bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression
Authors: Hickie Ian , Naismith Sharon , Ward Philip B. , Turner Keelin , Scott Elizabeth , Mitchell Philip , Wilhelm Kay , Parker Gordon
Published: March 2005

Background

Hippocampal volume reduction has been reported inconsistently in people with major depression.

Aims

To evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors.

Method

Totals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected.

Results

Reduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance.

Conclusions

Although reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.
Hypofrontality in men with first-episode psychosis
Authors: Molina V. , Sanz J. , Reig S. , Martínez R. , Sarramea F. , Luque R. , Benito C. , Gispert J. D. , Pascau J. , Desco M.
Published: March 2005

Background

Decreased metabolic activity in the prefrontal cortex during cognitive activation is a recurrent finding and a likely functional marker of schizophrenia.

Aims

To investigate the occurrence of hypofrontality in patients with first-episode psychosis, with or without evolution to schizophrenia.

Method

We used fluorodeoxyglucose positron emission tomography during the performance of an attention task and magnetic resonance imaging to study the dorsolateral prefrontal region in 13 men with a first episode of psychosis. Data from patients who progressed to schizophrenia were compared with those of patients who did not meet criteria for this diagnosis after 2 years.

Results

Patients who developed schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with the non-schizophrenia and control groups.

Conclusions

Our results suggest that hypofrontality could be a marker of schizophrenia at the time of the first psychotic episode, in agreement with neurodevelopmental theories of schizophrenia.
Nicotine dependence and symptoms in schizophrenia
Authors: Aguilar M. Carmen , Gurpegui Manuel , Diaz Francisco J. , De Leon Jose
Published: March 2005

Background

Smoking may have a beneficial effect on either schizophrenic symptoms or antipsychotic side-effects, but studies are hampered by the lack of control of confounding factors.

Aims

To explore the self-medication hypothesis in a large sample of stable out-patients with schizophrenia.

Method

Symptoms, assessed with the Positive and Negative Syndrome Scale (PANSS), and number of hospitalisations were compared in 250 out-patients with DSM–IV schizophrenia classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers. Log-linear analysis was used to control for potential confounding and interacting variables.

Results

High PANSS total scores and positive symptoms were less frequent in mildly dependent smokers than in non-smokers or highly dependent smokers. The highly dependent smokers had the worst outcome.

Conclusions

The data do not generally support the self-medication hypothesis but rather suggest a complex interaction between nicotine dependence and schizophrenic symptoms.
Escitalopram in the treatment of social anxiety disorder
Authors: Kasper Siegfried , Stein Dan J. , Loft Henrik , Nil Rico
Published: March 2005

Background

Selective serotonin reuptake inhibitors are effective in the treatment of social anxiety disorder and are currently regarded as the pharmacotherapy of choice.

Aims

To investigate the efficacy and tolerability of escitalopram in the treatment of generalised social anxiety disorder.

Method

Patients with generalised social anxiety disorder were randomised to receive placebo (n=177) or 10–20 mg escitalopram (n=181) in a 12-week, double-blind trial. The primary outcome measure was the mean change from baseline to last assessment in the Liebowitz Social Anxiety Scale (LSAS) total score.

Results

The study showed a statistically superior therapeutic effect for escitalopram compared with placebo on the LSAS total score (P=0.005). There were significantly more responders to treatment for escitalopram than for placebo (54% v. 39%; P < 0.0 1). The clinical relevance of these findings was supported by significant reduction in the work and social components of the Sheehan Disability Scale and by the good tolerability of escitalopram treatment.

Conclusions

Escitalopram was efficacious and well tolerated in the treatment of generalised social anxiety disorder.
Assessing adolescent personality pathology
Authors: Westen Drew , Dutra Lissa , Shedler Jonathan
Published: March 2005

Background

Personality pathology constitutes a major form of psychopathology in adolescents.

Aims

To examine the reliability and validity of a Q-sort instrument for assessing adolescent personality pathology designed for clinically experienced informants.

Method

A sample of 294 randomly selected psychiatrists and psychologists each provided data on a current patient, aged 14–18 years. Clinicians completed several measures, including the Shedler–Westen Assessment Procedure for Adolescents (SWAP–200–A).

