Monotherapeutic Agent Research Articles

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies.

The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin's lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents.

Abstract 1370: Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors

Abstract Anti-angiogenic therapy, mostly targeting vascular endothelial growth factor (VEGF), has been clinical applied in cancer patients for the last decade. However, often resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new anti-angiogenic strategies are needed. In this study we analyzed the potential anti-angiogenic effects of activin-receptor-like kinase (ALK)1-Fc protein. ALK1-Fc sequesters bone morphogenetic protein (BMP)-9 and -10 and prevents binding of these ligands to endothelial ALK1, which controls angiogenesis. Treatment of mice with breast cancer, head and neck cancer, or melanomas strongly decreased the tumors’ microvascular density, but this effect was not accompanied by a reduction in tumor volume. In contrast to anti-VEGF therapy, we observed decreased hypoxia, and increased staining for pericytes, consistent with the notion that ALK1-Fc may have induced a normalization of the remaining tumor vessels. Next we found that combined regimen of ALK1-Fc with chemotherapy inhibited tumor growth in the breast- and head and neck cancer models more efficiently than chemotherapy alone. Our results provide strong rational to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase-II clinical trials with ALK1-Fc. Citation Format: Lukas JAC Hawinkels, Amaya Garcia de Vinuesa, Madelon Paauwe, Marianna Kruithof-de Julio, Renier Heijkants, Marie-Jose Goumans, Timo ten Hagen, Peter ten Dijke. Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1370. doi:10.1158/1538-7445.AM2015-1370

Epinecidin-1 antimicrobial activity: In vitro membrane lysis and In vivo efficacy against Helicobacter pylori infection in a mouse model

Helicobacter pylori (H. pylori) infection is highly prevalent, and has a strong association with various gastric diseases, including gastritis, digestive ulcers, and cancer. H. pylori strains with resistance to existing antibiotics have emerged in the past two decades. Currently, treatment of H. pylori infection (involving the use of proton pump inhibitors, followed by triple therapy with broad-spectrum antibiotics) is suboptimal, with high failure rates. As such, there is a clear need for new approaches against H. pylori. Here, we report that Epinecidin-1 (Epi-1) shows effective bactericidal activity against H. Pylori in vitro, and modulates H. Pylori-induced host immune responses in a mouse model. Epi-1 exhibited a low minimum inhibitory concentration (MIC) against antibiotic-sensitive and clinical antibiotic-resistant strains. Moreover, Epi-1 treatment caused 1-N-phenylnaphthylamine (NPN)-fluorescent probe uptake, suggesting it induced membrane lysis; transmission electron micrographs revealed that membranes were destabilized by the generation of saddle-splay membrane curvature. Oral administration of Epi-1 (quaque die dose) in a mouse infection model had strong efficacy (p < 0.00152) against H. pylori, as compared with conventional proton pump inhibitor (PPI)-triple therapeutic antibiotics. Epi-1 inhibited infection through in vivo depletion of CD4+-FOXP3+ T Regulatory and Th17 subset populations, and aided in clearance of persistent H. pylori colonization. Flow cytometry and gene expression analysis of mouse splenic and gastric tissue indicated that Epi-1 inhibits IL-10, and thereby affects FOXP3 expression levels and reduces pro-inflammatory cytokine responses. Crucially, high doses of Epi-1 did not exert toxic effects in oral, dermal, and eye irritation models. Collectively, our results suggest that Epi-1 may be a promising, effective, and safe monotherapeutic agent for the treatment of multi-drug resistant H. pylori infection.

Efficacy of the antimicrobial peptide TP4 against Helicobacter pylori infection: in vitro membrane perturbation via micellization and in vivo suppression of host immune responses in a mouse model.

