Search

Purpose of reviewChronic kidney disease (CKD) is associated with the development of mineral and bone disorders (MBD), including renal osteodystrophy (ROD). ROD is a global disorder of bone strength that is associated with an increased fracture risk. The use of bisphosphonates for fracture risk reduction in CKD remains controversial. This review provides a synopsis of the state-of-the literature regarding the safety and potential antifracture benefits of bisphosphonates in CKD patients.Recent findingsIn preclinical studies of animals with CKD 3-4 and evidence of CKD-MBD, bisphosphonates resulted in changes in bone quality that improve bone strength. Bone turnover was generally reduced to a similar extent in animals with and without CKD. Post hoc analyses of randomized trials in patients with CKD 3-4 reported increases in bone mineral density (BMD) and fracture reduction that were similar in patients with and without CKD. There are no primary clinical trial data in patients with CKD-MBD.SummaryIn patients with CKD without evidence of CKD-MBD, the use of bisphosphonates should follow general population guidelines. The lack of data for patients with CKD 4-5D and evidence of CKD-MBD makes treatment decisions challenging. Clinical studies are urgently needed to provide data on the safety and antifracture benefits of bisphosphonates in these cohorts.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Purpose of reviewChronic kidney disease (CKD) is associated with the development of mineral and bone disorders (MBD), including renal osteodystrophy (ROD). ROD is a global disorder of bone strength that is associated with an increased fracture risk. The use of bisphosphonates for fracture risk reduction in CKD remains controversial. This review provides a synopsis of the state-of-the literature regarding the safety and potential antifracture benefits of bisphosphonates in CKD patients.Recent findingsIn preclinical studies of animals with CKD 3-4 and evidence of CKD-MBD, bisphosphonates resulted in changes in bone quality that improve bone strength. Bone turnover was generally reduced to a similar extent in animals with and without CKD. Post hoc analyses of randomized trials in patients with CKD 3-4 reported increases in bone mineral density (BMD) and fracture reduction that were similar in patients with and without CKD. There are no primary clinical trial data in patients with CKD-MBD.SummaryIn patients with CKD without evidence of CKD-MBD, the use of bisphosphonates should follow general population guidelines. The lack of data for patients with CKD 4-5D and evidence of CKD-MBD makes treatment decisions challenging. Clinical studies are urgently needed to provide data on the safety and antifracture benefits of bisphosphonates in these cohorts.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).Copyright © 2018, The Author(s).

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).Copyright © 2018, The Author(s).

Australian tea tree oil (TTO) and its extract terpinen-4-ol (T4O) are found to be effective in moderating demodex-related diseases. Their possible effects are lowering the mite counts, relieving the demodex-related symptoms and modulating the immune system especially the inflammatory response. This review summarizes the topical treatments of TTO and T4O in human demodicosis, their possible mechanism of actions, side-effects and potential resistance in treating this condition. Although current treatments other than TTO and T4O are relatively effective in controlling the demodex mite population and the related symptoms, more research on the efficacy and drug delivery technology is needed in order to assess its potential as an alternative treatment with minimal side-effect profile, low toxicity and low risk of demodex resistance.Copyright © Cambridge University Press 2018.

In this review, we discuss the potential use of antimalarial drugs as an adjuvant therapy for preeclampsia, focusing on the mechanisms of action of this class of drugs in the context of preeclampsia. In particular, hydroxychloroquine has been shown to have various beneficial effects on patients with systemic lupus erythematosus. There are several pathways targeted by the antimalarial drugs that are similar to the pathophysiology of preeclampsia and hence offering opportunities to develop novel therapies to treat the disease. Given the safety profile of hydroxychloroquine in pregnancy, there is merit in exploring the efficacy of this drug as an adjuvant therapy in women with early onset preeclampsia.Copyright © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Australian tea tree oil (TTO) and its extract terpinen-4-ol (T4O) are found to be effective in moderating demodex-related diseases. Their possible effects are lowering the mite counts, relieving the demodex-related symptoms and modulating the immune system especially the inflammatory response. This review summarizes the topical treatments of TTO and T4O in human demodicosis, their possible mechanism of actions, side-effects and potential resistance in treating this condition. Although current treatments other than TTO and T4O are relatively effective in controlling the demodex mite population and the related symptoms, more research on the efficacy and drug delivery technology is needed in order to assess its potential as an alternative treatment with minimal side-effect profile, low toxicity and low risk of demodex resistance.Copyright © Cambridge University Press 2018.