Results

Factor analysis identified II dimensions of adolescent personality: psychopathology/malignant narcissism, dysphoria/inhibition, psychological health, histrionic sexualisation, schizotypy, sexual conflict, emotional dysregulation, anxious obsessionality, peer rejection, delinquent behaviour and attentional dysregulation. These correlated in predicted ways with a range of criterion variables, including measures of adaptive functioning, Axis II pathology, the Five Factor Model and the Child Behavior Checklist.

Conclusions

The SWAP–200–A shows promise as an instrument for assessing personality pathology in adolescents. Trait dimensions such as delinquent behaviour and emotional dysregulation may prove useful additions to a classification of personality.
Suitability and utility of the CORE–OM and CORE–A for assessing severity of presenting problems in psychological therapy services based in primary and secondary care settings
Authors: Barkham Michael , Gilbert Naomi , Connell Janice , Marshall Chris , Twigg Elspeth
Published: March 2005

Background

There is a need for reliable assessment tools that are suitable for the counselling and the psychological therapy services in primary and secondary care settings.

Aims

To test the suitability and utility of the Clinical Outcomes in Routine Evaluation – Outcome Measure (CORE–OM) and CORE–Assessment (CORE–A) assessment tools.

Method

Service intake data were analysed from counselling and psychological therapy services in 32 primary care settings and 17 secondary care settings.

Results

Completion rates exceeded 98% in both of the settings sampled. Intake severity levels were similar but secondary care patients were more likely to score above the risk cut-off and the severe threshold and to have experienced their problems for a greater duration.

Conclusions

The CORE–OM and CORE–A are suitable assessment tools that show small but logical differences between psychological therapy services in primary- and secondary-based care.
Psychiatric advance directives: qualitative study of informed deliberations by mental health service users
Authors: Amering Michaela , Stastny Peter , Hopper Kim
Published: March 2005

Background

Established legal mandates and high expectations for psychiatric advance directives are not matched by empirical evidence documenting their actual implementation.

Aims

To explore the interests, concerns and planning activities of informed mental health service users contemplating such directives.

Method

Standard qualitative research techniques were used: field observations, interviews, focus groups, archival research and key informant interviews; 33 persons participated in the interviews and focus groups. Transcripts were coded and analysed for thematic content, and results were member-checked.

Results

Training set in motion labour-intensive projects: conceptualising how a psychiatric advance directive would work in one's life, mobilising resources, reviewing past experiences and assessing risks. Especially meaningful was the prospect of being treated as a responsible agent in future interactions with the mental health system.

Conclusions

Advance directives are best thought of as complex planning tools for future psychiatric crisis management, rather than focal interventions to enhance compliance. Research is needed to explore the institutional response to this prospective decision-sharing initiative.
Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis
Authors: Robertson Emma , Jones Ian , Haque Sayeed , Holder Roger , Craddock Nick
Published: March 2005

The clinical value of information on the risk of future psychiatric illness in women who have experienced puerperal (post-partum) psychosis has been limited by inconsistencies in terminology and nosology. Here we report rates of subsequent puerperal and non-puerperal episodes, in a well-characterised sample of women diagnosed with clearly defined bipolar affective puerperal psychosis (n=103). Out of 54 women having further children, 31 (57%; 95% Cl 44–69) experienced an additional puerperal psychotic episode, and 64 of 103 women (62%; 95%Cl 52–71) experienced a non-puerperal affective episode during the follow-up period (mean duration 9 years). A history of bipolar episodes prior to the puerperal psychosis did not predict risk following subsequent pregnancies, but positive family history of mental illness predicted shorter time to non-puerperal relapse.
Establishing a dose–response relationship for haloperidol decanoate
Authors: Taylor David
Published: March 2005

Aims and Method

The aim of this literature analysis was to establish the range of doses of haloperidol decanoate effective in preventing relapse in schizophrenia. Studies reporting relapse rates in patients treated for longer than 6 months were included. Relapse rate was then plotted against dose or log dose to allow drawing of dose–response curves.

Results

Fifteen publications reporting 13 individual studies were identified. of these, 6 studies met inclusion criteria and were analysed. Dose–response curves indicated limited effect at 25 mg/4 weeks but near maximal effect at doses of 50 mg/4 weeks. There was no clear evidence that increasing the dose above 100 mg/4 weeks provided additional benefit in preventing relapse.

