A phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493), a folate receptor targeted chemotherapeutic agent in humans with advanced solid tumors.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

Personality measures in former heroin users receiving methadone or in protracted abstinence from opiates.

OBJECTIVE: Methadone Maintenance Therapy (MMT) and detoxification to abstinence are among the most common treatment options for opiate-dependent patients. This paper compares personality traits in detoxified former heroin users and those on MMT in order to assess their relevance to treatment selection. METHOD: Twenty-six formerly heroin-dependent subjects receiving MMT (MM), 33 formerly heroin-dependent subjects withdrawn from MMT (MW), and 43 healthy controls were compared on the Millon Clinical Multiaxial Inventory-II (MCMI-II) and the Temperament and Character Inventory (TCI). RESULTS: On the TCI, MM patients had higher novelty seeking and lower self-directedness scores than controls. Both MM and MW subjects scored higher than controls on multiple MCMI-II scales. MW but not MM subjects scored higher than controls on two Cluster A Scales and the delusional disorder scale. CONCLUSION: Schizophrenia-spectrum pathology in former opiate users may be greater than previously recognized and could potentially be relevant to treatment selection.

Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma.

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.

Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days. RESULTS: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. CONCLUSIONS: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

Negative symptoms in patients with major depressive disorder: a preliminary report.

OBJECTIVE: The purpose of this study was to examine negative symptoms (NSs) in patients with major depressive disorder (MDD) and their relation to depressive symptoms (DSs) and other psychiatric symptoms. BACKGROUND: Features similar to NSs were previously described in patients with depression. METHOD: The Hamilton Rating Scale for Depression (HRSD), Positive and Negative Symptom Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), and Mini-Mental State Examination were administered to 23 patients with MDD and 10 normal control subjects. RESULTS: As expected, the mean scores of the HRSD, SANS, and negative symptom subscale of the PANSS of the patients with MDD were significantly higher than those of control subjects, validating the clinical significance of NSs as well as DSs in MDD patients. Within the MDD group, although measures of NSs were intercorrelated, there were no other correlations between the measures. Thus, measures of NSs and DSs were not intercorrelated. When the HRSD was divided in two subscales, HRSD negative symptom subscale scores but not HRSD depressive symptom subscale scores were correlated with PANSS negative symptom subscale and SANS total scores as well as with scores on the affective flattening subscale. CONCLUSIONS: These results suggest a high level of NSs in patients with MDD, which are distinct from positive symptoms of depression and may constitute a distinct dimension. Negative symptoms and DSs in MDD may represent separate constructs. Further, the HRSD might have possible subscales in MDD as it does in schizophrenia.

The influence of ethnicity and antidepressant pharmacogenetics in the treatment of depression.

Antidepressant disposition can be influenced by a variety of CYP isozymes and their effects in the treatment of depression are reviewed. The CYP isozymes 2D6, 3A4, 1A2 and 2C are discussed in regard to antidepressant drug pharmacokinetics, clinical relevance and variability in activity for each isozyme. Polymorphism has been identified with CYP 2D6 and 2C19. Disposition of antidepressants which are substrates of these two isozymes can also be influenced and contributes towards the wide interpatient and interethnic variability found with these drugs. Antidepressants (especially SSRIs) can be CYP isozyme inhibitors and produce significant drug-drug interactions.

Comorbid personality impairment in body dysmorphic disorder.

