Add-on combination and maintenance treatment: case series of five obese patients with different eating behavior

Obesity is a general medical condition associated with an increase in morbidity and mortality. Although it would be desirable to use efficacious prevention programs, the success rates reported to date have been rather disappointing. In this observational study, a new drug treatment regimen was evaluated in five obese patients with a mean age of 39.6 +/- 4.2 years and an initial body mass index between 34.5 and 38.3 kg/m for a period of 96 weeks. The patients showed restrained and unrestrained eating patterns according to a German version of the Three-Factor Eating Questionnaire and were treated in an add-on regimen with the combination of three drugs with different anorectic properties that were consecutively introduced in an interval of 16 weeks. First, orlistat (120 mg three times a day) was given as a monotherapy. Sibutramine (15 mg in the morning) and then topiramate (in a dose dependent on appetite suppression and side effects) were added for a total duration of 48 weeks. A 48-week maintenance and relapse prevention treatment period with topiramate monotherapy followed the discontinuation of orlistat and sibutramine. This outpatient treatment procedure was tolerated well, although side effects occurred in all patients depending on the phase of the treatment regimen. After 96 weeks, the mean body mass index was 25.7 +/- 1.2 kg/m. Moreover, a normalization of eating patterns according to the Three-Factor Eating Questionnaire could be noticed. Factor 3, hunger, was significantly reduced. This treatment plan may be highly effective and safe in a subpopulation of obese patients.     

Glufosfamide (Baxter Oncology)

Glufosfamide is a sugar phosphamide alkylating agent under development by Baxter Oncology (formerly ASTA Medica) as a potential treatment for cancer. By April 2000, glufosfamide had commenced phase II trials, one of which involved intrathecal administration to patients with carcinomatous meningioma.     

Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression

OBJECTIVE: Current clinical knowledge holds that antidepressants have a delayed onset of efficacy. However, the delayed onset hypothesis has been questioned recently by survival analytical approaches. We aimed to test whether early improvement under antidepressant treatment is a clinically useful predictor of later stable response and remission. METHOD: We analyzed data from a randomized double-blind controlled trial with mirtazapine and paroxetine in patients with major depression (DSM-IV). Improvement was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score reduction of > or = 20%. Stable response was defined as > or = 50% HAM-D-17 score reduction at week 4 and week 6, and stable remission as a HAM-D-17 score of < or = 7 at week 4 and week 6. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Improvement occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. CONCLUSION: Our results strongly suggest that early improvement predicts later stable response with high sensitivity. These empirically derived data question the delayed onset hypothesis for both antidepressants tested and provide important clinical clues for an individually tailored antidepressant treatment.     

Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines

The fermented wheat germ extract (code name: MSC, trade name: Avemar), with standardized benzoquinone content has been shown to inhibit tumor propagation and metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of intracellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the cell population. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence on cytofluorimeter using a monoclonal antibody to the non-polymorphic region of the human MHC class I. MSC stimulated tyrosine phosphorylation of intracellular proteins and the influx of extracellular Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell lines. As a result of the MSC treatment, the amount of the cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells. Inhibition of the cellular tyrosine phosphatase activity or Ca2+ influx resulted in the opposite effect increasing or diminishing the Avemar induced apoptosis as well as the MHC class I downregulation, respectively. A benzoquinone component (2,6-dimethoxi-p-benzoquinone) in MSC induced similar apoptosis and downregulation of the MHC class I molecules in the tumor T and B cell lines to that of MSC. These results suggest that MSC acts on lymphoid tumor cells by reducing MHC class I expression and selectively promoting apoptosis of tumor cells on a tyrosine phosphorylation and Ca2+ influx dependent way. One of the components in MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor in MSC mediated cell response.     

Three new prodrugs for suicide gene therapy using carboxypeptidase G2 elicit bystander efficacy in two xenograft models

Three new prodrugs, [prodrug 1: 4-[bis(2-iodoethyl)amino]-phenyloxycarbonyl-L-glutamic acid; prodrug 2: 3-fluoro-4-[bis(2-chlorethyl)amino]benzoyl-L-glutamic acid; and prodrug 3: 3,5-difluoro-4-[bis(2-iodoethyl)amino]benzoyl-L-glutamic acid] have been assessed for use with a mutant of carboxypeptidase G2 (CPG2, glutamate carboxypeptidase, EC 3.4.17.11,) engineered to be tethered to the outer tumor cell surface (stCPG2(Q)3) as the activating enzyme in suicide gene therapy systems. All three of the prodrugs produce much greater cytotoxicity differentials between stCPG2(Q)3- and control beta-galactosidase (beta-gal)-expressing breast carcinoma MDA MB 361 and colon carcinoma WiDr cells (70- to 450-fold) than was previously observed (19- to 27-fold) with 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA). Prodrug 1 is the most effective antitumor agent in xenografts in mice inoculated with 100% stCPG2(Q)3-expressing MDA MB 361 cells, whereas prodrugs 2 and 3 are most effective when the percentage of stCPG2(Q)3-expressing cells is 50% or 10%. In nude mice bearing xenografts arising from inocula of 100% stCPG2(Q)3-expressing WiDr cells, prodrug 2 is the most effective antitumor agent. All three of the prodrugs produced histological evidence of substantial bystander cell killing in WiDr xenografts in which only 10% or 50% of the cells inoculated were expressing stCPG2(Q)3. We conclude that all three of the prodrugs are more effective therapeutically with stCPG2(Q)3 than is the previously described prodrug CMDA and, also, that the optimal choice of prodrug varies among different tumor types and that prodrugs, optimized for their bystander effect, are effective when only low percentages of cells in a tumor express CPG2.     