Clinical Implications

The recommended dose range for haloperidol decanoate (50–300 mg/ 4 weeks) does not reflect the findings of this study. Optimally effective doses appear to be around 50–100 mg/4 weeks. The use of doses above 100 mg/4 weeks is difficult to support given data available.
Where would we be without the pharmaceutical industry? A service user's view
Authors: Beresford Peter
Published: March 2005

There was a time in my life, not that long ago, when I could have given a very simple answer to this question. Where would I have been without pharmaceutical companies, specifically without Wyeth? Life was terrible with the pills, but I dared not contemplate it without them.
The pharmaceutical industry and psychiatric research – a marriage for richer …?
Authors: Nutt David J.
Published: March 2005

It is timely to review the relationship between the pharmaceutical industry and psychiatry, given the continuing move towards more evidence-based practice in medicine, as well as two recent government initiatives to improve the value of research in the National Health Service (NHS), especially research that is commercially driven.
Parenteral thiamine use in the prevention and treatment of Wernicke–Korsakoff syndrome
Authors: McIntosh Claire , Kippen Valerie , Hutcheson Fiona , McIntosh Andrew
Published: March 2005

Aims and Method

A pre-/post-intervention audit of 163 case notes was conducted to assess the efficacy of printing information about the identification and treatment of the Wernicke–Korsakoff syndrome on the hospital alcohol detoxification sheet.

Results

Parenteral thiamine was indicated in 42 of 163 patients; 26 had symptoms suggestive of Wernicke's encephalopathy and 16 were at risk. The intervention increased the chance of appropriate parenteral treatment by an odds ratio of 5.9 (95% CI 1.3–27.8). Admission to a specialist alcohol unit increased the chance of appropriate treatment by an odds ratio of 7.0 (95% CI 1.52–32.25). The mean number of doses rose from 3.08 to 4.62.

Clinical Implications

A simple intervention may lead to improved treatment of patients with Wernicke–Korsakoff syndrome.
How safe is lithium prescribing? Audit of a local prescribing framework and patient survey
Authors: Glover Katherine J. , Lawley David
Published: March 2005

Aims and Method

To examine the standards of lithium monitoring in eastern Hull following the introduction of a local prescribing framework, we investigated the biochemistry records of patients currently prescribed lithium, identified from primary care computerised records. A survey of patients' knowledge about lithium therapy was also conducted.

Results

Inadequate standards of lithium monitoring were demonstrated, with only 50% of patients having a level recorded during the preceding 3 months. Monitoring of thyroid and renal function was better, with two-thirds of patients tested in the past year. Patients' knowledge of the side-effects and risks of lithium was minimal; only 7 out of 27 patients questioned felt able to identify the signs of lithium toxicity; three-quarters of those surveyed felt they had not been given enough information about their medication.

Clinical Implications

The introduction of prescribing frameworks or other guidelines does not ensure good practice. Further actions may be needed to ensure lithium is prescribed safely, such as patient registers, monitoring cards and automatic recall systems. Education of patients and primary care staff about the safe use of psychotropic drugs needs to be an ongoing process.
Mutations of the Epidermal Growth Factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients With Non–Small-Cell Lung Cancer With Postoperative Recurrence
Authors: Mitsudomi Tetsuya , Kosaka Takayuki , Endoh Hideki , Horio Yoshitsugu , Hida Toyoaki , Mori Shoichi , Hatooka Shunzo , Shinoda Masayuki , Takahashi Takashi , Yatabe Yasushi
Published: March 2005

Purpose

To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection.

Patients and Methods

We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels.

Results

EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053).

Conclusion

EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.
The Metabolic Syndrome and Disturbances in Hormone Levels in Long-Term Survivors of Disseminated Testicular Cancer
Authors: Nuver Janine , Smit Andries J. , Wolffenbuttel Bruce H.R. , Sluiter Wim J. , Hoekstra Harald J. , Sleijfer Dirk T. , Gietema Jourik A.
Published: March 2005

Purpose

The metabolic syndrome may be an important risk factor for cardiovascular disease in long-term survivors of testicular cancer (TC). We investigated the associations between hormone levels and the metabolic syndrome in these men.

