP类似物索拉非尼、尼洛替尼、帕唑帕尼、帕纳替尼和马赛替尼,其他TKI药物,如达沙替尼、瓦塔拉尼、莫特塞尼,以及其他靶向治疗药物依维莫司和ganetespib在临床试验中显示出对伊马替尼耐药胃肠间质瘤有效。综述伊马替尼治疗失败后用于临床治疗胃肠间质瘤的治疗药物的作用机制、临床应用、作用特点和主要副作用,为临床胃肠间质瘤的治疗药物选择提供参考。     

Sulfonamides: a patent review (2008 – 2012)

Introduction: The primary sulfonamide moiety is present in many clinically used drugs, such as diuretics (furosemide, indapamide, chlorthalidone, thiazides); carbonic anhydrase (CA) inhibitors (CAIs) (including acetazolamide, dichlorophenamide, dorzolamide and brinzolamide); antiepileptics (zonisamide and sulthiame); the antipsychotic sulpiride and the cycloxygenase 2 (COX2) inhibitors celecoxib and valdecoxib. Recently, novel drugs have been launched, such as apricoxib and pazopanib, which also incorporate this group.

Areas covered: The article presents the main classes of sulfonamides investigated between 2008 and 2012. Specifically, the authors review the scientific and patent literature on CAIs, COX2 inhibitors, pazopanib and its congeners, which are multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit.

Expert opinion: Most patents deal with sulfonamide CAIs incorporating NO-donating moieties as antiglaucoma agents, or with compounds targeting the tumor-associated isoforms CA IX/XII. The antidandruff actions of sulphonamides, which inhibit yeast CAs, were also claimed. Apricoxib (a COX2 inhibitor) and pazopanib, a tyrosine kinase inhibitor, show significant antitumor activity and several patents deal with these drugs. There is a constant need of novel sulfonamides to act as selective antiglaucoma drugs (targeting CA II), as antitumor agents/diagnostic tools (targeting CA IX/XII), and to treat and diagnose other disease. This privileged structural motif is likely to be present in other drugs in the future.     

Toxicities of targeted agents in advanced renal cell carcinoma

The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management.     

Clinical activity of tipifarnib in hematologic malignancies

Farnesyltransferase inhibitors are a novel class of anticancer agents that competitively inhibit farnesyltransferase. Initially developed to inhibit the farnesylation that is necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. Of the four classes of farnesyltransferase inhibitors, at least three agents have been investigated in hematologic malignancies. Tipifarnib (R-115777), an orally administered non-peptidomimetic farnesyltransferase inhibitor, has shown promising clinical activity. Preliminary results from clinical trials demonstrate enzyme target inhibition, an acceptable toxicity profile and promising evidence of clinical activity. Ongoing studies will better determine the mechanism of action of tipifarnib and the role of combination with other agents, defining its place in the therapeutic arsenal of hematologic disorders.     

Clinical activity of tipifarnib in hematologic malignancies

Farnesyltransferase inhibitors are a novel class of anticancer agents that competitively inhibit farnesyltransferase. Initially developed to inhibit the farnesylation that is necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. Of the four classes of farnesyltransferase inhibitors, at least three agents have been investigated in hematologic malignancies. Tipifarnib (R-115777), an orally administered non-peptidomimetic farnesyltransferase inhibitor, has shown promising clinical activity. Preliminary results from clinical trials demonstrate enzyme target inhibition, an acceptable toxicity profile and promising evidence of clinical activity. Ongoing studies will better determine the mechanism of action of tipifarnib and the role of combination with other agents, defining its place in the therapeutic arsenal of hematologic disorders.     

Progress and contrasts of the development of tivozanib for therapy of kidney cancer

INTRODUCTION: Targets for drug development for the treatment of kidney cancer (renal cell carcinoma; RCC) include vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin. Currently available oral multitargeted VEGF tyrosine kinase inhibitors (TKIs) that have been approved by the US Food and Drug Administration for advanced RCC, include sunitinib, sorafenib and pazopanib. Off-target TKI inhibition can potentially preclude full-dose combination with other targeted and chemotherapeutic agents. There is a need to develop more potent and selective targeted agents for RCC therapy, which are more effective and have minimal off-target effects. AREAS COVERED: This drug evaluation review addresses the ongoing development for the treatment of RCC with tivozanib: a potent, selective and long-half-life VEGF TKI. The testing for clinical efficacy alone or in combination with other therapies for RCC and for other tumor types, and the clinical and market relevance of introducing another RCC therapy are discussed. EXPERT OPINION: Tivozanib is distinguished by its high potency, selectivity, long-half-life and its potential to be effectively combined with other agents in RCC. This may offer more effective, yet well-tolerated treatment options. The relative clinical and market relevance remain to be seen, both for RCC therapy and other tumor types.     

