DMXAA (Vadimezan, ASA404) is a multi-kinase inhibitor targeting VEGFR2 in particular

The flavone acetic acid derivative DMXAA [5,6-dimethylXAA (xanthenone-4-acetic acid), Vadimezan, ASA404] is a drug that displayed vascular-disrupting activity and induced haemorrhagic necrosis and tumour regression in pre-clinical animal models. Both immune-mediated and non-immune-mediated effects contributed to the tumour regression. The vascular disruption was less in human tumours, with immune-mediated effects being less prominent, but nonetheless DMXAA showed promising effects in Phase II clinical trials in non-small-cell lung cancer. However, these effects were not replicated in Phase III clinical trials. It has been difficult to understand the differences between the pre-clinical findings and the later clinical trials as the molecular targets for the agent have never been clearly established. To investigate the mechanism of action, we sought to determine whether DMXAA might target protein kinases. We found that, at concentrations achieved in blood during clinical trials, DMXAA has inhibitory effects against several kinases, with most potent effects being on members of the VEGFR (vascular endothelial growth factor receptor) tyrosine kinase family. Some analogues of DMXAA were even more effective inhibitors of these kinases, in particular 2-MeXAA (2-methylXAA) and 6-MeXAA (6-methylXAA). The inhibitory effects were greatest against VEGFR2 and, consistent with this, we found that DMXAA, 2-MeXAA and 6-MeXAA were able to block angiogenesis in zebrafish embryos and also inhibit VEGFR2 signalling in HUVECs (human umbilical vein endothelial cells). Taken together, these results indicate that at least part of the effects of DMXAA are due to it acting as a multi-kinase inhibitor and that the anti-VEGFR activity in particular may contribute to the non-immune-mediated effects of DMXAA on the vasculature.     

Serotonin metabolism in cluster headache

Despite some evidence of the involvement of the serotonergic system in cluster headache (CH) pathophysiology, the serotonin (5HT) metabolism has so far been poorly studied. The aim of this study was to investigate plasma and platelet levels of 5HT and 5-hydroxyindoleacetic acid (5HIAA) in CH patients in the active period of the disease. Nineteen CH sufferers and 17 sex- and age-matched healthy controls were studied. CH patients showed significantly higher plasma levels of 5HT and 5HIAA compared to controls (5HT: 5.7±6.1 ng/ml vs 0.2±0.2 ng/ml; p =0.02; 5HIAA: 34.7±46.1 ng/ml vs 0.6±0.7 ng/ml; p =0.004). In platelet 5HT levels were slightly reduced in CH patients in comparison with those of control subjects (662.4±522.3 ng/10⁻⁸ platelets vs 832.1±587.9 ng/10⁻⁸ platelets; n.s.) and 5HIAA levels resulted significantly lower in CH sufferers than in control subjects (3.2±2.6 ng/10⁻⁸ platelets vs 6.7±4.8 ng/10⁻⁸ platelets; p =0.04). Our data suggest that CH is characterized by an increase of plasma serotonergic metabolism that could reflect an involvement of the central serotonergic system in the pathogenesis of CH.     

Serotonin metabolism in chronic tension-type headache

Serotonergic neurons play a major role in the regulation of pain and may therefore also be involved in the pathophysiology of tension-type headache. Platelets are important in the regulation of the free serotonin level in plasma and may be a model of serotonergic neurons. The aim of the present study was to investigate the peripheral serotonin (5HT) metabolism in patients with chronic tension-type headache. The 5HT levels in platelets and in plasma, the beta-thromboglobulin (ß-TG) levels in plasma, and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) were measured in 40 patients with chronic tension-type headache and in 40 healthy controls. The platelet uptake index was calculated as the ratio between platelet 5HT and plasma 5HT levels. There were, no significant differences in platelet 5HT, plasma 5HT ß-TG, or 5HIAA between patients and controls. The platelet uptake index was significantly lower in patients 243 (136–367) than in controls 352 (202–508), p =0.03. Our results indicate that the peripheral 5HT metabolism is largely normal in patients with chronic tension-type headache.     

