Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.

Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.

A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2) to the registered capecitabine dose of 1,250 mg/m(2) plus docetaxel 75 mg/m(2). We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and determine a minimum capecitabine dose noninferior to 1,250 mg/m(2). Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000 mg/m(2) starting dose and an increased number of PFS events. A starting dose of 1,000 mg/m(2) could be established as noninferior in terms of efficacy to the registered dose in the second-line MBC setting, with a potentially improved safety, in line with medical practice.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e19; doi:10.1038/psp.2012.20; advance online publication 26 December 2012.

Approaches to coping with chronic fatigue syndrome (CFS).

The 1994 approach to the definition of Chronic Fatigue Syndrome (CFS) describes a severe disorder with unknown etiology and pathophysiology. It results in substantial reduction in previous levels of occupational, educational, social, or personal activities. Most patients cannot continue their usual lifestyle. No causal treatments or other therapies suitable for all patients exist so far. Therefore it was intended to identify approaches to an effective disease management by the long time escort and observation of a CFS support group. CFS should be diagnosed according to the actual CDC guidelines. Conditions with similar symptoms explaining chronic fatigue have to be ruled out first. Then an individually shaped disease management comprising of different components plays a central role in the coping process. Medical long time care performed by a general practitioner and the membership in a suitable support group are integrated within this approach.

[Subjective criteria of schizophrenic patients in selecting a physician in ambulatory care]. / Subjektive Kriterien Schizophrener bei der Arztwahl in der ambulanten Betreuung.

PURPOSE: Several studies Conducted during the last 30 years have shown the high prevalence of mental disorder among patients of general practitioners (GPs). The integration of out patients care of schizophrenics into primary care remains controversial. Yet there is a lack of studies determining the subjective view of clients on their choice of their physician. METHODS: In this study we interviewed in patient schizophrenics on their choice of physician for out patient care. RESULTS: 27.3% were being treated only by a GP, 29.9% only by a psychiatrist and 36.4% by a GP and a psychiatrist. Those treated only by a GP knew him a lot longer. The appraisal was more positive for those treated only by a GP, while those treated by both psychiatrist and GP rated the competence of the psychiatrist more positive by. CONCLUSIONS: Those treated by both GP and psychiatrist had the longest length of illness, yet the lowest rate of rehospitalisation. Although these results cannot only be seen as a result of the choice of physician, they still confirm the importance of interdisciplinary cooperation and should encourage GPs and psychiatrists to recommend their schizophrenics to be treated cooperatively.

[Quantitative EEG, basic disorders and smoking in etiopathogenetically different groups of paranoid-hallucinatory psychoses--an exploratory study]. / Quantitatives EEG, Basisstörungen und Rauchen bei ätiopathogenetisch differenten Gruppen paranoid-halluzinatorischer Psychosen--eine explorative Studie.

We performed an exploratory study of quantitative EEG in aetiopathogenetically different paranoid-hallucinatory psychoses divided into the following groups: a) patients with familial psychoses (n = 12), b) patients with neuropsychological deficits (n = 16), c) patients with alcohol and drug abuse (n = 22) and d) patients with so-called sporadic psychoses (n = 12). We found a significant reduction of relative alpha power in the group with neuropsychological deficits. In the group with familial psychosis there was a significant reduction of absolute delta power and a significant increase of relative beta power and dominant beta frequency, especially for the frontal leads. Patients with drug abuse showed a reduction of absolute beta power and an increase of absolute and relative theta power. The group with sporadic psychosis showed a significant slowing of the dominant beta frequency and a significant increase of the absolute power of fast alpha rhythms. The group with sporadic psychoses showed lowered scores for the paranoid-hallucinatory basic symptom factor. The group with neuropsychological deficits showed the most visceral-somatoform basic symptoms, the highest nicotine consumption, increased dyskinesias and more perinatal complications. This group also showed the highest level of neuroleptic and antiparkinson medication. All in all, the group with neuropsychological deficits showed a complex interaction of somatic-exogenic and medical-iatrogenic factors. Furthermore, there was a significant positive correlation between paranoid-hallucinatory basic symptoms and nicotine abuse and high frequency beta waves.

[Schizophrenia: subjective theories of illness. An explorative study. Part 2: Relatives]. / Schizophrenie: Subjektive Krankheitstheorien. Eine explorative Studie. Teil 2: Angehörige.