Helicobacter pylori infection is marked by a strong association with various gastric diseases, including gastritis, ulcers, and gastric cancer. Antibiotic treatment regimens have low success rates due to the rapid occurrence of resistant H. pylori strains, necessitating the development of novel anti-H. pylori strategies. Here, we investigated the therapeutic potential of a novel peptide, Tilapia Piscidin 4 (TP4), against multidrug resistant gastric pathogen H. pylori, based on its in vitro and in vivo efficacy.TP4 inhibited the growth of both antibiotic-sensitive and -resistant H. pylori (CagA+, VacA+) via membrane micelle formation, which led to membrane depolarization and extravasation of cellular constituents. During colonization of gastric tissue, H. pylori infection maintains high T regulatory subsets and a low Th17/Treg ratio, and results in expression of both pro- and anti-inflammatory cytokines. Treatment with TP4 suppressed Treg subset populations and pro- and anti- inflammatory cytokines. TP4 restored the Th17/Treg balance, which resulted in early clearance of H. pylori density and recovery of gastric morphology. Toxicity studies demonstrated that TP4 treatment has no adverse effects in mice or rabbits. The results of this study indicate that TP4 may be an effective and safe monotherapeutic agent for the treatment of multidrug resistant H. pylori infections.

Proapoptotic and TRAIL-sensitizing constituents isolated from Salvia militiorrhiza (Danshen)

Natural compounds isolated from medicinal plants are invaluable resources for drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent unique by its cancer cell-specific proapoptotic action, but its potential is heavily curbed by acquired resistance. We herein reported for the first time the identification of cytotoxic and TRAIL-sensitizing components of Salvia miltiorrhiza (Danshen), a traditional medicinal plant effective for treating cardiovascular disorders. Specifically, we found that the ethanol extract and its group 5 fraction of S. miltiorrhiza showed evident cytotoxicity against the human lung adenocarcinoma cell line A549 and ovarian adenocarcinoma cell line TOV-21G in a concentration-dependent manner. Likewise, a dose-dependent cytotoxicity was exerted by the standard solutions of cryptotanshinone, tanshinone I and tanshinone IIA, the major components of the group 5 fraction, where tanshinone IIA were most potent and displayed an IC₅₀ of 2.00 ± 0.36 μM and 2.75 ± 0.23 μM for A549 and TOV-21G, respectively. Induction of apoptosis represents an essential mechanism underlying tanshinone IIA-mediated cytotoxic action, as evidenced by the proteolytic processing of PARP upon tanshinone IIA stimulation and, importantly, a marked rescue of the viability of tanshinone IIA-treated cells when co-treatment with the pan-caspase inhibitor z-VAD-fmk. Noteworthy, stimulation with cryptotanshinone, tanshinone I or tanshinone IIA all effectively potentiated TRAIL to reduce viability and inhibit the colony formation capacity of TRAIL-resistant TOV-21G and SKOV3. Collectively, we revealed the proapoptotic and TRAIL-sensitizing components of S. miltiorrhiza and further implicated the potential of developing these active compounds as monotherapeutic agent or TRAIL-based therapy for cancer chemoprevention or chemotherapy.

Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn(2+) binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. ©2012 AACR.

Using Paliperidone as a Monotherapeutic Agent on a Schizophrenic Patient With Cirrhosis of the Liver

Using Paliperidone as a Monotherapeutic Agent on a Schizophrenic Patient With Cirrhosis of the Liver

Emerging new therapeutic applications of capecitabine as a first-line chemotherapeutic agent in the management of advanced carcinomas other than colorectal carcinoma

Emerging new therapeutic applications of capecitabine as a first-line chemotherapeutic agent in the management of advanced carcinomas other than colorectal carcinoma Shailendra KapoorRichmond, VA, USAI read with great interest the recent article by Hameed et al in a recent issue of your journal.1 The article is very interesting. Interestingly, the past few years have seen the emergence of capecitabine as a highly potent first-line chemotherapeutic agent against advanced systemic carcinomas other than colorectal carcinoma. For instance, capecitabine has recently been used successfully as a first-line monotherapeutic agent for HER-2-negative metastatic breast cancer.2 Cotherapy with agents such as sorafenib and paclitaxel for HER-2-negative metastatic breast cancer has also been recently used first-line, and significantly improves progressionfree survival, in addition to being very safe.3,4 Similarly, in patients with advanced gastric carcinoma, capecitabine has been used successfully as first-line therapy in combination with agents such as cisplatin.5 The XELOX regimen comprising capecitabine in conjunction with oxaliplatin is another recent highly effective alternative for gastric carcinoma.6 The modified XELIRI regimen compromising capecitabine and irinotecan is a further option for advanced and unresectable gastric carcinoma.7View original paper by Hameed and colleagues.