蒙古沙土鼠急性脑缺血时新皮质中单胺类神经递质代谢的变化

目的】分析脑缺血时单胺类神经递质代谢变化的规律并比较其敏感性。【方法】结扎成年蒙古沙土鼠左侧颈总动脉建立脑缺血动物模型 ,以动脉假手术为对照组 ,采用高效液相色谱法 ,测定脑缺血 6h新皮层内去甲肾上腺素 (NE)、多巴胺 (DA )、5 羟色胺 ( 5 HT )、3 ,4 二羟基苯乙酸 (DOPAC)、高香草酸 (HVA )、5 羟吲哚乙酸 ( 5 HIAA )、色氨酸 (Trp)含量。【结果】结扎侧单胺递质含量显著降低 ,其代谢产物含量显著升高 ;结扎对侧也有类似的变化。【结论】单胺递质及其代谢产物水平的变化多数与缺血症状严重程度密切相关。多因素分析发现其中NE水平变化最明显。     

大鼠应激性胃溃疡的形成与中枢神经系统、胃和血浆中单胺类神经递质的关系

目的：了解应激性胃溃疡的形成与中枢神经系统、胃和血浆中单胺类神经递质的关系。方法：Ｗｉｓｔａｒ大鼠分成３个组，正常对照组、应激溃疡组和自然恢复组。应激溃疡组为应激７小时后立即取材检测，自然恢复组为应激性胃溃疡形成后自然恢复２４小时进行取材检测。取胃组织、血浆、端脑、间脑和脑干，采用荧光光度法测定单胺类神经递质。结果：应激在引起胃粘膜损伤的同时，中枢和外周神经系统的５羟色胺（５ＨＴ）和５羟吲哚乙酸（羟ＨＩＡＡ）以及去甲肾上腺素（ＮＥ）出现有意义的升高，而中枢和外周的多巴胺（ＤＡ）出现有意义的降低，经２４小时的自然恢复，随着胃粘膜损伤的逐渐修复，中枢和外周神经系统的５ＨＴ和５ＨＩＡＡ趋向正常，但中枢和外周神经系统的ＮＥ仍居高不下，ＤＡ仍维持低水平。结论：中枢和外周神经系统的单胺类神经递质参与了应激性胃溃疡的形成。     

立体定向手术对强迫症患者脑脊液5-羟色胺含量的影响

目的　探讨双侧多靶点立体定向手术对强迫症患者 5 羟色胺 (5 HT)代谢的影响。方法　双侧多靶点立体定向手术治疗强迫症患者 ,荧光分光光度法检测脑脊液 (CSF)中 5 HT及其代谢产物 5 羟基吲哚乙酸 (5 HIAA)。结果　强迫症患者CSF中 5 HT和 5 HIAA水平显著高于对照组 ,接受双侧多靶点立体定向手术治疗的患者 ,其CSF中 5 HT和 5 HIAA水平显著下降。结论　双侧多靶点立体定向手术可以有效纠正强迫症患者 5 HT的代谢紊乱     

Platelet serotonin pathway in menstrual migraine

In order to understand the possible 5-hydroxytryptamine (5HT) anomalies in migraine, particularly in the period before the headache attack, we compared the levels of 5HT, its stable metabolite 5-hydroxyindoleacetic acid (5HIAA) and platelet monoaminoxidase (MAO) activity in patients with menstrual migraine with those of healthy female controls. In every subject, blood samples were drawn during both follicular and late luteal phases of the menstrual cycle. In controls, platelet 5HT levels remained stable, whereas 5HIAA levels and MAO activity were higher in the luteal than in the follicular phase, suggesting an increased catabolism of 5HT which occurs physiologically just before menses. In menstrual migraine 5HIAA levels and MAO activity showed similar changes with higher values in the luteal than in the follicular phase. The luteal phase values were significantly higher than those of controls. Also, and in contrast to controls, 5HT levels decreased in the luteal phase. These data suggest that 5HT availability is reduced in menstrual migraine, possibly due to an increased catabolism and/or to a reduced synthesis, and hence predisposes patients to migraine attacks.     