Personality impairment was evaluated in 17 body dysmorphic disorder (BDD) patients undergoing a treatment study of clomipramine versus desipramine. Semistructured interviews were administered using both categorical (Structured Clinical Interview for DSM [SCID II]) and dimensional (Dimensional Assessment of Personality Impairment [DAPI]) methods. Personality measures were also correlated with a range of clinical variables (severity of BDD and depressive symptoms, age, duration of illness, and response to treatment). A secondary aim of the study was to provide preliminary validation for the DAPI. Consistent with previous studies, BDD patients showed considerable personality pathology. By SCID II, patients met criteria for a mean of 2.53 personality disorder diagnoses; 87% of patients met criteria for at least 1 diagnosis and 53% for more than 1. Cluster C diagnoses were the most common. Mean scores for the DAPI were 2.63 (3 = mild impairment) to 6.41 (7 = severe impairment), averaging 5.26 (5 = moderate). With regard to the DAPI, the results provided preliminary evidence of good reliability and validity. Moreover, both personality measures were highly intercorrelated. Although SCID II diagnoses correlated with baseline depression (Hamilton Rating Scale for Depression [HRSD]) scores, there were few other significant correlations between personality and other clinical variables. Of note, however, treatment responders demonstrated less personality impairment than nonresponders. The finding that personality measures were highly intercorrelated but, on the whole, not well correlated with other clinical measures supports the distinct and dissociable nature of personality phenomena in BDD. Despite the small sample size, these results suggest that personality impairment appears to be significant factor in BDD and may even play a role in treatment response.

The emerging role of psychiatric pharmacists.

The concept of pharmaceutical care has greatly expanded the role of the pharmacist, from that of strictly a drug dispenser to a more integrated member of a patient's healthcare team. In order for pharmaceutical care practice to succeed, the pharmacist must assume a more proactive role, using his or her knowledge of drug therapy and behavioral medicine to assume more responsibility in achieving improvement in patient health outcomes. The pharmacist must also develop open, professional relationships with patients, their families/caregivers, and other members of the healthcare team. Pharmaceutical care comprises 4 components: education, medical-legal issues, drug therapy knowledge, and communication. Through these efforts, and because pharmacists offer greater access to patients and a broader view of patient outcomes, pharmaceutical care affords the opportunity for these professionals to become patient advocates and prevent line-item decision making. Special considerations exist for psychiatric pharmacists practicing pharmaceutical care, especially in documentation and formulary decisions. Psychiatric pharmacists can ensure that patients have access to the safest, most efficacious (and cost-effective) drugs by considering more than just acquisition costs.

The role of neuropsychiatric pharmacists.

A modern pharmaceutical care model widens the traditional pharmacy role of medication dispenser to educator and information manager. The broad goals of a modern pharmacy service are to improve the efficiency and safety of drug therapy, to improve patient satisfaction and quality of life, to ensure medication compliance, to save time for physicians and other members of the health care team, and to save money. In this new model, drug acquisition costs are considered as a part of a total health care budget rather than as a single segment to be controlled irrespective of impact on other parts of the budget. More than 80% of patients with schizophrenia who are treated with conventional neuroleptics are rehospitalized within 2 years, and controlled studies have shown that inpatient costs are lower when atypical antipsychotics are used instead of typical antipsychotics. In the future, pharmacy departments with narrow responsibilities are likely to give way to a pharmaceutical care service in which the pharmacist is a vital member of the health care team.

Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial.

We examined the safety and efficacy of the docetaxel/cisplatin combination in patients with advanced, previously untreated NSCLC and evaluated changes in quality of life over time. Docetaxel was administered before cisplatin (both 75 mg/m2, 1-hour infusions) every 3 weeks to 47 patients with stage IIIB or stage IV NSCLC. Patients also received premedication of oral dexamethasone. The median age (range) of patients was 62 (45-78) years and 26 patients (55.3%) had adenocarcinoma. Of the 40 patients evaluable for response, one achieved a complete response and 14 had partial responses; the response rate was 37.5% (95% confidence intervals; 22.5, 52.5). In the intent-to-treat population the overall response rate was 31.9%. Time to response ranged from 3 to 20 weeks, and the median duration of response was 34.6 weeks. Median survival and median time to progression were 11.3 months and 18.9 weeks, respectively. One-year survival was 40%. Grade 3 or 4 neutropenia and febrile neutropenia were observed in 74.4% and 12.8% of patients, respectively. Severe asthenia was seen in 14.9% of patients. Other grade 3 or 4 toxicities included nausea (eight patients), vomiting (five), neurosensory effects (six), neuromotor effects (five), diarrhea (four), and infection (three). There was an improvement in emotional well-being; however, the overall quality of life score did not change with treatment. Docetaxel administered in combination with cisplatin is an active regimen in patients with NSCLC. This regimen of docetaxel (75 mg/m2) and cisplatin (75 mg/m2) repeated at 3-week intervals is being evaluated in an ongoing Eastern Cooperative Oncology Group (ECOG) randomized study in patients with advanced and metastatic NSCLC.