KAAD-cyclopamine sensitize malignant glioma cells to TRAIL-mediated apoptosis

2025 Background: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because TRAIL induces almost selectively apoptosis in cancer cells. The main obstacle in TRAIL-based therapy is that many glioblastoma cells are resistant. In the present study we found that the Hedgehog inhibitor, KAAD-cyclopamine, potently sensitized primary glioma cells to TRAIL-mediated apoptosis. Methods: Established cell lines and isolated primary tumor glioblastoma cells were treated with achievable plasma concentrations of TRAIL, KAAD-cyclopamine, or the combination of both. Apoptosis was assessed by Annexin V/Propidiumiodide staining and subsequent flow cytometric analysis. Activation of caspases and expression of apoptosis related proteins were determined by immunoblotting. For transfection experiments primary glioma cells were electroporated with plasmids encoding the cDNA of c-FLIP and bcl-2. Results: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Single treatment with KAAD-cyclopamine or TRAIL does not induce cytotoxicity in malignant glioma cells. However, treatment with KAAD-cyclopamine in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells. Notably, normal human astrocytes were not affected by the combination treatment consisting of KAAD-cyclopamine and TRAIL. KAAD-cyclopamine led to an upregulation of death receptor 4 and 5 and down-regulation of bcl-2 and c-FLIP. Furthermore, over-expression of both bcl-2 and c-FLIP attenuated KAAD-cyclopamine facilitated TRAIL-mediated apoptosis. Conclusion: The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by KAAD-cyclopamine cotreatment might, however, provide a powerful therapeutic option for glioma patients. No significant financial relationships to disclose.

Oseltamivir for treatment and prophylaxis of influenza infection

Background: Influenza infection is a global problem affecting millions of people worldwide, despite efficacious vaccines. Treatment and prophylaxis against influenza have been successful using antiviral medications such as adamantanes and neuraminidase inhibitors. Objective: To review the antiviral agents and specifically the neuraminidase inhibitor, oseltamivir, for use in treatment and prophylaxis of influenza infection. Methods: This review focuses on published literature regarding the clinical use of oseltamivir, as well as discussing emerging threats such as avian influenza, antiviral resistance, and strategies such as combination antiviral treatment to mitigate these threats. Results: Oseltamivir is effective in reducing symptom burden in those with influenza A or B infection, and is preventative against developing infection after exposure. Emergence of naturally occurring or post-treatment oseltamivir-resistant influenza as well as an avian influenza pandemic may limit its future use as a monotherapeutic antiviral treatment agent.

Safety and Efficacy of Pioglitazone/Metformin Combination Therapy in Treatment of Type 2 Diabetes: A Rationale for Earlier Use