Patients and Methods

We included TC patients cured by orchidectomy and cisplatin-based chemotherapy, stage I TC patients after orchidectomy only, and healthy men of comparable age. Presence of the metabolic syndrome was determined using guidelines from the National Cholesterol Education Program Adult Treatment Panel III. Thyroid-stimulating hormone, follicle-stimulating hormone (FSH), inhibin B, luteinizing hormone (LH), total testosterone, sex-hormone–binding globulin, free testosterone, estradiol, dehydroepiandrosterone sulfate, and insulin-like growth factor 1 were determined in blood. Cortisol metabolite excretion was measured in urine.

Results

Eighty-six chemotherapy patients (median follow-up, 7 years) were compared with 44 stage I patients and 47 controls. LH and FSH were higher, and inhibin B and total and free testosterone were lower in chemotherapy patients than controls. Adrenal and thyroid hormone production were unaffected. Chemotherapy patients with the metabolic syndrome (n = 22; 26%) had a higher body mass index (BMI) pretreatment, a larger BMI increase during follow-up, lower total testosterone, and higher urinary cortisol metabolite excretion than those patients without the metabolic syndrome. BMI and insulin were associated with the metabolic syndrome, while total testosterone and urinary cortisol metabolite excretion were associated with BMI.

Conclusion

We found gonadal dysfunction, but normal adrenal and thyroid function. Through its association with BMI, testosterone may play a role in the development of the metabolic syndrome in long-term TC survivors.
Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival
Authors: Moreton Paul , Kennedy Ben , Lucas Guy , Leach Michael , Rassam Saad M.B. , Haynes Andrew , Tighe Jane , Oscier David , Fegan Christopher , Rawstron Andy , Hillmen Peter
Published: March 2005

Purpose

To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival.

Patients and Methods

Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 105 normal cells).

Results

Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months.

Conclusion

MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.
Retrospective Analysis of Selective Lymphadenectomy in Apparent Early-Stage Endometrial Cancer
Authors: Cragun Janiel M. , Havrilesky Laura J. , Calingaert Brian , Synan Ingrid , Secord Angeles Alvarez , Soper John T. , Clarke-Pearson Daniel L. , Berchuck Andrew
Published: March 2005

Purpose

Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy.

Patients and Methods

Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model.

Results

Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence.

Conclusion

These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.
Addition of Bevacizumab to Bolus Fluorouracil and Leucovorin in First-Line Metastatic Colorectal Cancer: Results of a Randomized Phase II Trial
Authors: Kabbinavar Fairooz F. , Schulz Joseph , McCleod Michael , Patel Taral , Hamm John T. , Hecht J. Randolph , Mass Robert , Perrou Brent , Nelson Betty , Novotny William F.
Published: March 2005

Purpose

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan.

Patients and Methods

Patients had metastatic CRC and one of the following characteristics: age ≥ 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin ≤ 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed.

Results

Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation.

Conclusion

Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer
Authors: Buzdar Aman U. , Ibrahim Nuhad K. , Francis Deborah , Booser Daniel J. , Thomas Eva S. , Theriault Richard L. , Pusztai Lajos , Green Marjorie C. , Arun Banu K. , Giordano Sharon H. , Cristofanilli Massimo , Frye Debra K. , Smith Terry L. , Hunt Kelly K. , Singletary Sonja E. , Sahin Aysegul A. , Ewer Michael S. , Buchholz Thomas A. , Berry Donald , Hortobagyi Gabriel N.
Published: March 2005

Purpose

The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) –positive disease.

Patients and Methods

Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients.

Results

Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively.

Conclusion

Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.
Short-Course Versus Split-Course Radiotherapy in Metastatic Spinal Cord Compression: Results of a Phase III, Randomized, Multicenter Trial
Authors: Maranzano Ernesto , Bellavita Rita , Rossi Romina , De Angelis Verena , Frattegiani Alessandro , Bagnoli Rita , Mignogna Marcello , Beneventi Sara , Lupattelli Marco , Ponticelli Pietro , Biti Gian Paolo , Latini Paolo
Published: March 2005

Purpose

Hypofractionated radiotherapy (RT) is often used in the treatment of metastatic spinal cord compression (MSCC). This randomized trial was planned to assess the clinical outcome and toxicity of two different hypofractionated RT regimens in MSCC.

Patients and Methods

Three hundred patients with MSCC were randomly assigned to a short-course RT (8 Gy × 2 days) or to a split-course RT (5 Gy × 3; 3 Gy × 5). Only patients with a short life expectancy entered the protocol. Median follow-up was 33 months (range, 4 to 61 months).