Control of cervicovaginal HPV-16 E7-expressing tumors by the combination of therapeutic HPV vaccination and vascular disrupting agents

Abstract Antigen-specific immunotherapy and vascular disrupting agents, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), have emerged as attractive approaches for the treatment of cancers. In the current study, we tested the combination of DMXAA treatment with therapeutic human papillomavirus type 16 (HPV-16) E7 peptide-based vaccination for their ability to generate E7-specific CD8+ T-cell immune responses, as well as their ability to control E7-expressing tumors in a subcutaneous and a cervicovaginal tumor model. We found that the combination of DMXAA treatment with E7 long peptide (amino acids 43-62) vaccination mixed with polyriboinosinic:polyribocytidylic generated significantly stronger E7-specific CD8+ T-cell immune responses and antitumor effects compared with treatment with DMXAA alone or HPV peptide vaccination alone in the subcutaneous model. Additionally, we found that the DMXAA-mediated enhancement of E7-specific CD8+ T-cell immune responses generated by the therapeutic HPV peptide-based vaccine was dependent on the timing of administration of DMXAA. Treatment with DMXAA in tumor-bearing mice was also shown to lead to increased dendritic cell maturation and increased production of inflammatory cytokines in the tumor. Furthermore, we observed that the combination of DMXAA with HPV-16 E7 peptide vaccination generated a significant enhancement in the antitumor effects in the cervicovaginal TC-1 tumor growth model, which closely resembles the tumor microenvironment of cervical cancer. Taken together, our data demonstrated that administration of the vascular disrupting agent, DMXAA, enhances therapeutic HPV vaccine-induced cytotoxic T-lymphocyte responses and antitumor effects against E7-expressing tumors in two different locations. Our study has significant implications for future clinical translation.     

氟西汀对偏头痛的防治作用和机理

目的：为了寻找对偏头痛有防治作用的药物，进行了氟西汀对偏头痛防治作用的临床研究，并探讨其治疗机理。方法：28例确诊为偏头痛的门诊病人，持续服用氟西汀16周，每天20mg。治疗前及治疗结束后查血小板5－HT和血浆5－HIAA及血常规、血糖、电解质、肝肾功能。同时配对26例正常人的血小板5－HT和血浆5－HIAA作为对照。结果：经16周的氟西汀治疗后，28例病人的头痛完全消失。治疗前后的血常规、血糖、电解质、肝肾功能结果均在正常范围内。偏头痛组治疗后的血小板5－HT出现显著的下降，而血浆5－HIAA有显著提高，说明氟西汀有刺激血小板释放5－HT的作用。治疗过程中出现头昏1例（3．57％）；出汗增多6例（21．43％）。均能耐受，未行任何处理。电话随访1年无复发。结论：氟西汀通过刺激血小板释放5－HT，提高了血浆5－HT的浓度，中断了颅外血管扩张，从而起到防治偏头痛的作用。且不良反应轻，耐受性好，是防治偏头痛的安全有效药物。     

Determination of a reference range for whole blood serotonin in a pediatric population using high pressure liquid chromatography with electrochemical detection

Whole blood serotonin (5HT) concentrations were measured in a group of children and adolescents to determine a reference range for this population. Blood was collected after at least a 6-hour fast, mixed with ascorbic acid and EDTA, and frozen at -70 degrees C until analysis. 5HT was determined by HPLC with electrochemical detection. Matrix-matched whole blood standards and controls were used to determine 5HT concentrations, and monitor performance of the assay. 5HT concentrations in boys ranged from 0.53 to 3.13 mumol/L (mean = 1.27, SD = 0.47) while the range for girls was 0.63 to 2.46 mumol/L (mean = 1.21, SD = 0.47). There was no significant difference in 5HT concentrations between boys and girls, nor was there any significant change in 5HT concentration with age. The nonparametric central 95 percent reference range for boys and girls was determined to be 0.64-2.45 mumol/L.     