Although multiple new agents for the management of diabetes have become available in the past decade, less than 50% of diabetics in the United States have Hgb A-1-C levels below 7.0% and far fewer at the newer more stringent targets of 6.0% to 6.5%. It has become increasingly clear that the course of Type 2 diabetes is marked by progressive loss of beta-cell function in the setting of relatively fixed insulin resistance. However, treatment algorithms are based on initial monotherapy, usually with metformin, and only move to combination or add-on therapy when treatment has failed and disease has progressed. Few therapeutic agents address both insulin resistance and beta cell function, and no monotherapeutic agent fully addresses any physiologic defect. Metformin, a well-established therapy for diabetes is effective in reducing hepatic and to a lesser extent muscle insulin resistance primarily through AMP-kinase activation, but has only modest effects on long-term beta-cell function. Pioglitazone, an agent in the thiazolidinedione (TZD) class has mechanistically distinct effects on hepatic, muscle and adipocyte insulin resistance, primarily through PPAR-gamma activation, as well as having somewhat greater effects on beta-cell function and durability of glycemic control. The combination of the two agents, either as initial therapy, or as very rapid add-on therapy for the patient who does not achieve target glycemia soon after initiation of metformin is a mechanistically favorable and useful approach to early and durable glycemic control of many new-onset diabetic patients. The efficacy of both metformin and pioglitazone as monotherapy has been well-documented in numerous studies, and combination studies have demonstrated superiority in efficacy of combination therapy over monotherapy with either agent as well as superiority in durability of response over non-TZD based combinations such as sulfonylurea/metformin. Safety issues with metformin remain primarily tolerability based on GI side effects with the rare risk of lactic acidosis in patients with declining renal function. The safety of the TZD class, while well-documented, does carry the risks of volume expansion and resultant CHF, as well as weight gain, which while troublesome, uniquely does not impair glycemic control in these patients. A more recent concern has been raised regarding fracture risk and decreased bone density, and although the relative impact appears small it remains relevant. These risks may be somewhat balanced by more recent studies suggesting a favorable effect of pioglitazone on multiple metabolic risk factors for CVD such as lipids, C-reactive protein, and adipocytokines such as adiponectin. Recent mechanistic and outcome studies such as PROACTIVE and PERISCOPE which suggest there may also be modest benefit on plaque progression and CVD outcomes. Metformin has beneficial effects on metabolic CVD risk factors, such as triglycerides, insulin and PAI-1 and there is a persistent signal of favorable CV outcomes in metformin treated patients. This review will address the safety and efficacy of the agents as monotherapy as well as in combination, and explain the physiologic rationale for earlier or initial use of pioglitazone/metformin combination therapy for newly diagnosed diabetes as well as the long term potential benefit for ongoing management of the treated diabetic.

Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis

Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the therapeutic potential of TRAIL in primary human glioma cells. We isolated primary tumor cells from 13 astrocytoma and oligoastrocytoma patients of all four WHO grades of malignancy and compared the levels of TRAIL-induced apoptosis induction, long-term tumor cell survival, caspase, and caspase target cleavage. We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Regardless of the tumor heterogeneity, cotreatment with the proteasome inhibitor bortezomib efficiently sensitized all primary glioma samples for TRAIL-induced apoptosis and tremendously reduced their clonogenic survival. Due to the pleiotropic effect of bortezomib-enhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIP(L) and activation of the intrinsic apoptosis pathway seem to cooperatively contribute to the antitumor effect of bortezomib/TRAIL cotreatment. TRAIL sensitivity of tumor cell lines is not a reliable predictor for the behavior of primary tumor cells. The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by bortezomib cotreatment might, however, provide a powerful therapeutic option for glioma patients.

Update in retinoid therapy of acne

The pathogenesis of acne, the most common skin disease, is complex and multifactorial. Clinical experience has demonstrated that parallel targeting of various pathogenetic factors, achieved either by mono- or combination therapy with appropriate drugs, represents the most effective approach to treating acne. Topical retinoids have been shown to expulse mature comedones, reduce microcomedone formation, and exert immunomodulatory effects. They have broad anti-acne activity without the risk of inducing bacterial resistance, which justifies their use as first-line treatment in most types of noninflammatory and inflammatory acne and makes them uniquely suitable as long-term medication to maintain remission after cessation of initial combination therapy. Systemic isotretinoin as a monotherapeutic agent strongly affects all four major pathogenetic factors and has been, in the hand of experienced dermatologists, a potent and safe agent for the treatment of severe and recalcitrant acne forms for more that 20 years. However, patient counseling, careful monitoring, and evaluation and management of adverse events are necessary. The use of isotretinoin has experienced a drawback now that its indication has been lowered from a first-line to a second-line medication.