Results

A total of 276 (92%) patients were assessable; 142 (51%) treated with the short-course and 134 (49%) treated with the split-course RT regimen. There was no significant difference in response, duration of response, survival, or toxicity found between the two arms. When short- versus split-course regimens were compared, after RT 56% and 59% patients had back pain relief, 68% and 71% were able to walk, and 90% and 89% had good bladder function, respectively. Median survival was 4 months and median duration of improvement was 3.5 months for both arms. Toxicity was equally distributed between the two arms: grade 3 esophagitis or pharyngitis was registered in four patients (1.5%), grade 3 diarrhea occurred in four patients (1.5%), and grade 3 vomiting or nausea occurred in 10 patients (6%). Late toxicity was never recorded.

Conclusion

Both hypofractionated RT schedules adopted were effective and had acceptable toxicity. However, considering the advantages of the short-course regimen in terms of patient convenience and machine time, it could become the RT regimen of choice in the clinical practice for MSCC patients.
Effect of Docetaxel in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer
Authors: Goodin Susan , Medina Patrick , Capanna Terry , Shih Weichung J. , Abraham Sybil , Winnie Jessica , Doyle-Lindrud Susan , Todd Mary , DiPaola Robert S.
Published: March 2005

Purpose

To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy.

Patients and Methods

Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity.

Results

Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12).

Conclusion

This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.
Multicenter Randomized Phase II Study of Two Schedules of Docetaxel, Estramustine, and Prednisone Versus Mitoxantrone Plus Prednisone in Patients With Metastatic Hormone-Refractory Prostate Cancer
Authors: Oudard Stéphane , Banu Eugeniu , Beuzeboc Philippe , Voog Eric , Dourthe Louis Marie , Hardy-Bessard Anne Claire , Linassier Claude , Scotté Florian , Banu Adela , Coscas Yvan , Guinet François , Poupon Marie-France , Andrieu Jean-Marie
Published: March 2005

Purpose

Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP).

Patients and Methods

One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg PO tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily).

Results

One hundred twenty-seven patients were assessable for PSA response and safety. A ≥ 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic.

Conclusion

The results of this randomized phase II study showed significantly higher PSA decline ≤ 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.
The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension
Authors: Lennernäs Hans , Abrahamsson Bertil
Published: March 2005

Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Applications (NDAs) of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate-release (IR) dosage form. The aim of the BCS is to provide a regulatory tool for replacing certain BE studies by accurate in-vitro dissolution tests. The aim of this review is to present the status of the BCS and discuss its future application in pharmaceutical product development. The future application of the BCS is most likely increasingly important when the present framework gains increased recognition, which will probably be the case if the BCS borders for certain class II and III drugs are extended. The future revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting and will hopefully result in an increased applicability in drug development. Finally, we emphasize the great use of the BCS as a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate, and that will automatically increase the importance of the BCS as a regulatory tool over time.
Synthesis and evaluation of gadolinium complexes based on PAMAM as MRI contrast agents
Authors: Yan Guo-Ping , Hu Bin , Liu Mai-Li , Li Li-Yun
Published: March 2005

Diethylenetriaminepentaacetic acid (DTPA) and pyridoxamine (PM) were incorporated into the amine groups on the surface of ammonia-core poly(amidoamine) dendrimers (PAMAM, Generation 2.0–5.0) to obtain dendritic ligands. These dendritic ligands were reacted with gadolinium chloride to yield the corresponding dendritic gadolinium (Gd) complexes. The dendritic ligands and their gadolinium complexes were characterized by 1HNMR, IR, UV and elemental analysis. Relaxivity studies showed that the dendritic gadolinium complexes possessed higher relaxation effectiveness compared with the clinically used Gd-DTPA. After administration of the dendritic gadolinium complexes (0.09 mmol kg−1) to rats, magnetic resonance imaging of the liver indicated that the dendritic gadolinium complexes containing pyridoxamine groups enhanced the contrast of the MR images of the liver, provided prolonged intravascular duration and produced highly contrasted visualization of blood vessels.
Tetanus toxoid-loaded transfersomes for topical immunization
Authors: Gupta Prem N , Mishra Vivek , Singh Paramjit , Rawat Amit , Dubey Praveen , Mahor Sunil , Vyas Suresh P
Published: March 2005