Clinical pharmacology of flavopiridol following a 72-hour continuous infusion

BACKGROUND: Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile. OBJECTIVE: To characterize the clinical pharmacology of flavopiridol. METHODS: Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis. RESULTS: Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%). CONCLUSIONS: The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.     

STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.     

Non-classical anti-factor VIII C2 domain antibodies are pathogenic in a murine in vivo bleeding model

Summary.  Objective: The pathogenicity of anti-human factor (F) VIII monoclonal antibodies (MAbs) was tested in a murine bleeding model. Methods: MAbs were injected into the tail veins of hemophilia A mice to a peak plasma concentration of 60 n m , followed by injection of human B domain-deleted FVIII at 180 U kg⁻¹, producing peak plasma concentrations of ∼2 n m . At 2 h, blood loss following a 4-mm tail snip was measured. The following MAbs were tested: (i) 4A4, a type I anti-A2 FVIII inhibitor, (ii) I54 and 1B5, classical type I anti-C2 inhibitors, (iii) 2–77 and B45, non-classical type II anti-C2 inhibitors, and (iv) 2–117, a non-classical anti-C2 MAb with inhibitory activity less than 0.4 Bethesda Units per mg IgG. Results: All MAbs except 2–117 produced similar amounts of blood loss that were significantly greater than control mice injected with FVIII alone. Increasing the dose of FVIII to 360 U kg⁻¹ overcame the bleeding diathesis produced by the type II MAbs 2–77 and B45, but not the type I antibodies, 4A4, I54, and 1B5. These results were consistent with the in vitro Bethesda assay in which 4A4 completely inhibited both 1 U mL⁻¹ and 3 U mL⁻¹ FVIII, while there was 40% residual activity at saturating concentrations of 2–77 at either concentration of FVIII. Conclusions: For patients with an inhibitor response dominated by non-classical anti-C2 antibodies both the in vivo and in vitro results suggest that treatment with high-dose FVIII rather than bypassing agents may be warranted.     

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

INTRODUCTION: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood-brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents. AREAS COVERED: (131)I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex. It carries (131)I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with (131)I-chTNT-1/B mAB, detailing results of completed Phase I and II trials. EXPERT OPINION: Novel agents and therapeutic modalities, such as (131)I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. (131)I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of (131)I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.     

Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects

More than 14,000 people die from invasive transitional cell carcinoma (TCC) of the urinary bladder yearly in the United States. Cyclooxygenase (COX)-inhibiting drugs are emerging as potential antitumor agents in TCC. The optimal in vitro or in vivo systems to investigate COX inhibitor antitumor effects have not been defined. The purpose of this study was to determine COX-1 and COX-2 expression and antitumor effects of COX inhibitors in human TCC cell lines (HT1376, RT4, and UMUC3 cells) and xenografts derived from those cell lines. COX-2 expression (Western blot, immunocytochemistry) was high in HT1376, modest in RT4, and absent in UMUC3 cells in vitro. Similarly, COX-2 expression was noted in RT4 but not UMUC3 xenografts. COX-2 expression in HT1376 xenografts was slightly lower than that observed in vitro. None of four COX inhibitors evaluated (celecoxib, piroxicam, valeryl salicylate, and NS398) reduced TCC growth in standard in vitro proliferation assays at concentrations that could be safely achieved in vivo (< or =5 micromol/L). Higher celecoxib concentrations (> or =50 micromol/L) inhibited proliferation and induced apoptosis in all three cell lines. Celecoxib or piroxicam treatment in athymic mice significantly delayed progression of HT1376 xenografts, which express COX-2, but not UMUC3 xenografts that lack COX-2 expression. In conclusion, standard in vitro assays were not useful in predicting COX inhibitor antitumor effects observed in vivo. Athymic mice bearing TCC xenografts provide a useful in vivo system for COX inhibitor studies. Results of this study provide justification for further evaluation of COX inhibitors as antitumor agents against TCC.     