Artemisinin (ART) and its derivatives are one of the most important classes of antimalarial agents, originally derived from a Chinese medicinal plant called Artemisia annua L. Beyond their outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess both in-vitro and in-vivo activities against various types of cancer. Their anticancer effects range from initiation of apoptotic cell death to inhibition of cancer proliferation, metastasis and angiogenesis, and even modulation of the cell signal transduction pathway. This review provides a comprehensive update on ART and its derivatives, their mechanisms of action, and their synergistic effects with other chemicals in targeting leukemia cells. Combined with limited evidence of drug resistance and low toxicity profile, we conclude that ART and its derivatives, including dimers, trimers, and hybrids, might be a potential therapeutic alternative to current chemotherapies in combating leukemia, although more studies are necessary before they can be applied clinically.Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

In this review, we discuss the potential use of antimalarial drugs as an adjuvant therapy for preeclampsia, focusing on the mechanisms of action of this class of drugs in the context of preeclampsia. In particular, hydroxychloroquine has been shown to have various beneficial effects on patients with systemic lupus erythematosus. There are several pathways targeted by the antimalarial drugs that are similar to the pathophysiology of preeclampsia and hence offering opportunities to develop novel therapies to treat the disease. Given the safety profile of hydroxychloroquine in pregnancy, there is merit in exploring the efficacy of this drug as an adjuvant therapy in women with early onset preeclampsia.Copyright © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Background Epidemiological studies and randomised clinical trials (RCTs) report disparate findings in relation to omega-3 polyunsaturated fatty acids (n-3 PUFA) benefit for cardiac patients. With RCTs interpretation is potentially confounded by background n-3 PUFA intake. The goal of this pilot, small cohort, pre-surgical supplementation study was to evaluate postoperative atrial fibrillation (AF) and cardiac molecular expression profiles employing two data analysis approaches - by treatment randomisation and by stratification using measured n-3 PUFA. Methods Patients (n = 20) received 3 g/day of fish or placebo oil (FO vs PO) in a double blind randomised protocol prior to elective coronary artery graft and valve surgery. Groups were matched for age, gender, and mean treatment duration (~20 days). Resected atrial myocardium was sampled for assay of viability metabolic markers, and blood obtained for erythrocyte membrane lipid measurement. Results There was substantial overlap of cell membrane n-3 PUFA content across PO and FO groups, and no group treatment effects on AF incidence or myocardial molecular marker levels were detected. In contrast, data stratification using membrane n-3 PUFA content (at 8% total membrane lipid) achieved significant separation of patients (by n-6:n-3 PUFA ratio), a significant differential cardiac expression of the marker peroxisomal proliferator-activated receptor, but no difference in AF incidence. Conclusions This small n-3 PUFA case study demonstrates that the same cohort may yield differing findings when evaluated using randomisation or stratification approaches based on direct molecular measures in cell membranes.Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)

The regulatory role of a novel miRNA, miR-378, was determined in the development of fibrosis through repression of the MAPK1 pathway, miR-378 and fibrotic gene expression was examined in streptozotocin (STZ)-induced diabetic mice at 18 weeks or in unilateral ureteral obstruction (UUO) mice at 7 days. miR-378 transfection of proximal tubular epithelial cells, NRK52E and mesangial cells was assessed with/without endogenous miR-378 knockdown using the locked nucleic acid (LNA) inhibitor. NRK52E cells were co-transfected with the mothers against decapentaplegic homolog 3 (SMAD3) CAGA reporter and miR-378 in the presence of transforming growth factor-beta (TGF-beta1) was assessed. Quantitative polymerase chain reaction (qPCR) showed a significant reduction in miR-378 (P < 0.05) corresponding with up-regulated type I collagen, type IV collagen and a-smooth muscle actin (SMA) in kidneys of STZ or UUO mice, compared with controls. TGF-beta1 significantly increased mRNA expression of type I collagen (P < 0.05), type IV collagen (P < 0.05) and alpha-SMA (P < 0.05) in NRK52E cells, which was significantly reduced (P < 0.05) following miR-378 transfection and reversed following addition of the LNA inhibitor of endogenous miR-378. Overexpression of miR-378 inhibited mesangial cell expansion and proliferation in response to TGF-beta1, with LNA-miR-378 transfection reversing this protective effect, associated with cell morphological alterations. The protective function of MAPK1 on miR-378 was shown in kidney cells treated with the MAPK1 inhibitor, selumetinib, which inhibited mesangial cell hypertrophy in response to TGF-beta1. Taken together, these results suggest that miR-378 acts via regulation of the MAPK1 pathway. These studies demonstrate the protective function of MAPK1, regulated by miR-378, in the induction of kidney cell fibrosis and mesangial hypertrophy.Copyright © 2017 The Author(s).

