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.

Timing of neuroendocrine responses and effect of m-CPP and fenfluramine plasma levels in OCD.

The present study assesses the timing of and relationship between neuroendocrine response and metabolite blood levels following the partial serotonin (5-HT) agonist m-CPP and the 5-HT releaser/reuptake blocker fenfluramine. Cortisol levels peaked significantly earlier than did prolactin, m-CPP, fenfluramine, or norfenfluramine blood levels by time-to-peak analysis. This earlier cortisol response to both 5-HT agents raises the possibility that peripheral mechanisms may play a role in cortisol release. Since peak m-CPP level correlated even more closely to peak prolactin rise than did peak fenfluramine, this suggests that prolactin response to oral m-CPP challenge is useful in assessing 5-HT function.

The unstated problem in a psychological testing referral.

There is a manifest and a latent content to many psychological testing refereals. Although a diagnostic problem is usually the stated reason for the referral, the unstated and more basic reason frequently has to do with problems the therapist is encountering in attempting to deal with a difficult treatment situation. The testing psychologist who responds at the manifest level alone may not help and at times may even be a hindrance.

Suicide and schizophrenia: data from a prospective community treatment study.

This article reports the analysis of prospectively gathered data on eight young adults who committed suicide during an ongoing longitudinal study of long-term treatment of schizophrenia in the community. Young adult men with an early onset of psychiatric illness were identified as a high-risk subgroup. At the time of admission to the study, the subjects who eventually committed suicide reported significantly more distress and tended to be less satisfied with their lives than the other subjects. Specifically, baseline measures of self-reported subjective distress were consistently predictive of later suicide, whereas interviewer-rated measures and postbaseline assessments were not.

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.

The assessment and treatment of refractory anxiety.

Most patients with anxiety disorders can be effectively treated with the use of specific pharmacologic and psychological approaches. Nevertheless, some anxiety patients remain refractory to standard treatments. For these patients, reappraisal and a systematic approach can be helpful. A common problem in patients with "treatment-resistant" anxiety is the use of inadequate doses or inadequate duration of medication treatment. Alternatively, the diagnosis may need to be reconsidered, and comorbid diagnoses carefully assessed. Comorbid psychiatric, medical, and neurologic conditions may complicate the treatment of anxiety or require additional specific treatments. Finally, alternative pharmacologic approaches for specific types of anxiety can yield successful outcomes.

Trichotillomania and obsessive-compulsive disorder.

Trichotillomania, a disorder characterized by repetitive hair pulling, has been only recently systemically investigated. Such research was encouraged by data that showed obsessive-compulsive disorder, which is also characterized by ritual behaviors, responds selectively to serotonin reuptake inhibitors. In this review, we consider similarities and contrasts in the diagnosis, demographics, phenomenology, neurochemistry, neuropsychiatry, and treatment of trichotillomania and obsessive-compulsive disorder. We argue that a view of trichotillomania as an obsessive-compulsive spectrum disorder that may involve disturbances in grooming behaviors comprises a useful clinical and research heuristic. Nevertheless, there may also be important differences between the two disorders; in particular, trichotillomania has a number of characteristics in common with impulsive disorders. Further empirical investigation is necessary to determine the nature of these complex disorders and their relationship to one another.

Clinical profile, comorbidity, and treatment history in 123 hair pullers: a survey study.

BACKGROUND: Trichotillomania, characterized by an irresistible urge to pull one's hair, may be more prevalent than previously believed. Despite increasing attention devoted to this topic in the recent literature, there are few studies based on large samples that are potentially generalizable to a community population. METHOD: Surveys addressing clinical profile, comorbidity, and treatment history were mailed to all responders to a nationally distributed magazine article on trichotillomania. Out of 772 surveys sent, 123 completed surveys were returned. RESULTS: While there was a predominance of females in the whole sample, female-to-male prevalence was lower in children than adults. Onset was predominantly in childhood (mean age = 11 years), most frequently in middle childhood and least frequently before age 6. Subjects pulled hair from a variety of sites, including scalp, eyelashes, eyebrows, pubic region, face, and body, but the highest incidence and severity involved scalp hair. Children under 6 were more likely than other age groups to pull scalp hair and possibly less likely to pull other hair. In adults, symptom profile was not associated with age at onset. While subjects reported high rates of comorbid conditions in both self and family, trichotillomania was reportedly formally diagnosed in only 40% of the subjects. Although subjects reported a range of treatments, the majority (58%) reported no treatment history. Finally, only minimal improvement was reported for all modalities, with no significant difference in response to psychotherapy, behavior therapy, clomipramine, or fluoxetine. CONCLUSION: Trichotillomania is a chronic illness that may be difficult to treat. Controlled studies on comorbidity, epidemiology, treatment-seeking patterns, and long-term treatment response are needed.