Increased p21/WAF-1 and p53 protein levels following sequential three drug combination regimen of fludarabine, cytarabine and docetaxel induces apoptosis in human leukemia cells.

Combinations of nucleoside analog drugs, such as F-araA and ara-C, combined with Topoisomerase II inhibitors, such as anthracyclines, are synergistic against human leukemic T-cells and induce apoptotic cell death. Similarly, nucleoside analog drugs followed by mitotic inhibitors also have a synergistic effect. Sequence specific combinations of F-araA followed by ara-C and Taxotere (docetaxel) in CEM/0 cells showed a 2- to 3-fold synergism over the two drug (F-araA + ara-C) combinations and 2- to 4-fold synergism over Taxotere alone. This synergism was evident due to enhanced cellular apoptosis. In the CEM/ara-C/7A cell line, which is partially resistant to ara-C, the synergy observed with the triple drug combination was 9-fold greater than the F-araA plus araC combination, and 3-fold greater than Taxotere alone, making this three-drug regimen collaterally sensitive to ara-C. This study describes the mechanisms of the synergistic effect in regards to apoptosis achieved by three-drug regimens comprised of two nucleoside analog drugs and a mitotic inhibitor in comparison with the combination of two nucleotide analog drugs. The study also demonstrates that the possible biochemical mechanism of cellular toxicity and drug synergism is attributed to induction of apoptosis following drug treatment and the onset of the apoptotic cascade is primarily regulated by p21/WAF-I, which is transcriptionally activated by p53 following DNA damage. The anti-apoptotic protein, bcl-2, seemed to have no effect in inhibiting apoptosis following treatment with the two or three drug regimens in this in vitro leukemia model. The three-drug combination induced greater cellular apoptosis than the two-drug combination or Taxotere monotherapy. We conclude that the greater drug synergism observed in human leukemic cells, sensitive or resistant to ara-C, by Fludarabine + ara-C + Taxotere can be explained by the greater oligonucleosomal DNA fragmentation indicative of increased cellular apoptosis. The mechanism of this increased cytotoxic action is due to the upregulation of p53 and p21/WAF-1 with a down regulation of bcl-2. These studies are encouraging, and testing this three drug regimen in a clinical setting may result in improved antileukemic therapies.

Trauma in children of Holocaust survivors: transgenerational effects.

The effect of parental Holocaust trauma on their children's Jewish identity and Holocaust-related ideation was investigated by comparing survivors' children with children of American Jews. Parental communication style as a possible mediating factor was also assessed. Children of survivors showed significantly more Holocaust ideation than did those of American Jews, but did not differ appreciably on measures of Jewish identity. Parental communication style was associated with ethnic identification, suggesting its mediating influence on the transgenerational effects of parental trauma.

Depression in primary care: review of AHCPR guidelines.

OBJECTIVE: To present an overview and evaluation of the Agency for Health Care Policy and Research (AHCPR) clinical practice guidelines for the treatment of depression. INTRODUCTION: One responsibility of the AHCPR is the development and periodic review and update of clinical practice guidelines. This process is undertaken by an independent panel composed of groups of clinicians and other experts from the private sector. Their findings are published in a four-volume, softcover set of booklets. DATA SOURCE AND EVALUATION: Volume 2 in the four-volume set includes a comprehensive complication, synthesis, and critical evaluation of the studies of different treatments for depression. Studies included for evaluation were randomized, prospective clinical trials that were pertinent to all topics concerning the treatment of depression. In some areas, the opinions of the panel were included due to a paucity of data from well-controlled clinical trials. Each AHCPR guideline was followed by a code that indicated whether the strength of evidence supporting that guideline was based on good or fair research-based evidence, or whether it was based primarily on panel members' opinions. CONCLUSIONS: With regard to drug treatment, the guidelines are good. However, since these guidelines were published in 1993 they might be considered somewhat dated because more antidepressants have become available in the interim. Overall, the AHCPR guidelines reflect an extensive review of the literature provided by the panel, as well as input from a highly respected group of reviewers. The panel included physicians, a nurse, a social worker, a psychologist, and a consumer representative. Unfortunately, a pharmacist was not included on the panel. Input from pharmacy practitioners would have been valuable.