Background Epidemiological studies and randomised clinical trials (RCTs) report disparate findings in relation to omega-3 polyunsaturated fatty acids (n-3 PUFA) benefit for cardiac patients. With RCTs interpretation is potentially confounded by background n-3 PUFA intake. The goal of this pilot, small cohort, pre-surgical supplementation study was to evaluate postoperative atrial fibrillation (AF) and cardiac molecular expression profiles employing two data analysis approaches - by treatment randomisation and by stratification using measured n-3 PUFA. Methods Patients (n = 20) received 3 g/day of fish or placebo oil (FO vs PO) in a double blind randomised protocol prior to elective coronary artery graft and valve surgery. Groups were matched for age, gender, and mean treatment duration (~20 days). Resected atrial myocardium was sampled for assay of viability metabolic markers, and blood obtained for erythrocyte membrane lipid measurement. Results There was substantial overlap of cell membrane n-3 PUFA content across PO and FO groups, and no group treatment effects on AF incidence or myocardial molecular marker levels were detected. In contrast, data stratification using membrane n-3 PUFA content (at 8% total membrane lipid) achieved significant separation of patients (by n-6:n-3 PUFA ratio), a significant differential cardiac expression of the marker peroxisomal proliferator-activated receptor, but no difference in AF incidence. Conclusions This small n-3 PUFA case study demonstrates that the same cohort may yield differing findings when evaluated using randomisation or stratification approaches based on direct molecular measures in cell membranes.Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)

The regulatory role of a novel miRNA, miR-378, was determined in the development of fibrosis through repression of the MAPK1 pathway, miR-378 and fibrotic gene expression was examined in streptozotocin (STZ)-induced diabetic mice at 18 weeks or in unilateral ureteral obstruction (UUO) mice at 7 days. miR-378 transfection of proximal tubular epithelial cells, NRK52E and mesangial cells was assessed with/without endogenous miR-378 knockdown using the locked nucleic acid (LNA) inhibitor. NRK52E cells were co-transfected with the mothers against decapentaplegic homolog 3 (SMAD3) CAGA reporter and miR-378 in the presence of transforming growth factor-beta (TGF-beta1) was assessed. Quantitative polymerase chain reaction (qPCR) showed a significant reduction in miR-378 (P < 0.05) corresponding with up-regulated type I collagen, type IV collagen and a-smooth muscle actin (SMA) in kidneys of STZ or UUO mice, compared with controls. TGF-beta1 significantly increased mRNA expression of type I collagen (P < 0.05), type IV collagen (P < 0.05) and alpha-SMA (P < 0.05) in NRK52E cells, which was significantly reduced (P < 0.05) following miR-378 transfection and reversed following addition of the LNA inhibitor of endogenous miR-378. Overexpression of miR-378 inhibited mesangial cell expansion and proliferation in response to TGF-beta1, with LNA-miR-378 transfection reversing this protective effect, associated with cell morphological alterations. The protective function of MAPK1 on miR-378 was shown in kidney cells treated with the MAPK1 inhibitor, selumetinib, which inhibited mesangial cell hypertrophy in response to TGF-beta1. Taken together, these results suggest that miR-378 acts via regulation of the MAPK1 pathway. These studies demonstrate the protective function of MAPK1, regulated by miR-378, in the induction of kidney cell fibrosis and mesangial hypertrophy.Copyright © 2017 The Author(s).