Topical immunization is a novel immunization strategy by which antigens and adjuvants are applied topically to intact skin to induce potent antibody and cell-mediated responses. Among various approaches for topical immunization, the vesicular approach is gaining wide attention. Proteineous antigen alone or in combination with conventional bioactive carriers could not penetrate through the intact skin. Hence, specially designed, deformable lipid vesicles called transfersomes were used in this study for the non-invasive delivery of tetanus toxoid (TT). Transfersomes were prepared and characterized for shape, size, entrapment efficiency and deformability index. Fluorescence microscopy was used to investigate the mechanism of vesicle penetration through the skin. The immune stimulating activity of these vesicles was studied by measuring the serum anti-tetanus toxoid IgG titre following topical immunization. The immune response was compared with the same dose of alum adsorbed tetanus toxoid (AATT) given intramuscularly, topically administered plain tetanus toxoid solution, and a physical mixture of tetanus toxoid and transfersomes again given topically. The results indicated that the optimal transfersomal formulation had a soya phosphatidylcholine and sodium deoxycholate ratio of 85:15%, w/w. This formulation showed maximum entrapment efficiency (87.34±3.81%) and deformability index (121.5±4.21). An in-vivo study revealed that topically administered tetanus toxoid-loaded transfersomes, after secondary immunization, elicited an immune response (anti-TT-IgG) comparable with that produced by intramuscular AATT. Fluorescence microscopy revealed the penetration of transfersomes through the skin to deliver the antigen to the immunocompetent Langerhans cells.
Effects of non-steroidal anti-inflammatory drugs on the pharmacokinetics and elimination of aciclovir in rats
Authors: Gwak Hye-Sun , Oh Jung-Hyun , Han Hyo-Kyung
Published: March 2005

This study aims to investigate the effect of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics and the renal elimination of aciclovir in rats. Pharmacokinetic parameters were determined following an intravenous administration of aciclovir (5 mg kg−1) to rats in the presence and absence of ketoprofen or naproxen (25 mg kg−1). Compared with the control (given aciclovir alone), pre-treatment with ketoprofen or naproxen 30 min before aciclovir administration significantly altered the pharmacokinetics of aciclovir. Renal clearance of aciclovir was reduced by approximately two fold in the presence of ketoprofen or naproxen. Consequently, the systemic exposure (AUC) to aciclovir in the rats pre-treated with ketoprofen or naproxen was significantly (P < 0.05) higher than that from the control group given aciclovir alone. Furthermore, the mean terminal plasma half-life of aciclovir was enhanced by 4–5 fold by pre-treatment with ketoprofen or naproxen. These results suggest that NSAIDs, such as ketoprofen and naproxen, are effective in altering the pharmacokinetics of aciclovir by inhibiting the organic anion transporter-mediated tubular secretion of aciclovir. Therefore, concomitant use of ketoprofen or naproxen with aciclovir should require close monitoring for clinical consequence of potential drug interaction.
Cellular uptake of a radiolabelled analogue of neurotensin in the Caco-2 cell model
Authors: Hadden M Kyle , Walle Thomas , Dix Thomas A
Published: March 2005

Neurotensin is a linear tridecapeptide that elicits a variety of physiological responses in the brain, including hypothermia and antinociception, and reduced levels have been linked to schizophrenia. Previously in our laboratory we developed a truncated neurotensin derivative, KK13. This hexapeptide exhibited key pharmacokinetic and behavioural characteristics of an antipsychotic and elicited central effects after oral administration. To examine the potential mechanism(s) of uptake, a radioactive analogue of KK13 (*KK13) was synthesized, characterized, and evaluated in the Caco-2 cell model of the human intestinal epithelium. Results suggested that uptake of *KK13 was a time-dependent passive process. A general linear trend in uptake was demonstrated over the concentration range (10 μM−1 mM) tested, and uptake was neither pH- nor sodium-dependent. Finally, after 60 min, intact *KK13 was identified associated with the cell components, providing further evidence for uptake and stability of the peptide.
Molecular interactions in celecoxib-PVP-meglumine amorphous system
Authors: Gupta Piyush , Bansal Arvind K
Published: March 2005

