Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer.

AIMS: To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. PATIENTS AND METHODS: Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). RESULTS: Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. CONCLUSIONS: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.

Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor.

MS-275 (MS-27-275; 3-pyridylmethyl-N-[4-[(2-aminophenyl)-carbamoyl]-benzyl-carbamate) is a histone deacetylase inhibitor under clinical development as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of MS-275. The distribution of MS-275 in plasma was studied in vitro using equilibrium dialysis and ex vivo in five cancer patients receiving the drug orally at a dose of 10 mg/m(2). The dialysis method uses a tracer amount of [G-(3)H]MS-275 on a 96-well microdialysis plate with a 5-kDa cut-off membrane, and requires 250 microl sample. The time to equilibrium was established to be within 5 h, and the mean unbound fraction of MS-275 (f (u)) over a presumed therapeutic concentration range in healthy volunteer human plasma was 0.188 +/- 0.0075 as compared to 0.168 +/- 0.0144 in cancer patients. The binding was concentration-independent, indicating a low affinity, possibly non-specific and non-saturable process. MS-275 was found to bind in decreasing order to plasma > alpha(1)-acid glycoprotein > albumin. Among 19 tested drugs, a slightly increased f (u) was observed in the presence of only ibuprofen (f (u), 0.236 +/- 0.001) and metoclopramide (f (u), 0.270 +/- 0.042), suggesting weakly competitive displacement from protein-binding sites (P < 0.01). Compared to humans, f (u) was significantly higher in plasma from mouse (0.376), rat (0.393), rabbit (0.355), dog (0.436), and pig (0.439) (P < 0.01), which may explain, in part, the species-dependent pharmacokinetic profile of MS-275 observed previously.

Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel.

Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [3H]docetaxel and [3H]paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 microM), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes.

Rational development of histone deacetylase inhibitors as anticancer agents: a review.

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.

Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2.

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine.

OBJECTIVE: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients. EXPERIMENTAL DESIGN: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day). RESULTS: Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744). CONCLUSION: The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.

Chemically modified tetracyclines as inhibitors of matrix metalloproteinases.

Matrix metalloproteinases belong to a diverse group of enzymes that are not only involved in restructuring the extracellular matrix, but also play a major role in various pathophysiological conditions by virtue of their complicated expression, activation, and regulation processes. They have been widely implicated to function as major contenders in cancer progression, frequently due to their role in invasion, proliferation and metastasis. MMP inhibitors have been specifically designed to target these altered activities of MMPs, mostly by means of inhibiting their function and by diminishing their increased expression in various disease states, particularly cancer. Tetracyclines and chemically modified tetracyclines (CMTs) have been rationally designed to inhibit the activity of MMPs and thus decrease the potential risk of spread of tumor cells to distant sites by invasion and metastasis. Pre-clinical and early clinical data for one of these CMTs, COL-3 (formerly CMT-3) indicate considerable potential for this group of anticancer agents. Further testing and rational modifications of these CMT analogues might lead to new anticancer agents.

Histone deacetylase inhibitor enhances the anti-leukemic activity of an established nucleoside analogue.

Interest in histone deacetylase (HDAC) inhibitors as antineoplastic agents has been accelerating over the last several years and increasing number of compounds are in or entering clinical trials in humans. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbations in cell cycle regulatory proteins (e.g. p21CIP1), down regulation of survival signaling pathways (e.g. Raf/MAPkinase/ERK), and disruption of cellular redox state (e.g. reactive oxygen species, ROS). In April 2004 issue of Cancer Research, Maggio et al. report that pre-treatment of human leukemic cells with a histone deacetylase inhibitor, MS-275 significantly enhances the abrogative capacity of an established nucleoside analogue, fludarabine. The study indicates that apart from promoting acetylation of histones and regulation of genes involved in differentiation and apoptosis, MS-275 also induces multiple perturbations in signal transduction, survival and cell cycle regulatory pathways that increase the fludarabine-mediated cell death.

Herbal remedies in the United States: potential adverse interactions with anticancer agents.

PURPOSE: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. METHODS: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. RESULTS: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. CONCLUSION: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry.

A rapid method was developed for the quantitative determination of the novel histone deacetylase inhibitor, MS-275, in human plasma. Calibration curves were constructed in the range of 1-100 ng/ml, and were analyzed using a weight factor proportional to the nominal concentration. Sample pretreatment involved a one-step protein precipitation with acetonitrile of 0.1 ml samples. The analysis was performed on a column (75 mm x 4.6 mm i.d.) packed with 3.5 microm Phenyl-SB material, using methanol-10mM ammonium formate (55:45 (v/v)) as the mobile phase. The column effluent was monitored by mass spectrometry with positive electrospray ionization. The values for precision and accuracy were always < or =5.58 and <11.4% relative error, respectively. The method was successfully applied to examine the pharmacokinetics of MS-275 in a cancer patient.

Sertraline effects in adolescent major depression and dysthymia: a six-month open trial.

This 6-month open-label study evaluated the efficacy, tolerability, and safety of sertraline in 21 adolescent psychiatric outpatients, ages 12 to 18 years, diagnosed with major depressive disorder (MDD, n = 13) or dysthymic disorder (DD, n = 8). Both groups showed clinically significant improvements on the Hamilton Depression Scale (HAM-D), Hamilton Anxiety Scale, and the Clinical Global Impression Scale-Severity (CGI-S). The MDD group showed maximal clinical response (based on the method of last observation carried forward) on the HAM-D and CGI at weeks 12 (76.9%) and 20 (76.9%), respectively. Response rates were maintained at week 24 with all six MDD study completers (100%) responding to treatment. The DD group achieved maximal response on the HAM-D (100%) and the CGI (75%) at week 6. Response rates in this group did not remain as elevated over time with two out of three (66.7%) DD study completers responding to treatment at week 24. Generally, sertraline was safe and well tolerated. Most adverse events were mild to moderate in severity and resolved with no action taken. Results suggest that sertraline may be efficacious in acute and continuation treatment of MDD in adolescents. DD patients showed evidence of clinical response and improvement, particularly in the acute treatment phase. Incorporating a longer evaluation period in the study of antidepressant therapy for adolescents with MDD and/or DD is emphasized.