Novel targets for VEGF-independent anti-angiogenic drugs

INTRODUCTION: In the last decades, the active research in the field of tumor angiogenesis led to the development of a class of agents providing an effective inhibition of neovessels formation through the blockade of VEGF-related pathways. More recently, the identification of several non-VEGF factors such as PDGF, FGF, HGF, angiopoietins, ALK1/endoglin, endothelis and ephrins involved in tumor angiogenesis have emphasized the need to develop agents targeting multiple pro-angiogenic pathways. AREAS COVERED: This review aimed at summarizing the role of non-VEGF molecular pathways in targeting tumor angiogenesis. Preclinical and clinical data for investigational agents against non-VEGF targets have been reviewed emphasizing the role of combined inhibition strategies. EXPERT OPINION: Besides the successful development of drugs providing a specific VEGF blockade, novel agents targeting alternative angiogenesis-related pathways are being tested. Although it seems that the potential clinical usefulness of these novel compounds have been not yet fully investigated, sunitinib, sorafenib, pazopanib and other multikinase inhibitors have certainly displayed encouraging results. A more in-depth clarification of anti-angiogenic agents is still needed, in order to design the best clinical setting and schedule for target-based agents and possibly anticipate potential tools to overcome the emerging issue of anti-angiogenic drug resistance.     

The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta-analysis

Pazopanib is a novel multikinase inhibitor that shares a similar spectrum of target receptors with sorafenib and sunitinib. We have performed a systematic analysis to investigate the risk of HFSR to pazopanib and compare the difference in incidence between sorafenib, sunitinib, and pazopanib. Relevant studies were identified from PubMed (1998-2010) and abstracts presented at the American Society of Clinical Oncology Conferences between 2004 and 2010. Eligible studies were limited to prospective Phase II-III clinical trials in which cancer patients were treated with pazopanib 800 mg orally once daily. Incidence, relative risk (RR), and 95% confidence intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. A total of 1,163 patients from 10 prospective clinical trials were included in the analysis. The overall incidence of all-grade and high-grade HFSR was 4.5% (95% CI: 2.5-7.9%) and 1.8% (95% CI: 0.7-4.6%), respectively. The relative risks of all-grade and high-grade HFSR to pazopanib monotherapy in comparison with controls were increased for all-grade (RR = 6.09, 95% CI: 1.11-33.36, p = 0.037) and high-grade HFSR (RR = 2.51, 95% CI: 0.12-51.9, p = 0.55). The risk of all-grade and high-grade HFSR to pazopanib was significantly lower as compared to sorafenib and sunitinib (RR = 7.5, 95% CI: 5.5-10.2, p < 0.001; RR = 5.9, 95% CI: 3.5-10.0, p < 0.001 and RR = 4.2, 95% CI: 3.0-5.7, p < 0.001; RR = 3.6, 95% CI: 2.1-6.2, p < 0.001). Despite sharing the same spectrum of target receptors with sorafenib and sunitinib, pazopanib is associated with an unexpectedly low risk of HFSR. Further investigations are needed to elucidate HFSR pathogenesis.     

Studies on an anti-inflammatory agent. III. Pharmacological investigations of a new non-steroidal anti-inflammatory agent: 2-oxo-3-[4-(1-oxo-2-isoindolinyl)-phenyl]-butanamide (GP 650)

The anti-inflammatory, analgesic, antipyretic and ulcerogenic activities and acute toxicity of 2-oxo-3-[4-(1-oxo-2-isoindolinyl)-phenyl]-butanamide (GP 650) were investigated in laboratory animals and compared with those of phenylbutazone, acetylsalicylic acid (ASA), ibuprofen, tiaramide-HCl and tinoridine-HCl. The anti-inflammatory and analgesic activities of GP 650 were found to be almost equivalent to those of phenylbutazone on the basis of various anti-inflammatory and analgesic tests while its antipyretic activity was less marked, and its ulcerogenic action and acute toxicity were much lower than those of the other agents. It is interesting to note that GP 650 possesses marked anti-inflammatory activity similar to acidic anti-inflammatory agents in chronic inflammatory models along with mild antipyretic and ulcerogenic activities found in basic anti-inflammatory agents. Therefore, GP 650 appears to be a promising anti-inflammatory and analgesic agent.