The use of opioids for chronic pain has increased significantly due to a combination of the high patient burden of pain and the more widespread availability of a range of long-acting opioid preparations. This increased opioid use has translated into the care of many patients with fibromyalgia. The pain mechanism in fibromyalgia is complex but does not seem to involve disturbance of opioid analgesic functions. Hence, there is general concern about the harms in the absence of benefits of opioids in this setting. There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia.Copyright © 2016 Future Medicine Ltd.

BACKGROUND: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHOD(S): The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOME(S): Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is >= 35 kg/m2 and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good

In recent years, the negative impact of oxidative stress on fertility has become widely recognised. Several studies have demonstrated its negative effect on the number and quality of retrieved oocytes and embryos following in-vitro fertilisation (IVF). Melatonin, a pineal hormone that regulates circadian rhythms, has also been shown to exhibit unique oxygen scavenging abilities. Some studies have suggested a role for melatonin in gamete biology. Clinical studies also suggest that melatonin supplementation in IVF may lead to better pregnancy rates. Here we present a critical review and summary of the current literature and provide suggestions for future well designed clinical trials.Copyright © 2014 Fernando and Rombauts.

The use of opioids for chronic pain has increased significantly due to a combination of the high patient burden of pain and the more widespread availability of a range of long-acting opioid preparations. This increased opioid use has translated into the care of many patients with fibromyalgia. The pain mechanism in fibromyalgia is complex but does not seem to involve disturbance of opioid analgesic functions. Hence, there is general concern about the harms in the absence of benefits of opioids in this setting. There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia.Copyright © 2016 Future Medicine Ltd.

BACKGROUND: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHOD(S): The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOME(S): Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is >= 35 kg/m2 and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good

In recent years, the negative impact of oxidative stress on fertility has become widely recognised. Several studies have demonstrated its negative effect on the number and quality of retrieved oocytes and embryos following in-vitro fertilisation (IVF). Melatonin, a pineal hormone that regulates circadian rhythms, has also been shown to exhibit unique oxygen scavenging abilities. Some studies have suggested a role for melatonin in gamete biology. Clinical studies also suggest that melatonin supplementation in IVF may lead to better pregnancy rates. Here we present a critical review and summary of the current literature and provide suggestions for future well designed clinical trials.Copyright © 2014 Fernando and Rombauts.

Summary: The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-kappaB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-kappaB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.Copyright © 2014 John Wiley & Sons Ltd.

Summary: The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-kappaB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-kappaB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.Copyright © 2014 John Wiley & Sons Ltd.

Four direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) have been shown to be at least as effective and safe as warfarin for the prevention of stroke in atrial fibrillation and the prevention and treatment of venous thromboembolism. Although they are administered in fixed doses without routine coagulation monitoring, measurement of anticoagulant effect or drug levels may be useful to determine if: anticoagulant effect is present in patients who are bleeding or require an urgent procedure or thrombolysis; levels are within usual on-therapy range in patients with recurrent thromboembolism during treatment; and levels are outside of the usual on-therapy range in patients with overdose or with extreme clinical characteristics. Traditional coagulation assays are widely available but lack sensitivity to detect clinically relevant anticoagulant effects, and lack accuracy in quantitating drug levels. Specific drug assays are less widely available but can accurately measure drug levels and should be preferred.Copyright © 2015 Taylor & Francis.

Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed. © 2013 Elsevier Ltd. All rights reserved.

Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed. © 2013 Elsevier Ltd. All rights reserved.

OBJECTIVES: * To review the literature regarding ischaemic, non-ischaemic and stuttering priapism * To provide management recommendations PATIENTS AND METHODS: * A Medline search was carried out to identify all relevant papers with management guidelines for priapism. RESULT(S): * Ischaemic priapism represents a compartment syndrome of the penis and urgent intervention is required to decrease the risk of erectile dysfunction. * Non-ischaemic priapism is not a medical emergency; however, it can result in erectile dysfunction. * The treatment objective for stuttering priapism is to reduce future episodes with systemic treatments, whilst treating each ischaemic episode as an emergency. CONCLUSION(S): * Priapism is a complex condition that requires expert care to prevent complications and irreversible erectile dysfunction. © 2012 The Authors © 2012 BJU International.

Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60 of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-B1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial

Aim: To examine the efficacy and safety of nimodipine as an alternative to papaverine for the treatment of cerebral vasospasm following subarachnoid haemorrhage. Method(s): We retrospectively reviewed the procedure reports, anaesthetic records, clinical charts and CT and angiographic images of 9 patients who had received intra-arterial nimodipine; 1 of these patients received both nimodipine and papaverine. The difference in arterial luminal diameter before and after treatment was calculated as a percentage change. Result(s): The average dose of nimodipine administered per vessel was 3.3 mg. The mean increase in arterial diameter was 66.6% in the vasospastic segment. There was no significant change in blood pressure of any of the subjects during endovascular treatment of vasospasm. Conclusion(s): Intra-arterial nimodipine is effective in improving angiographic vasospasm complicating subarachnoid haemorrhage. Further studies aimed at examining the clinical benefits of nimodipine are warranted, particularly in view of the low risk of adverse side effects of nimopidine when compared with papaverine. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Background. Ketamine has been found to exert antinociceptive effects in animals and to be analgesic at subanaesthetic doses in humans. This study was designed to investigate the involvement of spinal cord mechanisms in the potentiation of opioid analgesia by parenteral non-spinal administration of ketamine. Methods. Thresholds for nociception were measured in an acute pain model in rats that allowed identification of antinociceptive effects due to drug action in the spinal cord. Dose-response curves for the antinociceptive effects of ketamine alone and ketamine in conjunction with the mu opioid fentanyl were constructed. Results. Intraperitoneal ketamine up to 3.75 mg kg-1 caused no sedative or antinociceptive effects and intrathecal ketamine caused dose-dependent, spinally mediated antinociceptive effects. Injections of ketamine doses that caused no antinociceptive effects when given alone (intrathecal 25 mug and intraperitoneal 3.75 mg/kg) significantly increased spinally mediated antinociception produced by intrathecal fentanyl injections when assessed using noxious heat (tail-flick test) but not when assessed by noxious electrical current (electrical current threshold test). Conclusions. We conclude that ketamine can potentiate the effects of fentanyl by an interaction at the level of the spinal cord even when ketamine is given via a non-spinal route of administration.

Background: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. Method(s): This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. Result(s): Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m-2). Doses up to 202 mg m-2 were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m 2, consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour Ktrans values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of 65 mg m-2. Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for 2 cycles. Conclusion(s): CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours. © 2010 Cancer Research UK All rights reserved.

Aspirin resistance refers to less than expected suppression of thromboxane A2 production by aspirin and has been reported to be independently associated with an increased risk of adverse cardiovascular events. Possible causes of aspirin resistance include poor compliance, drug interaction, inadequate aspirin dose, increase turnover of platelets, genetic polymorphisms of cyclo-oxygenase-1, and upregulation of alternate (non-platelet) pathways of thromboxane production. Laboratory methods used to detect aspirin resistance include those that measure thromboxane A2 production and thromboxane A2-dependent platelet function. However, since there is currently no standardised approach to the diagnosis and there are no proven effective treatments for aspirin resistance that improve outcome, patients with cardiovascular disease receiving aspirin should not be routinely tested for aspirin resistance. Instead physicians should be aware of the factors that may impair aspirin function, ensure that they use an appropriate dose of aspirin and optimise compliance with aspirin therapy. Further research exploring the mechanisms of aspirin resistance is needed in order to better define and develop a standardised test for aspirin resistance that is specific, reliable, can be readily applied in routine laboratories and correlate with an increased risk of cardiovascular events. © 2006 Elsevier Ltd. All rights reserved.

In a retrospective cohort study we have previously shown that administration of betamethasone to women with a pregnancy complicated by absent end-diastolic flow in the umbilical artery (UA) is associated with altered UA flow velocity waveforms. To examine this phenomenon further we undertook a prospective study of 30 similar singleton pregnancies. Umbilical artery FVWs were recorded before and after betamethasone administration using real-time pulsed wave colour flow Doppler. The results of this prospective cohort were similar to those of the retrospective study allowing pooling of the data. Of the 55 total pregnancies with umbilical artery AEDF studied betamethasone administration was associated with the return of end-diastolic flow in 39 (71 per cent; 95 per centCI: 59-83 per cent). The median (range) duration of this change was 3 (1-10) days. There is no evidence that this change has either a beneficial or detrimental effect on foetal health. Administration of betamethasone to women with a pregnancy complicated by umbilical artery AEDF is associated with the transient return of end-diastolic flow in most cases. While the mechanisms underlying this effect are yet to be fully elucidated it has implications for foetal surveillance in these high-risk pregnancies. © 2002 Elsevier Science Ltd. All rights reserved.