Video-assisted thoracoscopic thymectomy--preliminary results

Video-assisted thoracoscopic surgery (VATS) provides a new approach to thymectomy. From April 1999 to December 1999, we performed a total of 10 video-assisted thoracoscopic thymectomies for myasthenia gravis (MG). There were one male and nine female patients with ages ranging from 8 to 59 years. Thymoma was present in one of the ten patients. We considered that complete thymectomy was accomplished in all cases by examination of the thymic bed and of the resected specimen. There was no mortality or intraoperative complications. The median postoperative hospital stay was 4 days. Clinical improvement was observed in all patients after this short follow-up. Compared with a similar historical group of patients with MG who underwent transsternal thymectomy, the VATS group was associated with significantly less analgesic requirement and shortened hospital stay. We conclude that VAT thymectomy is technically feasible and is associated with a favorable postoperative course compared with the transsternal approach. We believe that complete thymectomy can be achieved by this approach. Further investigation with long-term follow-up is needed to further clarify the role of VAT thymectomy in thoracic surgery.     

Thiocyanatochromium(III) complexes with pilocarpine and the analytical determination of this alkaloid (author's transl)]

Thiocyanatochromium(III) Complexes with Pilocarpine and the Analytical Determination of this Alkaloid A new reinecke salt-like compound NH₄[Cr(NCS)₄ (pilocarpine)₂] · H₂O was obtained from K₃[Cr(NCS)₆] and pilocarpine in the molten state. The constitution of the complex anion was proven by means of a series of double decomposition reactions with amines and cobalt(III)-amine bases. The structure and the thermal stability of the title compound were studied by means of UV and IR spectroscopy and derivatography. The slightly soluble compounds pilocarpine H[Cr(NCS)₄ (aniline)₂] and pilocarpine · H[Cr(NCS)₄ (morpholine)₂] were used for the oxidimetric and spectrophotometric determination of pilocarpine.     

A particular case of a "captive forceps" in the esophagus

We present a particular case of a "captive" forceps in the esophagus in an attempt to remove a foreign body in a patient with previous esophageal post-caustic stenosis. The mechanism of incarceration and the surgical therapeutic option consisting of open thoracic surgery are detailed and argumented. Postoperative course was favorable, though the patient developed a small esophageal fistula visible at radiology without any clinical expression. This case emphasizes the difficulties that may occur but in the management of esophageal foreign bodies in patients with esophageal post-caustic stenosis, which may lead finally to open surgery.     

Open-label simultaneous radio-chemotherapy of glioblastoma multiforme with topotecan in adults

BACKGROUND: Due to its radioresistance, the prognosis of glioblastoma multiforme (GBM) remains poor. Therefore, we investigated the impact of simultaneous radio-chemotherapy with topotecan (Hycamtin) on clinical outcome, tolerability and quality of life. PATIENTS AND METHODS: In this multicenter trial, 60 patients (19 females, 41 males) with histologically proven (5x biopsy, 31x subtotal resection, 24x total resection) GBM were included. Radio-Chemotherapy was performed with daily doses of 2.0 Gy (total, 60 Gy), and 0.5 mg (absolute dose) of topotecan intravenously 1 h prior to irradiation. Toxicity was assessed using common toxicity criteria (CTC). General condition and quality of life were assessed at baseline, at the end of therapy, and 6 weeks post-therapy. Local control and length of survival were compared with an historical control group of 67 patients only treated with postoperative radiotherapy following stereotactic biopsy (15x), subtotal resection (39x), or total resection (13x). RESULTS: 57 patients completed the therapy. Median radiation dose was 60 Gy (range 16-76 Gy). Median cumulative topotecan dose was 15 mg (range 7.5-18.5 mg). CTC toxicity grade 3 was observed in six patients and grade 4 toxicity in two patients (three events). Two patients died of septic disease. Mean Karnofsky index was 87% at baseline, 81% at the end of therapy, and 80% at 6 weeks post-therapy. Median survival time was 15 months, significantly longer than the 11 months seen in the control group (P < 0.002). Extent of tumour resection or patient age did not have a significant effect on survival. CONCLUSION: This multimodal approach is well tolerated, and quality of life remains preserved. The relatively long median survival time is promising but a further randomised double blind placebo controlled parallel designed clinical trial should be performed to confirm these results.