Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC₅₀ values, independent of their log P value.     

Multimodality imaging for focus localization in pediatric pharmacoresistant epilepsy.

Multiple structural and functional imaging modalities are available to localize the epileptogenic focus. In pre-surgical evaluation of children with pharmacoresistant epilepsy, investigations with the maximum yield should be considered in order to reduce the complexity of the workup. OBJECTIVE: To determine the extent to which PET, ictal/interictal SPECT and its co-registration with the patient's MRI contributes to correct localization of the epileptogenic focus, surgical intervention and to the post surgical outcome in paediatric patients. METHODS: The study population included children and adolescents with pharmacoresistant epilepsy (n = 50) who underwent preoperative evaluation, surgery and had postoperative follow-up for at least 12 months. Outcome was measured by postoperative seizure frequency using Engel's classification. RESULTS: Thirty-nine patients (78%) became completely seizure free after surgical intervention. The likelihood to benefit from surgical treatment was significantly higher if localization with more imaging modalities (MRI, PET, SPECT) were concordant with respect to the resected brain area (p < 0.01). Preoperative PET examination provided better localizing information in patients with extratemporal epilepsy and/or dysplastic lesions, whereas SPECT was found to be superior to PET in patients with temporal lobe epilepsy and/or tumors (p < 0.05). No significant difference was noted in the surgical outcome in younger or older age group, in children with or without special education needs. CONCLUSION: In paediatric epilepsy pre-surgical evaluation, the combined use of multiple functional imaging modalities for a precise localisation of the epileptogenic focus is worthwhile for both extratemporal and temporal lobe epilepsy, also when EEG and MRI alone are non-contributive, given the potential benefit of complete postoperative seizure control.     

Tumor scintigraphy with cobalt bleomycin in ORL tumors

Our experiences with cobalt bleomycin scintigraphy in the treatment planning of ORL tumors are described. 142 scintigrams taken from 127 patients have been examined. As is shown by our investigation, cobalt bleomycin scintigraphy is a good examination method, however, too much expenditure is needed to have the necessary data for therapy planning. To our opinion, the information obtained in oto-rhino-laryngology by an exact clinical examination is as good as that of cobalt bleomycin scintigraphy. Our treatment schemes had only to be revised in some exceptional cases.     

The orthopan tomoscintigram — a new application of emission computed tomography for facial bone scanning

The exact regional correlation of findings of facial bone scans, planar or SPECT, to dental orthopan X-ray films (OPT) is difficult because of the very different projection techniques. To improve correlative imaging in this regard a projection algorithm was developed that uses SPECT data of the skull for reconstructing an orthopan tomoscintigraphic projection. Fourteen conventional SPECT slices of the upper and lower jaws were obtained during bone scanning. All mandibular slices were superimposed resulting in a horseshoe shaped structure, which was marked by an ROI which was divided into segments. All 14 SPECT slices were then masked by this segmental ROI, thereby marking the teeth-carrying bone in all slices. The information from this horseshoe like ROI is then transformed into lines. Line by line arrangement results in an orthopan projection, the orthopan tomoscintigram. This new display allows 1:1 true scale superimposition with the X-ray OPT and markedly facilitates correlative imaging.     

Hirschsprung's disease: associated abnormalities and demography.

We here examine the demographic parameters of patients with Hirschsprung's disease. The study population includes all patients with histologically confirmed disease treated at the Children's Hospital Medical Center of Boston over the 25-year period extending from 1961 through the first quarter of 1986. There were 179 cases. Overall, children with Hirschsprung's disease were found less likely to be first born (P less than .01). This relationship was seen to persist irrespective of maternal age, maternal race, or type of disease. The implications of this finding are discussed. Overall, 22% of these children had one or more associated abnormalities involving the neurological, cardiovascular, urological, and gastrointestinal systems. Many of the disorders appeared to be related to neurocrestopathies. Frequent associations included Down's syndrome, defects in cardiac septation, tetralogy of Fallot, and Dandy-Walker syndrome. These conditions occurred more frequently than would have been predicted through chance alone. This study found no association between an increased maternal age and the occurrence of Hirschsprung's disease. This study also found that approximately 7% of the affected children had been born prematurely.     