Many women using progestogen (P)-only contraceptives experience uterine bleeding problems. In clinical trials, a single low dose of mifepristone, given to Implanon users at the beginning of a bleeding episode reduced the number of bleeding days by - 50% compared with controls. In this study, a single dose of mifepristone was administered to etonogestrel (ENG)-exposed pseudo-pregnant mice, 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding. Control mice received vehicle alone. Mice were culled 12-, 18-, 24- and 48-h post-treatment. In the continued presence of ENG, a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair: most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment. During repair, proliferating cells (Ki67 immunostained) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands. Progesterone receptor-positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls. Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues. It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity: such action may be a key event in reducing the number of bleeding days observed in women using Implanon who were treated with a single dose of mifepristone. © 2008 Society for Reproduction and Fertility.

It has been suggested that endometrial angiogenesis in response to the sex steroids oestrogen and progesterone is mediated at a local level via compounds such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), acting through their respective tyrosine kinase receptors. The aim of the present study was to use SUGEN tyrosine kinase receptor angiogenic inhibitor compounds SU5416, SU5402, SU11652 and SU11685, to determine whether VEGF, FGF or PDGF play a role in mediating endometrial endothelial cell proliferation after administration of oestrogen and progesterone. Endometrial endothelial cell proliferation was induced in adult ovariectomized mice by either oestrogen alone for 24 h (E1), or a regimen using oestrogen alone, then progesterone with low dose oestrogen, followed by progesterone with high-dose oestrogen (PE) over a total of 7 days. Each angiogenesis inhibitor compound was injected daily for 4 days (100 mg kg-1 day-1, s.c.) before endometrial tissue collection at either the E1 or PE stage. This study also evaluated the effect of VEGF antiserum (0.2 ml, i.p.) on endothelial cell proliferation at the E1 stage. All four angiogenic inhibitor compounds significantly reduced endothelial cell proliferation activity at the E1 and PE stages. The greatest reduction in the endothelial cell proliferative index was at the E1 stage in the group treated with the VEGF receptor inhibitor SU5416 (2.5 +/- 0.7% versus 27.9 +/- 1.1%, P < 0.001), with a reduction of similar magnitude in the group treated with anti-VEGF antibody. At the PE stage, all four inhibitors significantly reduced endothelial cell proliferation to a similar extent, indicating that VEGF, FGF and PDGF are all involved. These results demonstrate that endometrial angiogenesis after acute oestrogen treatment is primarily mediated by VEGF, but that under the influence of combined oestrogen and progesterone, FGF and PDGF are also probably involved.

OBJECTIVES: * To review the literature regarding ischaemic, non-ischaemic and stuttering priapism * To provide management recommendations PATIENTS AND METHODS: * A Medline search was carried out to identify all relevant papers with management guidelines for priapism. RESULT(S): * Ischaemic priapism represents a compartment syndrome of the penis and urgent intervention is required to decrease the risk of erectile dysfunction. * Non-ischaemic priapism is not a medical emergency; however, it can result in erectile dysfunction. * The treatment objective for stuttering priapism is to reduce future episodes with systemic treatments, whilst treating each ischaemic episode as an emergency. CONCLUSION(S): * Priapism is a complex condition that requires expert care to prevent complications and irreversible erectile dysfunction. © 2012 The Authors © 2012 BJU International.

Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60 of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-B1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial

Activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in the immune response; however, little is known of its role in immune-induced renal injury. In this study, we examine JNK signaling in the rat anti-glomerular basement membrane (GBM) disease model using CC-401, a specific JNK inhibitor. Animals were given CC-401, vehicle alone or no treatment starting before anti-GBM serum injection and continued treatment until killing. In acute disease, CC-401 blocked JNK signaling and reduced proteinuria in the first 24 h. The transient neutrophil influx seen at 3 h of disease was not affected, however. Continued CC-401 treatment suppressed glomerular and tubulointerstitial damage usually seen at 14 days. The protective effect may be due to modulation of macrophage activation, as CC-401 had no effect upon glomerular macrophage infiltration at day 14 despite the suppression of glomerular lesions and a marked reduction in renal tumor necrosis factor-alpha and inducible nitric oxide synthase messenger RNA levels. Treatment with CC-401 had no apparent effect on T cell or humoral immune responses. These studies suggest that JNK signaling promotes renal injury in acute and progressive rat anti-GBM disease. JNK inhibitors may be a novel therapeutic approach for the treatment of human glomerulonephritis. © 2007 International Society of Nephrology.