Outcome and follow-up study of an adolescent psychiatric day treatment school program.

OBJECTIVES: To evaluate outcome and follow-up of 55 subjects who attended a classroom-based, adolescent psychiatric day treatment unit school program (ADTU) situated in a community high school by examining pre-post changes in emotional, behavioral, family, and academic functioning and to identify preadmission and family variables associated with outcome. METHOD: Student-patients were assessed on clinical/academic variables at admission, discharge, and follow-up, using standardized assessment measures. Patient satisfaction was also evaluated. RESULTS: Significant improvements in emotional-behavioral and academic functioning were found at discharge and follow-up. Hierarchical regression analysis revealed that parent and clinician ratings at admission, total number of separations from family greater than 3 months, parental history of mental illness, and patient history of treatment for emotional problems were significantly associated with outcome. Satisfaction questionnaires revealed a high degree of satisfaction with the program. CONCLUSIONS: The ADTU is a successful treatment program for adolescents with chronic, severe emotional and behavioral disorders, despite limitations of the study.

Case study: withdrawal syndrome in adolescent chronic cannabis users.

Cannabis use is common among adolescents and has recently been increasing, especially among young teenagers. Whether the reduction of cannabis in chronic heavy users results in a clinically significant withdrawal syndrome is controversial. This article presents three case vignettes supporting the view that chronic cannabis use by adolescents may result in a clinically significant withdrawal syndrome and that the associated physiological symptoms directly contribute to the persistent use of the substance.

Pharmacological treatment of psychiatric disorders in children and adolescents: focus on guidelines for the primary care practitioner.

This article is a practical review of the current psychopharmacological agents used in the treatment of child and adolescent psychiatric disorders. Psychostimulants such as methylphenidate, dexamphetamine and pemoline are effective in the control of symptoms associated with attention deficit hyperactivity disorder. The controlled release preparations and the adjunctive use of clonidine are helpful to extend stimulant effects and control adverse effects. Tricyclic antidepressants are helpful in individual cases of child and adolescent depression, but adverse effects may limit their use. Clomipramine has been found to be effective for childhood obsessive-compulsive disorder. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) appear to be safer for depression and are also useful in obsessive-compulsive disorder. Buspirone is effective for the treatment of anxiety disorders in children. Newer atypical antipsychotics such as risperidone may have less limiting adverse effects than older antipsychotics in the treatment of psychosis and severe behaviour disorders, but the physician must be vigilant for the emergence of tardive dyskinesia. Drug treatment in children and adolescents must take into account the child's environmental influences and be part of an overall treatment plan where individual, familial and cultural issues are addressed.

Morphodynamic response of the rat light pinealocytes to an injection act. Implication of beta-adrenoreceptors.

The implication of beta-adrenoreceptor-mediated noradrenalin action on the reactive morphodynamic response of light pinealocytes (LP) to an injection act, conceived as a short-lasting stress attack, is reported. An injection act, realized by saline-injection, was manifested in the occurrence of clustered "dusk" and "bright" cells--the representative forms of functionally activated LP. The time-related incidence of these cells entities--the appearance of "dusk" and "bright" cells at 5 min, transitory domination of "bright" cells and the nadir of "dusk" cells at 20 min, sporadic recognition of "bright" cells, lack of "dusk" cells at 45 min and the absence of both cell forms at 180 min--displayed that LP-reactive response promptly appeared and rapidly ceased. The injection of beta-adrenoreceptor antagonist, propranolol, did not considerably alter the pattern of LP-reactive response proper for saline-injected rats at 5 min. The constant presence of "dusk" and "bright" cells, structurally changed in all the following time periods under investigation, showed that this drug disordered the course of LP-reactive response to an injection act. On the contrary, LP of resting state was not found to be affected. Estimating functionally, the present results indicate that beta-adrenoreceptor-mediated noradrenalin action is required to promote, maintain and accomplish the LP-reactive response to a short-lasting stress inducement.

Psychopathology among substance abusing juvenile offenders.

The prevalence of substance abuse and coexisting DSM-III psychiatric disorders was evaluated in 111 juvenile offenders. As expected, a high rate of conduct disorder (91%) was present in both substance abusing and nonsubstance abusing juvenile offenders. However, significantly higher rates of attention deficit disorder and aggressive subtype of conduct disorder were present in those offenders who abused drugs and alcohol (54%). Excluding all conduct and oppositional disorder diagnoses, 39% of substance abusers versus 14% of the nonsubstance abusers demonstrated comorbid psychiatric diagnoses. These findings suggest that careful psychiatric evaluation of juvenile substance abusers may be necessary to optimize treatment planning.

Adolescent couple suicide: literature review.

A suicide pact is a mutual arrangement between two people to kill themselves at the same time, usually in the same place. A summary of the highlights from a literature survey on suicide pacts with a major focus on high risk factors is presented in this paper. The victims of suicide pacts are usually the spouses over age 50. The instigator is usually a depressed male with a history of self-destructive behaviour. In many cases the presence of an overdependent relationship, and a threat to the maintenance of closeness are strongly associated with the attempt. Since there were no adolescent couple suicide pacts in the literature, a case of a serious adolescent couple suicide attempt assessed and treated by the authors is reported here. The dynamics of this case are compared to the findings, the studies and case reports on adult suicide pacts.