Safety, efficacy and pharmacokinetics of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, as monotherapy in patients with locally advanced or metastatic pancreatic cancer (PC)

12504 Background: Nimotuzumab (OSAG101, Theraloc) is a humanized monoclonal antibody (mAb) that binds to the EGFR. In preclinical studies the antibody has shown potent antitumor activity. Based on phase I data, the recommended dose has been established at 200 mg weekly. A previous phase II study in children with high grade brain tumors showed activity of nimotuzumab as a monotherapeutic agent, even in prognostically very unfavorable pontine glioma. No drug related side effects were reported. The present ongoing phase II study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic PC. Methods: Pts who failed standard chemotherapy with gemcitabine or another first line regimen for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given iv as induction therapy at 200 mg once weekly for 6 weeks. Follow up by CT was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), time to disease progression, and safety. Blood samples were collected prior to first dose, at end of infusion, and 3h, 6h, 48h, as well as every time before subsequent nimotuzumab doses were administered. Nimotuzumab concentrations in serum were measured by cellular ELISA. Results: Enrollment is complete, with treatment ongoing. In total, 55 pts were treated (28 women/ 27 men; ECOG status of 1 [n= 41] or 0 [n=14], median age 63.6 yrs [range 46–83 yrs]). Pts evaluable for response: n= 36; CR:0; PR:0; SD:6 pts (median TTP 19.2 weeks; 14.1–26.1). The only reported treatment-related adverse event was rash grade 1 in 1 pt. After 200 mg single dose, the mean value of Cmax was calculated to 141 ± 33 μg/ml. The t1/2 was calculated to 45 h, volume of distribution to 1.46 ± 0.3 l, respectively. The total clearance was determined to 23 ± 6 ml/h. The trough values after 168 h were 6.2 ± 6.3 μg/ml. Conclusions: These data confirm that nimotuzumab is safe and well tolerated. To improve efficacy, a combination trial with gemcitabine is planned. [Table: see text]

Bipolar depression: management options.

Bipolar depression is the predominant abnormal mood state in bipolar disorder. However, despite the key pertinence of this phase of the condition, the focus of research and indeed of clinical interest in the management of bipolar disorder has been mainly on mania. Bipolar depression has been largely neglected, and early studies often failed to distinguish depression due to major unipolar depression from that due to bipolar disorder. Consequently, many treatments used in the management of major depression have been adopted for use in bipolar depression without any robust evidence of efficacy. The selective serotonin reuptake inhibitors (SSRIs), bupropion, tricyclic antidepressants and monoamine oxidase inhibitors are all effective antidepressants in the management of bipolar depression. They are all associated with a small risk of antidepressant-induced mood instability. The mood stabilisers lithium, carbamazepine and valproate semisodium (divalproex sodium) all appear to have modest acute antidepressant properties. Among these, lithium is supported by the strongest data, but the use of lithium in the treatment of bipolar depression as a monotherapeutic agent is limited by its slow onset of action. Recently, there has been a growing body of evidence suggesting that lamotrigine may have particular effectiveness in both the acute and prophylactic management of bipolar depression. Clinical management of bipolar depression involves various combinations of antidepressants and mood stabilisers and is partly determined by the context in which the depressive episode occurs. In general, 'de novo' and 'breakthrough' (where the patient is already receiving medication) bipolar depression may be successfully managed by initiating mood stabiliser monotherapy, to which an antidepressant or second mood stabiliser may be added at a later date, if necessary. Breakthrough episodes of bipolar depression occurring in patients receiving combination therapy (two mood stabilisers or a mood stabiliser plus an antidepressant) require either switching of ongoing medications or further augmentation. If this fails, then novel strategies or ECT should be considered. Bipolar depression is a disabling illness and the predominant mood state for the vast majority of those with bipolar disorder. It therefore warrants prompt management once suitably diagnosed, especially as it is associated with a considerable risk of suicide and in the majority of instances is eminently treatable.