Aim: To examine the efficacy and safety of nimodipine as an alternative to papaverine for the treatment of cerebral vasospasm following subarachnoid haemorrhage. Method(s): We retrospectively reviewed the procedure reports, anaesthetic records, clinical charts and CT and angiographic images of 9 patients who had received intra-arterial nimodipine; 1 of these patients received both nimodipine and papaverine. The difference in arterial luminal diameter before and after treatment was calculated as a percentage change. Result(s): The average dose of nimodipine administered per vessel was 3.3 mg. The mean increase in arterial diameter was 66.6% in the vasospastic segment. There was no significant change in blood pressure of any of the subjects during endovascular treatment of vasospasm. Conclusion(s): Intra-arterial nimodipine is effective in improving angiographic vasospasm complicating subarachnoid haemorrhage. Further studies aimed at examining the clinical benefits of nimodipine are warranted, particularly in view of the low risk of adverse side effects of nimopidine when compared with papaverine. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Background. Ketamine has been found to exert antinociceptive effects in animals and to be analgesic at subanaesthetic doses in humans. This study was designed to investigate the involvement of spinal cord mechanisms in the potentiation of opioid analgesia by parenteral non-spinal administration of ketamine. Methods. Thresholds for nociception were measured in an acute pain model in rats that allowed identification of antinociceptive effects due to drug action in the spinal cord. Dose-response curves for the antinociceptive effects of ketamine alone and ketamine in conjunction with the mu opioid fentanyl were constructed. Results. Intraperitoneal ketamine up to 3.75 mg kg-1 caused no sedative or antinociceptive effects and intrathecal ketamine caused dose-dependent, spinally mediated antinociceptive effects. Injections of ketamine doses that caused no antinociceptive effects when given alone (intrathecal 25 mug and intraperitoneal 3.75 mg/kg) significantly increased spinally mediated antinociception produced by intrathecal fentanyl injections when assessed using noxious heat (tail-flick test) but not when assessed by noxious electrical current (electrical current threshold test). Conclusions. We conclude that ketamine can potentiate the effects of fentanyl by an interaction at the level of the spinal cord even when ketamine is given via a non-spinal route of administration.

Painful bladder syndrome (PBS) is the term used to refer to a chronic symptom complex of urinary frequency and bladder 'pressure', discomfort or pain in the absence of any other reasonable cause for these symptoms (such as infection). Interstitial cystitis (IC) is the established term used by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consensus workshop for which a research definition was formulated in the late 1980s. Opinion varies regarding not only definition but also the usefulness of diagnostic investigations such as urodynamic assessment and the potassium sensitivity test. There are still controversies concerning the most basic investigation of cystoscopy in PBS/IC. New developments in the study of PBS/IC include the identification of a potential urinary biomarker, antiproliferative factor (APF), which is produced by urothelial cells in IC and thought to inhibit proliferation. In addition, condition-specific validated questionnaires should aid evaluation, and a growing number of randomised controlled trials should enable clinicians to use evidence-based therapeutic options. © 2005 Elsevier Ltd. All rights reserved.

Background: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. Method(s): This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. Result(s): Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m-2). Doses up to 202 mg m-2 were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m 2, consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour Ktrans values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of 65 mg m-2. Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for 2 cycles. Conclusion(s): CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours. © 2010 Cancer Research UK All rights reserved.