The growing acceptance of Zubin's vulnerability-stressor-modell in research and clinical practice stresses the importance of schizophrenic patients individual coping strategies. Coping strategies are influenced not only by individual cognitions concerning the actual illness but also by opinions of key-persons within the social network of the patient. Research on the acquisition of patients subjective view of the schizophrenic illness has to integrate both the individual psychological resources as well as the social context variables. The present paper reports about in depth open interviews with six patients and their key relatives. The results were derived from a structural analysis of the tape-recorded and transcribed interviews. Patients showed a broad variety of etiological explanations of their illness and expressed a need for more comprehensive information (part 1). Parents stated a more pessimistic prognosis of the course of illness than patients. Both patients and parents complained about the lack of mutual communication about the illness and its symptoms (part 2). Implications of these results concerning psychoeducational programs for patients and families as well are discussed.

[Schizophrenia: subjective illness theories--an explorative study. 1: Patients]. / Schizophrenie: Subjektive Krankheistheorien--Eine explorative Studie. Teil 1: Patienten.

The growing acceptance of Zubin's vulnerability-stressor-model in research and clinical practice stresses the importance of schizophrenic patients individual coping strategies. Coping strategies are influenced not only by individual cognitions concerning the actual illness but also by opinions of key-persons within the social network of the patient. Research on the acquisition of patients subjective view of the schizophrenic illness has to integrate both the individual psychological resources as well as the social context variables. The present paper reports about in depth open interviews with six patients and their key relatives. The results were derived from a structural analysis of the tape-recorded and transcribed interviews. Patients showed a broad variety of etiological explanations of their illness and expressed a need for more comprehensive information (part 1). Parents stated a more pessimistic prognosis of the course of illness than patients. Both patients and parents complained about the lack of mutual communication about the illness and its symptoms (part 2). Implications of these results concerning psychoeducational programs for patients and families as well are discussed.

[Management of depressed patients by family physicians. Questionnaire study in Hamburg]. / Betreuung depressiver Patienten durch Allgemeinärzte. Eine Fragebogen-Studie in Hamburg.

METHOD: With the aid of a questionnaire specially developed for the purpose, general practitioners were questioned about their management of depressed patients attending their offices. A number of physician-related aspects that might have been the cause of the differences in prevalence and management of the patients, were investigated. RESULTS: Estimations on the part of the physicians that patients with psychological problems accounted for some 20% of their total case load were in agreement with figures obtained from other studies. Those specifically with depression accounted for 8.6%. The practitioners' assessment of their own competence in caring for depressed patients, and their cooperation with other institutions play a key role in the incidence of the diagnosis and the nature of medical treatment--by means of drugs, psychotherapy, referral, yes or no. The results obtained suggest a need to improve the psychiatric training of general practitioners and for closer cooperation with neurologists, psychologists, and hospitals.

[Child rearing style, social behavior dimensions and severity of schizophrenic illness]. / Erziehungsstil, soziale Verhaltensdimensionen und Schwere der schizophrenen Erkrankung.

In a sample of 53 schizophrenic patients, perceived parental rearing attitudes were rated with the EMBU inventory, the quality of relationship to key relatives was measured with the AfS, and social anxiety was assessed with the U-Scale. The values obtained were intercorrelated and compared with selected parameters for disease severity: age at first hospital admission, number of treated episodes, and duration of inpatient treatment. The results show that disease parameters rather than parental rearing behaviour determine the quality of contact with key relatives. Rearing patterns more likely influence the age at first hospital admission and social anxiety. The findings further suggest that, considering the length of "face-to-face" contact, the quality of the relationships between the schizophrenic patients and their key relatives is likely to be associated with the duration of inpatient treatment. The results of the explorative study confirm the importance of family intervention programmes.

Dealing with practical problems in nursing management.

Nursing supervisors hear certain complaints from nurses with unusual frequency. In this article, seven common complaints are presented, and an example demonstrating each complaint is described. The obvious and not-so-obvious reasons behind each complaint are analysed, and suggestions made for supervisory behaviour which will reduce the likelihood of such complaints. When nursing supervisors actively pursue good managerial practices, the frequency of complaints will decline, interpersonal relations will improve, and increased supervisory effectiveness will result.

Do perceived parental rearing patterns influence social behaviour dimensions and disease severity in schizophrenia?

In an explorative study, a clinical sample of 53 schizophrenic patients was examined. The EMBU inventory was used for measuring perceived parental rearing practices, the AfS for rating the quality of relationship to key relatives and the U-Scale for assessing social anxiety. The findings obtained were intercorrelated and compared with 3 selected parameters of disease severity: age at first hospitalization, number of treated episodes and length of hospital stay. The results suggest that the quality of contact with key relatives is determined to a larger extent by the schizophrenia than by parental rearing attitudes. Rearing behaviour more likely influences the age at first hospitalization and social anxiety, whereas considering the length of face-to-face contact, the quality of the relationships between patients and their key relatives can be assumed to be associated with the duration of hospital stays.