Olanzapine for the Treatment of Bipolar Disorder.

Sir: In a recent issue of the Companion, Masand and colleagues1 report a retrospective analysis of 36 outpatients with bipolar or schizoaffective disorder in which risperidone and olanzapine were comparable in efficacy and safety, but treatment costs were lower for risperidone-treated patients. Although the acquisition costs of risperidone are lower than those of olanzapine, when other factors are taken into account, the costs of the 2 agents do not differ appreciably. As the authors point out in their article, atypical antipsychotics are becoming commonly prescribed agents in primary care settings. At the same time, primary care providers are assuming the responsibility of managing bipolar disorders. It is sometimes tempting to categorize newer antipsychotic agents into one class for the management of these conditions. However, at the moment there is considerably more evidence supporting the use of olanzapine in bipolar illness than for any other atypical antipsychotic agent, and much more than the “preliminary” evidence to which the authors allude. On the strength of 2 placebo-controlled studies that tested its efficacy as monotherapy for acute mania in 139 and 115 patients, respectively,2,3 olanzapine is currently the only atypical antipsychotic that has been approved by the U.S. Food and Drug Administration for this indication. The strength of these data is one reason olanzapine is more prominent than other atypical antipsychotics in recently published treatment guidelines.4,5 Although a well-controlled study recently demonstrated that risperidone in combination with lithium or divalproex was efficacious as an adjunctive agent for the treatment of mania,6 no clinical trial demonstrating risperidone's efficacy as a monotherapeutic agent has ever been reported. Three head-to-head monotherapy studies7–9 of olanzapine versus FDA-approved mood stabilizers have been conducted in acute mania, with a total of 398 randomized patients. In one study, olanzapine was superior to divalproex in the primary and several secondary outcome measures at 3 weeks7 and at 47 weeks,8 and in the second study, these 2 agents had comparable efficacy at 3 weeks.9 In the third study, the efficacy of olanzapine was similar to lithium on all reported outcome measures.10 Direct comparisons of this sort between other atypical antipsychotics and established mood stabilizers for the treatment of mania are not yet available. Treatment of mania is only one aspect of the comprehensive management of bipolar disorder. Treatment of bipolar depression and long-term prevention of acute mood episodes are important goals, and in these areas olanzapine's efficacy is more firmly established than any other atypical antipsychotic agent. In the only placebo-controlled study of an atypical antipsychotic in bipolar depression, the efficacy of olanzapine statistically separated from placebo after 1 week of treatment, and this effect was sustained throughout the 8 weeks of double-blind treatment.11 Finally, 2 studies12,13 evaluating long-term efficacy have been reported. Open-label therapy with olanzapine was continued for up to 1 year in 113 patients who entered one placebo-controlled registration study.12 In this study, patients demonstrated improvement in mania and depressive symptoms; 88% ultimately achieved protocol-defined remission of symptoms, with only a 25% rate of subsequent relapse. In the second longer-term study, blinded placebo-controlled olanzapine added to lithium or divalproex in 99 patients was much more effective in preventing both depressive and manic relapses than either mood stabilizer alone over a period of 18 months.13 Two other 1-year studies of olanzapine, one versus placebo and the other versus lithium, will be completed this year. In summary, among atypical antipsychotic agents, olanzapine has the most supportive data for the treatment of bipolar disorder. Therefore, it is premature to place these agents into a single category. In addition to acquisition costs, which favor risperidone, available clinical trial data on olanzapine should be considered in treatment choice.

The ADHD-Autism Connection

Article Abstract Because this piece has no abstract, we have provided for your benefit the first 3 sentences of the full text. Sir: I read with interest the letter to the editor by Dr. Ahmed and colleagues at the Lilly Research Laboratories in Indianapolis, Indiana, regarding our article1 in the last issue of the journal. I agree with the authors that olanzapine has the best available data for efficacy in bipolar disorder, which is the reason, as they point out, that it has approval from the U.S. Food and Drug Administration(FDA) for the treatment of acute mania. However, the authors are incorrect in stating that there is no clinical trial demonstrating risperidone's efficacy as a monotherapeutic agent in bipolar disorder.