Aspirin resistance refers to less than expected suppression of thromboxane A2 production by aspirin and has been reported to be independently associated with an increased risk of adverse cardiovascular events. Possible causes of aspirin resistance include poor compliance, drug interaction, inadequate aspirin dose, increase turnover of platelets, genetic polymorphisms of cyclo-oxygenase-1, and upregulation of alternate (non-platelet) pathways of thromboxane production. Laboratory methods used to detect aspirin resistance include those that measure thromboxane A2 production and thromboxane A2-dependent platelet function. However, since there is currently no standardised approach to the diagnosis and there are no proven effective treatments for aspirin resistance that improve outcome, patients with cardiovascular disease receiving aspirin should not be routinely tested for aspirin resistance. Instead physicians should be aware of the factors that may impair aspirin function, ensure that they use an appropriate dose of aspirin and optimise compliance with aspirin therapy. Further research exploring the mechanisms of aspirin resistance is needed in order to better define and develop a standardised test for aspirin resistance that is specific, reliable, can be readily applied in routine laboratories and correlate with an increased risk of cardiovascular events. © 2006 Elsevier Ltd. All rights reserved.

In a retrospective cohort study we have previously shown that administration of betamethasone to women with a pregnancy complicated by absent end-diastolic flow in the umbilical artery (UA) is associated with altered UA flow velocity waveforms. To examine this phenomenon further we undertook a prospective study of 30 similar singleton pregnancies. Umbilical artery FVWs were recorded before and after betamethasone administration using real-time pulsed wave colour flow Doppler. The results of this prospective cohort were similar to those of the retrospective study allowing pooling of the data. Of the 55 total pregnancies with umbilical artery AEDF studied betamethasone administration was associated with the return of end-diastolic flow in 39 (71 per cent; 95 per centCI: 59-83 per cent). The median (range) duration of this change was 3 (1-10) days. There is no evidence that this change has either a beneficial or detrimental effect on foetal health. Administration of betamethasone to women with a pregnancy complicated by umbilical artery AEDF is associated with the transient return of end-diastolic flow in most cases. While the mechanisms underlying this effect are yet to be fully elucidated it has implications for foetal surveillance in these high-risk pregnancies. © 2002 Elsevier Science Ltd. All rights reserved.

Many women using progestogen (P)-only contraceptives experience uterine bleeding problems. In clinical trials, a single low dose of mifepristone, given to Implanon users at the beginning of a bleeding episode reduced the number of bleeding days by - 50% compared with controls. In this study, a single dose of mifepristone was administered to etonogestrel (ENG)-exposed pseudo-pregnant mice, 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding. Control mice received vehicle alone. Mice were culled 12-, 18-, 24- and 48-h post-treatment. In the continued presence of ENG, a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair: most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment. During repair, proliferating cells (Ki67 immunostained) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands. Progesterone receptor-positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls. Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues. It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity: such action may be a key event in reducing the number of bleeding days observed in women using Implanon who were treated with a single dose of mifepristone. © 2008 Society for Reproduction and Fertility.

It has been suggested that endometrial angiogenesis in response to the sex steroids oestrogen and progesterone is mediated at a local level via compounds such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), acting through their respective tyrosine kinase receptors. The aim of the present study was to use SUGEN tyrosine kinase receptor angiogenic inhibitor compounds SU5416, SU5402, SU11652 and SU11685, to determine whether VEGF, FGF or PDGF play a role in mediating endometrial endothelial cell proliferation after administration of oestrogen and progesterone. Endometrial endothelial cell proliferation was induced in adult ovariectomized mice by either oestrogen alone for 24 h (E1), or a regimen using oestrogen alone, then progesterone with low dose oestrogen, followed by progesterone with high-dose oestrogen (PE) over a total of 7 days. Each angiogenesis inhibitor compound was injected daily for 4 days (100 mg kg-1 day-1, s.c.) before endometrial tissue collection at either the E1 or PE stage. This study also evaluated the effect of VEGF antiserum (0.2 ml, i.p.) on endothelial cell proliferation at the E1 stage. All four angiogenic inhibitor compounds significantly reduced endothelial cell proliferation activity at the E1 and PE stages. The greatest reduction in the endothelial cell proliferative index was at the E1 stage in the group treated with the VEGF receptor inhibitor SU5416 (2.5 +/- 0.7% versus 27.9 +/- 1.1%, P < 0.001), with a reduction of similar magnitude in the group treated with anti-VEGF antibody. At the PE stage, all four inhibitors significantly reduced endothelial cell proliferation to a similar extent, indicating that VEGF, FGF and PDGF are all involved. These results demonstrate that endometrial angiogenesis after acute oestrogen treatment is primarily mediated by VEGF, but that under the influence of combined oestrogen and progesterone, FGF and PDGF are also probably involved.