Rational drug use in the treatment of depression.

New drugs are being developed for the management of depression in response to the growing awareness of the prevalence and disability associated with the disorder and the need for agents with improved side effect profiles. All antidepressants are equally effective for treating uncomplicated unipolar depression without psychotic features. For patients with atypical depression with prominent anxiety, agitation, sleep loss, and irritability, monoamine oxidase inhibitors are the first choice. Data are accumulating supporting the efficacy of selective serotonin reuptake inhibitors (SSRIs) in these depressive subtypes. Factors to consider when choosing an antidepressant include spectrum of adverse effects, long-term tolerability, dosing schedule, clinically significant drug interactions, underlying medical conditions, earlier response to therapy, and pharmacoeconomics. Based on these criteria, it is suggested that a trial with the SSRIs be attempted first. Venlafaxine and nefazodone are newer agents with mechanisms of action that have advantages over tricyclic antidepressants and monoamine oxidase inhibitors. Choosing a drug that is effective, tolerable, and convenient will improve the likelihood of achieving and maintaining a full remission. It will also decrease the morbidity and mortality of this very treatable disease.

Looking beyond the formulary budget in cost-benefit analysis.

With the introduction of newer, more expensive psychotropic medications, healthcare providers and managed care administrators must consider whether these drugs offer "value for the money." A true picture of the benefits of these drugs emerges only when all the costs of treatment are considered. Focusing exclusively on the acquisition cost of the drug can result in a misleading impression of the drug's worth. Although the medication costs associated with treating a patient with a newer drug increase, use of these agents may actually result in an overall decrease in healthcare costs, through reductions in hospitalization and length of stay, use of mental health services, and prescriptions for adjunctive drugs. In one study of the newer antipsychotic agent risperidone, the overall annual costs of treating a patient with schizophrenia were reduced by nearly $8,000 (Canadian dollars), even though medication costs increased by approximately $1,200 (Canadian dollars). Retrospective and prospective pharmacoeconomic studies can provide valuable data on the cost effectiveness of treatment with newer psychotropic medications.

Clinical implications of antidepressant pharmacokinetics and pharmacogenetics.

OBJECTIVE: To review available data on pharmacokinetic and pharmacogenetic influences on the response to antidepressant therapy, analyze the mechanisms for and clinical significance of pharmacokinetic and pharmacogenetic differences, and explain the implications of pharmacokinetics and pharmacogenetics for patient care. DATA SOURCES: A MEDLINE search of English-language clinical studies, abstracts, and review articles on antidepressant pharmacokinetics, pharmacogenetics, and drug interactions was used to identify pertinent literature. DATA SYNTHESIS: The pharmacokinetic profiles of selected antidepressants are reviewed and the impact of hepatic microsomal enzymes on antidepressant metabolism is considered. How phenotypic differences influence the metabolism of antidepressant drug therapy is addressed. To evaluate the clinical implications of these pharmacokinetic and pharmacogenetic considerations, the findings of studies designed to elucidate drug interactions involving antidepressant agents are discussed. CONCLUSIONS: Differences in antidepressant plasma concentrations, and possibly safety, are caused by polymorphism in the genes that encode some of the cytochrome P450 isoenzymes that metabolize antidepressants. The isoenzymes 1A2, 2C9/19, 2D6, and 3A4 are the major enzymes that catalyze antidepressant metabolic reactions. Antidepressants can be either substrates or inhibitors of these enzymes, which also metabolize many other pharmacologic agents. Although the cytochrome enzymes that metabolize antidepressants have not been fully characterized, interaction profiles of the newer antidepressants are becoming more clearly defined. Determining patient phenotypes is not practical in the clinical setting, but an awareness of the possibility of genetic polymorphism in antidepressant metabolism may help explain therapeutic failure or toxicity, help predict the likelihood of drug interactions, and help clinicians better manage antidepressant drug therapy.