Benign lymphocytic angiitis and granulomatosis: a case report with evidence of an autoimmune etiology.

Benign lymphocytic angiitis and granulomatosis (BLAG) is characterized by dense benign-appearing infiltrates of mature lymphocytes, plasma cells, and histiocytes within the pulmonary parenchyma and vasculature. The disorder typically is restricted to the lungs and has a good prognosis. The authors report a patient with BLAG and involvement of lung, kidney, and prostate. This is the first report of prominent systemic distribution in this disease. Another unique feature of this case was the presence of serum antinuclear antibodies and evidence of immune complex deposition in both lung and kidney, suggesting an underlying autoimmune disorder. An association of this entity with lymphomatoid granulomatosis (LG) has been suggested, and the prominent genitourinary disease in this patient may be indicative of a transitional stage leading to LG. An autoimmune state may be the underlying stimulus for the development of BLAG and LG.

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.

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.

Risperidone.

Risperidone, a benzisoxazole derivative, is a novel antipsychotic agent that has an extremely strong binding affinity for serotonin 5-HT2 receptors, a strong binding affinity for dopamine D2 receptors, and a high affinity for alpha 1- and alpha 2-adrenergic receptors and histamine H1 receptors. Its affinity for serotonin receptors is approximately 200 times greater than that of haloperidol, and its dopamine antagonistic potency is comparable to that of haloperidol. Its major metabolite, 9-hydroxyrisperidone, has similar pharmacologic activity, and thus the parent compound and metabolite form the active antipsychotic moiety. Clinical trials demonstrate that risperidone is an effective antipsychotic agent that improves negative as well as positive symptoms of schizophrenia. At recommended dosages, the frequency of extrapyramidal side effects is no greater than that seen with placebo. The drug appears to be an advance in the treatment of psychoses.

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.

The decontextualization of mental illness: the portrayal of work in psychiatric drug advertisements.

This paper explores the decontextualization of mental illness in psychiatric drug advertisements. Taking the portrayal of work in several drug advertisements which appeared in the American Journal of Psychiatry* as the object of our analysis, we show how these ads tend to individualize mental illness and its treatment by failing to consider the social realities that contribute to or, in some way, affect mental illness. We conclude with a discussion of how such ads distort debate over treatment options and legitimize existing social relations and attitudes.

Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

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.

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.

Conventional versus modified morphologic criteria for ganglioneuroblastoma. A review of cases from the Pediatric Oncology Group.

BACKGROUND: Conventional criteria for ganglioneuroblastoma (GNB) do not require the presence of ganglioneuromatous component for pathologic diagnosis. This leads to inclusion of a mixed variety of neuroblastic tumors in the category of GNB. Therefore, GNB diagnosed by conventional criteria includes tumors showing more than 5% ganglion cells but no predominant ganglioneuromatous component, as well as tumors containing predominant ganglioneuromatous component. By previously described modified criteria, the former would be considered differentiating neuroblastoma (NB), and only the latter would be considered GNB. Data on Pediatric Oncology Group cases were analyzed to compare the prognostic subgroups of GNB diagnosed by conventional and modified criteria. The two prognostic subgroups (low risk and high risk) were defined on the basis of previously described prognostic differences between histologic grades of differentiating NBs and subtypes of GNB. METHODS: Pathologic data from cases of neuroblastic tumors registered on Pediatric Oncology Group NB protocols 8104 and 8441 were reviewed. The GNBs diagnosed by conventional and modified criteria were divided into low-risk and high-risk histology subgroups as follows: (1) GNB by conventional criteria: low-risk group, differentiating NB of histologic grades 1 and 2 and GNB of intermixed and borderline subtypes; high-risk group, differentiating NB of histologic grade 3 and GNB of nodular subtype; (2) GNB by modified criteria: low-risk group, GNB of intermixed and borderline subtypes; high-risk group, GNB of nodular subtype. RESULTS: The low- and high-risk subgroups of GNBs diagnosed by conventional (69 cases) and modified (36 cases) criteria showed statistically significant differences in survival (P = .03 and .01, respectively). However, from the histologic point of view, GNBs diagnosed by modified criteria form a more uniform morphologic group, which can be divided into low- and high-risk subgroups by a single set of morphologic criteria. In contrast, GNBs diagnosed by conventional criteria form a heterogeneous group, which requires two sets of criteria (ie, histologic grade and subtypes of GNB) for its classification into low- and high-risk subgroups. CONCLUSIONS: The modified criteria for GNB define a morphologically uniform group of neuroblastic tumors to which a single set of prognostic criteria can be applied. It is recommended that the term GNB should be used both clinically and pathologically to designate a distinctive subgroup of neuroblastic tumors, in contrast to the current use, which designates both NB and GNB.

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.