[The five-minute interview. A brief method for assessing expressed emotion status]. / Das Fünfminuteninterview. Eine Kurzfassung zur Erfassung des Expressed Emotion Status.

The Camberwell Family Interview (CFI) has been developed to assess the expressed emotion status (EE), a measure of the attitudes and feelings that a relative expresses about a schizophrenic family member. The EE measure has shown to be a good predictor of relapses in the course of schizophrenia, and has proved valid in a number of different cultures. However, the extensive, semistructured CFI is so time-consuming, that it only has been employed in a few specialized research centers. Therefore a brief method for assessing the EE index has been developed on the basis of a 5-minute speech sample (FMSS), which showed a reasonable correspondence with EE ratings derived from the CFI. The present article describes the development of a German version of the FMSS. The correspondence between blind EE ratings derived from the FMSS and the CFI was investigated on a sample of 176 interviews of relatives of schizophrenics. The relationship between the procedures to assess the EE index was significantly close. These results show the validity of the FMSS as a brief EE screening procedure for German-speaking populations.

Schizophrenic patients' attitudes to therapists using behavioral and holistic-humanistic techniques.

In a preliminary study of patients' perceptions of therapists' styles, 18 subjects with diagnoses of schizophrenia were randomly assigned either to social skills training or holistic health therapy. Four therapists conducted each treatment session in pairs, rotating between treatment conditions daily. At the end of 10 weeks of treatment, patients were able to discriminate among therapists on three interactional styles-"understanding," "independence-encouraging," and "and "critical-hostile"-and were able to differentiate between behavioral and holistic health treatments on "authoritarian" attitudes.

Merkel cells in vitro: production of nerve growth factor and selective interactions with sensory neurons.

A method has been developed for obtaining mixed primary cultures of dissociated epidermis enriched in Merkel cells. Merkel cells obtained from embryonic rat buccal pads were grown in serum-free medium and identified in vitro using a variety of histological and immunohistochemical markers. Quinacrine, a fluorescent amine, which has been used to identify Merkel cells in situ, labeled a morphologically distinct population of cells in vitro. Cells labeled with quinacrine had a large, phase bright nucleus with prominent nucleoli, surrounded by a phase dark perinuclear ring. Antibodies directed against neuron-specific enolase, another marker for Merkel cells in situ, and antibodies against a well-characterized neuroendocrine vesicle antigen also labeled this population of quinacrine fluorescent cells. Electron microscopic examination of our cultures indicated that cells containing characteristic features of Merkel cells including cytoplasmic dense-cored granules were present. A small but significant increase in the number of Merkel cells was observed over time in culture. Merkel cells supported the survival and outgrowth of both trigeminal ganglion sensory neurons and sympathetic neurons from the superior cervical ganglion in serum-free medium in the absence of exogenous nerve growth factor (NGF). Immunoblots probed with antibodies directed against NGF demonstrated that NGF was present in the medium taken from these cultures. NGF-like immunoreactivity colocalized to cells containing quinacrine fluorescence in situ and in vitro. Addition of antibodies directed against NGF to cocultures of Merkel cells and neurons decreased survival of sympathetic neurons by 90% and decreased survival of sensory neurons by 60%. These results suggest that Merkel cells are capable of providing trophic support for their normal complement of sensory neurons by producing NGF. Selective recognition of these targets was studied in vitro by characterizing the interactions between Merkel cells and growth cones from sensory or sympathetic neurons using both time-lapse videomicroscopy and standard morphometry of fixed cocultures. The majority of trigeminal ganglion sensory neurons (approximately 60%) extended growth cones onto clusters of Merkel cells. Neurites which contacted clusters of Merkel cells were significantly more highly branched than those growing on collagen. In contrast, the majority of sympathetic neurons (greater than 90%) failed to grow onto Merkel cells. Growth cones of sympathetic neurons often "collapsed" and retracted when contact was made with a cluster of Merkel cells. Fixation of Merkel cells with paraformaldehyde prior to coculture did not affect this difference between sensory and sympathetic neurite extension onto the Merkel cells. However, prior fixation of Merkel cells eradicated the apparent Merkel ce-induced branching of sensory neurites.(ABSTRACT TRUNCATED AT 400 WORDS)