Role of coenzyme Q10 in chronic heart failure, angina, and hypertension.

Coenzyme Q10 (CoQ10) has a pathophysiologic role in many disease states. The purpose of this review is to provide recommendations regarding the safety, efficacy, and dosing of CoQ10 in the management of chronic heart failure (CHF), angina, and hypertension. Literature pertaining to the safety and efficacy of CoQ10 specifically in cardiovascular indications was reviewed. We used relevant clinical trials, articles, reviews, and letters that were selected from a literature search of the MEDLINE database (1974-2000), Micromedex Healthcare Series, and the Natural Medicines Comprehensive Database. Coenzyme Q10 administered orally has favorable actions in the described cardiovascular conditions and appears to be safe and well tolerated in the adult population. Issues concerning optimum target dosages, potential interactions, monitoring parameters, and the role of CoQ10 as a monotherapeutic agent need to be investigated further. Favorable effects of CoQ10 on ejection fraction, exercise tolerance, cardiac output, and stroke volume are demonstrated in the literature; thus, the use of CoQ10 as adjuvant therapy in patients with CHF may be supported. Coenzyme Q10 therapy in angina and hypertension cannot be substantiated until additional clinical trials demonstrate consistent beneficial effects. However, CoQ10 may be recommended as adjuvant therapy in selected patients with CHE At this time, CoQ10 should not be recommended as monotherapy or first-line therapy in any disease state.

Lamotrigine monotherapy in children

The effectiveness of lamotrigine as a monotherapeutic agent for a variety of pediatric epilepsies was reviewed retrospectively. Children were categorized as having focal vs generalized epilepsy and according to whether they were antiepileptic drug naive or drug exposed. Data collected included dosages, side effects, length of follow-up, number of prior drugs, and treatment response. Treatment was considered successful if the patient was seizure free for 6 months or more. Eighty-three children were identified (average age = 8.7 years); 43 had focal epilepsy, 32 had generalized epilepsy, and eight were not classified. Twenty-nine patients were classified as having specific syndromes. Fourteen patients were drug naive. The median follow-up period was 8 months (mean = 8.5). Overall, 45% were seizure free, 44% with focal epilepsy and 36% with generalized epilepsy. All children with juvenile myoclonic epilepsy and benign rolandic epilepsy of childhood were seizure free, although not all had been treated for at least 6 months. One third of drug-naive patients were seizure free. Rash was the most common side effect and was reported in five patients (6%); two patients discontinued the drug. None had Stevens-Johnson syndrome. One quarter of children experienced nonquantifiable improvements, namely increased alertness and improved behavior regardless of seizure control. Lamotrigine is effective as a monotherapeutic agent in children for both focal and generalized epilepsies. Side effects are relatively uncommon. Lamotrigine may be an effective firstline agent.

Low-dose antihypertensive combination therapy: its rationale and role in cardiovascular risk management

Antihypertensive monotherapy, although commonly used, does not address the multifactorial nature of hypertension as a disease with many pathways. Using more than one drug makes more therapeutic sense because combination agents cover more than one pathway, yet the use of drugs in tandem is typically relegated to more problematic patients later in therapy. Many patients with hypertension are not controlled, because the monotherapeutic agent is used at its highest dose, resulting in side effects that lead to noncompliance. As opposed to fixed-dose combinations that merge two drugs at their highest doses, low-dose combination therapy provides more novel coverage of two or more metabolic pathways that contribute to hypertension. Their once-daily dosing encourages compliance. In addition, because the two drugs are combined at low doses, the probability of side effects is decreased and efficacy is often enhanced. The use of low-dose combination antihypertensive agents is a good contemporary strategy for first-line therapy in that patients can take advantage of their cardiovascular benefits and the control these agents offer early in therapy.