Patterns of Endogenous Platelet Serotonin Release

The release of endogenous serotonin (5HT) from the platelets of normal human subjects was studied using adenosine diphosphate (ADP), thrombin, and connective tissue (CT) as aggregating agents. Clot retraction was found to release from 60 to 100 per cent of available platelet 5HT. Of the aggregating agents studied, only connective tissue was accompanied by the release of endogenous SHT in all subjects. Low concentrations of ADP gave no release, and high concentrations of ADP as well as thrombin-induced aggregation gave release in the minority of subjects.
The pattern of release of endogenous 5HT in response to aggregating agents was found to differ from results of studies reported by others 18, 19 using exogenous radioactive 5HT.     

Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17)

Summary. Background: Peripheral serotonin (5‐hydroxytryptamine, 5‐HT) is transported by platelets and released upon stimulation. In the platelet cytoplasm, 5‐HT is transamidated to small GTPases, promoting α‐granule release and primary hemostasis. Objective: We hypothesized that 5‐HT could also stimulate platelet receptor shedding after binding to the membrane 5‐HT receptor (5‐HT2AR). Methods: Western blot and flow cytometry were used to determine levels of the adhesion receptor glycoprotein (GP)Ibα on platelets or its shed fragment glycocalicin in plasma and serum from wild‐type mice, Tph1^?/? mice lacking peripheral 5‐HT, and mice lacking functional tumor necrosis factor‐alpha‐converting enzyme (TACE, ADAM17). Flow chamber experiments and intravital microscopy were used to examine the adhesive properties of platelets after stimulation of 5‐HT2AR. Results: Glycocalicin was significantly reduced in Tph1^?/? plasma and serum. In isolated platelets, 5‐HT induced shedding of GPIbα, which was increased to 60% when 5‐HT uptake was inhibited by the selective serotonin reuptake inhibitor fluoxetine. Specific 5‐HT2AR agonism and antagonism suggested activation of this receptor. The shedding could not be induced in TACE^ΔZn/ΔZn platelets, suggesting that activated TACE mediated the shedding of GPIbα. Intracellular signaling involved phosphorylation of p38 mitogen‐activated protein kinase rather than G‐protein signaling. 5‐HT2AR stimulation decreased platelet adhesion to collagen‐bound von Willebrand factor under arterial shear (1500 s^?1) and incorporation into FeCl₃‐induced thrombi in mesenteric arterioles. Conclusions: Stimulation of 5‐HT2AR on platelets induces TACE‐mediated shedding of GPIbα, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5‐HT could modulate cardiovascular disease.     

Platelet changes after placement of aortic prostheses in dogs. I. Biochemical and functional alterations

Changes in circulating platelets were observed after placement of woven Dacron aortic prostheses in dogs. Platelets had increased sensitivity to aggregating agents for up to 6 months postoperatively, during which period platelet survival was maximally shortened. Platelet survival gradually lengthened but remained less than preoperative values, even at 18 months. Platelet 5HT, consistently reduced after placement of aortic prostheses, closely paralleled changes in platelet survival. Studies with platelets labeled simultaneously with 14C-5HT and 51Cr suggested in vivo platelet release and reutilization of 5HT. In vitro platelet uptake of 14C-5HT, however, was depressed. Urinary excretion of 5HIAA increased slightly, but not significantly, after placement of aortic prostheses. These findings suggested that platelet interaction with the prosthetic surface led to partial release of platelet storage granule contents. Reutilization of released 5HT occurred but was limited because of impaired platelet uptake or storage of 5HT. Platelet damage was suggested by 51Cr-platelet cross-transfusion experiments. Platelets from normal dogs had normal recovery and reduced survival when cross-transfused into animals with aortic prostheses. When platelets from dogs with aortic prostheses were cross-transfused into normal animals, recovery was strikingly reduced and survival very short. Taken together, these studies suggest that, in dogs, platelet interaction in thrombosis on prosthetic surfaces is, in part, a reversible process, with platelets re-entering the circulation in an altered state.     