Stabilization of the amorphous form of a drug is conferred by additives that interact with it at the molecular level. Ternary systems of celecoxib, poly(vinyl pyrrolidone) (PVP) and meglumine were studied for molecular interactions responsible for enhanced drug stability and solubility in amorphous form. Meglumine was found to lower the glass transition temperature (Tg) of the drug due to its plasticization effect. However, the presence of PVP masked its destabilizing effect and provided net anti-plasticization to the celecoxib-PVP-meglumine (7:2:1 w/w) ternary amorphous system. Positive deviation of the experimentally determined Tg mix value for this composition, from those predicted by the Gordon-Taylor/Kelley-Bueche equation, inferred molecular interaction between the three species, which was also supported by band shifts from their Fourier-transform infra-red (FTIR) spectra. Further, shift of differential scanning calorimetry (DSC) melting endotherms of celecoxib in its amorphous systems from those observed for crystalline celecoxib confirmed the complexation between these components, which was also substantiated by molecular modelling studies that showed H-bonding of -S=O, 2-N of the pyrazole ring and -C-F groups of celecoxib with -O-H group of meglumine. These molecular interactions of amorphous celecoxib with meglumine were found to be the potential cause for enhanced stability and solubility of the celecoxib-PVP-meglumine ternary system.
Scavenging of nitric oxide by an antagonist of adenosine receptors
Authors: Sousa Teresa , Fernandes Eduarda , Nunes Carla , Laranjinha João , Carvalho Félix , Pinho Dora , Morato Manuela , Albino-Teixeira António
Published: March 2005

Chronic treatment of rats with 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), an antagonist of adenosine receptors, causes hypertension, cardiovascular hypertrophy and hyperplasia and impaired endothelium-dependent vasodilatation. An accelerated degradation of nitric oxide (NO) by scavenging molecules could account for endothelial dysfunction and trophic changes in this hypertension. Our aim was to determine whether DPSPX is a scavenger of NO and if this putative effect is shared by caffeine (1,3,7-trimethylxanthine) and DPCPX (1,3-dipropyl-8-ciclopentylxanthine), which are also adenosine receptor antagonists but do not induce hypertension in rats. This effect was evaluated by electrochemical and spectrofluorometric assays. Urinary NOx (nitrate + nitrite) excretion was also evaluated in controls and DPSPX-treated rats as a marker for NO bioavailability. DPSPX behaved as a scavenger of NO in a concentration-dependent manner in the electrochemical and spectrofluorometric assays. Caffeine and DPCPX had no scavenging effect. DPSPX-treated rats had decreased excretion of urinary nitrites. We can conclude that: DPSPX has NO scavenging properties that may be involved in the alterations described for DPSPX-hypertensive rats; this NO-scavenging effect is not shared by caffeine and DPCPX, which are also xanthine derivatives and adenosine antagonists.
Effect of N-benzoyl-d-phenylalanine on streptozotocin-induced changes in the lipid and lipoprotein profile in rats
Authors: Ashokkumar N , Pari L , Manimekalai A , Selvaraju K
Published: March 2005

The effect of N-benzoyl-d-phenylalanine (NBDP) and metformin combination treatment on circulatory lipids, lipoproteins and lipid peroxidation markers were studied in neonatal streptozotocin (nSTZ) non-insulin dependent diabetic rats. Non-insulin dependent diabetes mellitus (NIDDM) was induced by a single dose injection of streptozotocin (100 mg kg−1, i.p.) to two-day-old rats. After 10–12 weeks, rats weighing above 150g were selected for screening for the NIDDM model. The rats were checked for fasting blood glucose levels to confirm the status of NIDDM. NBDP (50,100 or 200 mg kg−1) was administered orally for six weeks to the confirmed diabetic rats (to evaluate the effective dose). The levels of serum lipids and lipid peroxidation markers were significantly increased, whilst the activity of glucose-6-phosphate dehydrogenase was significantly decreased in nSTZ diabetic rats. NBDP and metformin were able to restore the altered serum lipids, lipoproteins, lipid peroxidation marker levels and glucose-6-phosphate dehydrogenase activity to almost control levels. The results showed the antihyperlipidaemic properties of NBDP and metformin in addition to its antidiabetic action. Combination treatment was more effective then either drug alone. The results indicated that the coadministration of NBDP with metformin to nSTZ diabetic rats normalized blood glucose and caused marked improvement in altered serum lipids, lipoproteins and lipid peroxidation markers during diabetes. The data indicated that NBDP represented an effective antihyperglycaemic and antihyperlipidaemic adjunct for the treatment of diabetes, and may be a potential source of new orally active agents for future therapy.