Interleukin-6 and selected plasma proteins in healthy persons of different ages

In the present study, interleukin-6(IL-6) and several acute phase proteins were measured in healthy participants (23–87 years of age). A linear correlation between IL-6 and age was established with an increase of 0.016 pg/ml(00.004) per year of life. Whereas CRP remained below 0.5 mg/dl in all participants, an increase with age for fibrinogen and an inverse relation for albumin as well as transferrin were obtained. However, the increase of IL-6 did not correlate with any of these changes. IL-6 associated diseases may therefore occur more often with advancing age, but in healthy participants IL-6 does not explain the changing plasma protein pattern resembling that of an acute phase reaction.     

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t _1/2), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t _1/2 values were 5.5 and 4.7 h, respectively, mean-g t _max data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g C _max ^maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag,t _max, andC _max. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite reduced benperidol were found to be very low.     

Pharmacokinetics of 4′-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m₂ THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t_1/2), 3.15 min; terminal elimination half-life (t _1/2), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml^–1mg^–1m^–2, resulting in a mean plasma clearance of 86.91 h^–1m^–2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadrimycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r=0.800,P<0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.     

MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease?

Hirayama’s disease is a benign juvenile form of focal amyotrophy affecting the upper limbs. Previous studies have suggested that the disorder is a neck flexion induced cervical myelopathy. We report clinical and magnetic resonance imaging findings in nine patients with Hirayama’s disease. Cervical imaging of seven patients revealed spinal cord changes consisting of focal atrophy and foci of signal alterations. On neck flexion a forward movement and mild reduction in the anteroposterior diameter of the lower cervical cord against the vertebral bodies was noted in affected individuals as well as in five normal controls. In contrast to earlier reports, none of our patients showed complete obliteration of the posterior subarachnoid space. Measurement of the anteroposterior spinal cord diameter in each vertebral segment (C4–C7) revealed no significant differences in the degree of spinal cord flattening between the two groups. Furthermore, two of our patients had significant degenerative changes in the cervical spine (disc herniation, retrospondylosis) contralateral to the clinically affected side. These degenerative changes resulted in a marked cord compression on neck flexion but were not associated with ipsilateral clinical abnormalities or spinal cord alterations. Our results argue against a flexion-induced cervical myelopathy and support the view that Hirayama’s disease is an intrinsic motor neuron disease. Received: 15 March 1999 Received in revised form: 25 May 1999 Accepted: 1 June 1999     

Visual network activation in recovery from sensorimotor stroke

Recovery of finger movements after hemiparetic stroke has been shown to involve sensorimotor brain areas in perilesional and remote locations. Hand use, however, critically depends on visual guidance in such patients with stroke lesions in the middle cerebral artery territory. Using regional cerebral blood flow measurements, we wished to identify interrelated brain areas that are engaged in relation to manual activity in seven patients after their first hemiparetic brain infarction. During the blind-folded performance of sequential finger movements, the patients differed significantly from healthy controls (n = 7) by the recruitment of a predominantly contralesional network involving visual cortical areas, prefrontal cortex, thalamus, hippocampus, and cerebellum. Greater expression of this cortical-subcortical network correlated with a more severe sensorimotor deficit in the acute stage after stroke reflecting its role for post-stroke recovery. Patients also differed from controls on a lesion-related pattern expressed during rest. A third differentiating pattern involved the ipsilesional supplementary motor area and the contralesional premotor cortex. Our results suggest that post-stroke recovery form impaired sensorimotor integration utilizes crossmodal plasticity of a visual network.     

Chronic diarrhea: Causes,presentation, and mangement

Important inroads are being made into understanding the pathophysiology of diarrhea. Clear understanding of key mechanisms should suggest new approaches to combat disease. Exciting developments are occurring in terms of super-ORS solutions, particularly with the promise of short chained glucose polymers and glutamine. Perhaps the most important development is the prospect of a good rotavirus vaccine being available before the end of the decade. Chronic diarrhea seems to be on the increase globally, probably because of the success of ORS. The mechanisms that lead to mucosal injury are elusive, and therapy still largely supportive and empiric. Celiac disease continues to be a puzzle, because of the uncomfortable feeling that a majority of cases may be missed because of atypical presentations. The successful use of long term parenteral nutrition has allowed survival and better charaterization of cases that otherwise would have perished as ‘lethal protracted diarrhea’. Microvillus inclusion disease may be the commonest congenital secretory diarrhea. The role of the recently reported high prevalence of glucoamlase deficiency may be important. Lastly, attention to micronutrients, particularly low vitamin A and probably zinc may prove to be important in prevention and amelioration of diarrhea and growth failure.     

The vigilance scale: An analysis of elicited behavioral responses

Summary The Vigilance Scale (VS) is a 12-step additive scale (Guttman scale) that allows assessment of the behavioral deficit in the unconscious state and the state of clouding of consciousness. Despite restrictions on its applicability, which are discussed in detail, the VS seems to be a useful measuring device that indicates the level of brain function a patient with a disturbance of consciousness can actually attain. There are two categories of scale errors to be found, the first being caused by various instrumental disorders, i.e., severe motor deficits, the second resulting from the probabilistic approach of the VS to a Guttman scale.     

Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II).

PURPOSE: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-idiotypic antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. EXPERIMENTAL DESIGN: Using the complete intention-to-treat population (n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. RESULTS: In 81 patients (68.1%), a specific anti-anti-idiotypic antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1') and antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5-56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P < 0.0001) as compared with Ab3-negative patients (median, 4.9 months). A positive Ab3 response remained associated with longer survival when controlling for other prognostic factors including FIGO (International Federation of Gynecologists and Obstetricians) stage, response to and type of first-line chemotherapy, number of previous treatments, or concomitant antitumor therapy. With regard to safety, repeated vaccination was well tolerated. No serious adverse events related to the application of ACA125 occurred. CONCLUSIONS: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.     

Intensity modulated radiation therapy with electrons using algorithm based energy/range selection methods.

BACKGROUND AND PURPOSE: In recent years photon intensity modulated radiation therapy (IMRT) has gained attention due to its ability to improve conformity of dose distributions. A potential advantage of electron-IMRT is that the dose fall off in the depth dose curve makes it possible to modulate the dose distribution in the direction of the beam by selecting different electron energies. This paper examines the use of a computer based energy selection in combination with the IMRT technique to optimise the electron dose distribution. MATERIALS AND METHODS: One centimetre square electron beamlets ranging from 2.5 to 50 MeV were pre-calculated in water using Monte Carlo methods. A modified IMRT optimisation tool was then used to find an optimum mix of electron energies and intensities. The main principles used are illustrated in some simple geometries and tested on two clinical cases of post-operated ca. mam. RESULTS: It is clearly illustrated that the energy optimisation procedure lowers the dose to lung and heart and makes the dose in the target more homogeneous. Increasing the energy at steep gradients compensates for lack of target coverage at beam edges and steep gradients. Comparison with a clinically acceptable four segment plan indicates the advantage of the used electron IMRT technique. CONCLUSIONS: Using an intensity optimised mix of computer selected electron energies has the potential to improve electron treatments for mastectomy patients with good target coverage and reduced dose to normal tissue such as lung and heart.     

Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene--amplified breast cancer cells.

PURPOSE: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members. EXPERIMENTAL DESIGN: Bcl-2 and Bcl-XL expression and apoptosis induction were analyzed in HER-2 gene-amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1. RESULTS: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-XL, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 +/- 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-XL expression, resulting in a 21 +/- 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 +/- 6%, P <0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index=0.58 +/- 0.18), as assessed by isobologram analysis. CONCLUSIONS: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.