Liquid-chromatographic assay of ibuprofen enantiomers in plasma

This stereospecific "high-performance" liquid-chromatographic (HPLC) assay is suitable for pharmacokinetic studies of ibuprofen (IB). Very efficient extraction of the drug and internal standard, (+/-)-2-(4-benzoylphenyl)butyric acid, from plasma with isooctane/isopropanol (95/5, by vol) is followed by sequential reaction of the enantiomers with ethyl chloroformate and (S)-(-)-1-(1-naphthyl)ethylamine. The reactions take place at ambient temperature in less than 4 min. The naphthylethylamide derivatives of IB enantiomers and internal standard are then extracted into chloroform. After the organic layer is evaporated, the reconstituted residue is chromatographed at ambient temperature on a C18 reversed-phase column with a mobile phase of acetonitrile/water/acetic acid/triethylamine (55/45/0.1/0.02 by vol) at a flow rate of 1 mL/min. The IB diastereoisomers, detected at 232 nm, are free of interfering peaks and have a resolution factor of 2.2. Within the examined enantiomer concentration range of 0.1 to 20 mg/L in plasma, the peak-area ratios varied linearly with the corresponding IB concentrations. We used the assay to study the pharmacokinetics of IB enantiomers in plasma of a subject who took a single 600-mg dose of racemic drug.     

An overview of infliximab, etanercept, efalizumab, and alefacept as biologic therapy for psoriasis

BACKGROUND: Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European populations. One of the major focuses in psoriasis research has been the development of biologic therapies that provide selective, immunologically directed intervention with fewer adverse effects than traditional therapies. OBJECTIVE: The aim of this review was to summarize the progress of 4 biologic agents available or under investigation for clinical use: infliximab, etanercept, efalizumab, and alefacept. METHODS: Relevant information was identified through a MEDLINE search of the literature (1966 to May 2003) using the terms biologic therapy, psoriasis, infliximab, etanercept, efalizumab, and alefacept. In addition, meeting posters from the American Academy of Dermatology (2003) and International Investigative Dermatology (2003) were reviewed and included if perceived to be reliable and relevant. RESULTS: In a Phase II trial of infliximab, the percentages of patients reaching > or =75% improvement from baseline in the psoriasis area and severity index (PASI 75) at week 10 were as follows: 6% with placebo (3/51), 72% with infliximab 3 mg/kg (71/98), and 88% with infliximab 5 mg/kg (87/99). In a Phase III study, 34% of patients receiving etanercept 25 mg SC twice weekly (55/162) achieved PASI 75 at 12 weeks and 44% (71/162) at 24 weeks. Also, 49% of those receiving etanercept 50 mg (81/164) achieved PASI 75 at 12 weeks, and 59% (97/164) at 24 weeks. In 2 Phase III trials with SC efalizumab 1.0 mg/kg or 2.0 mg/kg or placebo, 30% in the 1.0-mg/kg per week group (117/394) achieved PASI 75; in the 2.0-mg/kg per week group, 28% (113/409) did. In the placebo, 3.4% (10/292) achieved PASI 75. In a Phase III trial of IM alefacept 15 mg once weekly for 12 weeks, IM alefacept 10 mg once weekly for 12 weeks, or placebo, 21% of the 15-mg dose group (35/166) achieved PASI 75 at 2 weeks after the last dose, compared with 5% of the placebo group (8/168). In a Phase III study of the efficacy and tolerability of once-weekly alefacept 7.5 mg via IV bolus, 14% (53/367) and 4% (7/186) of patients receiving alefacept and placebo achieved PASI 75 at week 14, respectively. Among those who received 2 courses of alefacept, 40% (73/183) and 71% (130/183) achieved PASI 75 and > or = 50% improvement in PASI, respectively. All 4 drugs have been generally well tolerated. CONCLUSIONS: In the patients treated to date, infliximab, etanercept, efalizumab, and alefacept have achieved successful therapy of psoriasis without the organ toxicity seen with traditional systemic therapies. Potential limitations in the use of these agents include the expected high costs of treatment, lack of long-term follow-up, and the selective nature of the patient populations treated thus far.