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside,tetrahydrouridine, and carboplatin

Summary Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m² in three patients, 1,200 mg/m² in five patients), tetrahydrouridine (THU: 2,800 mg/m² in two patients, 2,646 mg/m² in one patient, 2,100 mg/m² in five patients), and carboplatin (900 mg/m² in four patients, 720 mg/m² in one patient, 450 mg/m² in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630±1170 ng/ml).Supported by the Don Monti Memorial Research Foundation     

Stress fracture as a cause of chronic pain following revision total hip arthroplasty. Report of two cases

Femoral stress fractures following revision total hip arthroplasty developed about a cortical window in two patients. These cases differ from previously reported fractures in that there was no significant trauma, the pain was gradual in onset, and there was no displacement at the fracture site. Tomograms and radionuclide bone scans were necessary to reveal the fracture. One femur healed with hip spica immobilization, while the other required bone grafting. Femoral stress fractures should be considered in the differential diagnosis of patients with thigh pain after revision total hip arthroplasty, particularly if a cortical window had been necessary.     

Randomized Controlled Clinical Trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany

Although both diabetes and the efficacy of medical management are international issues, psycho-educational interventions might be culturally bound. Blood Glucose Awareness Training (BGAT) is a psycho-educational program for patients with type 1 diabetes mellitus. It is focused on improving recognition and management of extreme blood glucose levels, and is the best documented American psycho-educational program for this purpose. A randomized controlled clinical trial of BGAT's long-term benefits in a non-American setting has been lacking. One hundred and eleven adults with type 1 diabetes mellitus from Switzerland and Germany participated. After a 6 months baseline assessment, subjects were randomly assigned to receive either 2 months of BGAT (n = 56) or a physician-guided self-help control intervention (n = 55). BGAT improved recognition of low (p = 0.008), high (p = .03), and overall blood glucose (p = 0.001), and reduced frequency of severe hypoglycemia (p = 0.04), without compromising metabolic control. BGAT reduced both the external locus of control (p < 0.02) and fear of hypoglycemia (p < 0.02). BGAT was efficacious in reducing adverse clinical events and achieving clinically desirable goals in a European, as well as American setting.     

Trends in HIV prevalence among public sexually transmitted disease clinic attendees in the Western region of the United States (1989-1999)

OBJECTIVES: Using data from anonymous unlinked testing of routinely collected sera, trends in HIV are compared among sexually transmitted disease patients in 4 Western urban centers. METHODS: Between 1989 and 1999, remnant sera obtained for routine syphilis testing from 256,819 patient visits to Denver, Los Angeles, San Francisco, and Seattle clinics were tested for HIV antibodies in an unlinked survey. HIV antibody test results were linked to anonymous demographic and risk information abstracted from the medical record. RESULTS: Overall cumulative HIV seroprevalences among women and among men who had sex exclusively with women were < or = 2%, declined over time, and did not exceed 8% among those who injected drugs. In contrast, cumulative HIV seroprevalences among men who have sex with men ranged from 13% in Seattle to 30% in San Francisco and declined a mean of 2.1% (95% CI, 1.6, 2.6) to 2.8% (CI 2.6, 3.1) per year, after adjustment. CONCLUSIONS: HIV infection declined over time across counties. Relative levels of HIV differed little by demographic and behavioral risk group despite differences in the severity of each county's epidemic. Because of the unique contribution of unlinked serosurveillance studies in monitoring these trends, their reinstitution in high-risk settings should be considered.     

Slow event-related brain activity of aphasic patients and controls in word comprehension and rhyming tasks

Slow event-related potentials (ERP) were examined in healthy and aphasic subjects in two-stimulus designs comprising a word comprehension and a rhyming task. Aphasics, though selected to perform above chance level, made significantly more errors and responded more slowly than controls, although canonical correlations did not indicate a statistical relationship between performance measures and ERP amplitudes. A discriminant analysis of ERP amplitudes distinguished the groups for the slow wave (SW; 0.5-1.0 s post-S1 onset) in the word comprehension, for the SW and the initial contingent negative variation (iCNV; 1.0-2.0 s post-S1 onset) in the rhyming task. Similarly for both tasks, ERP topography showed left-anterior predominance of the negative SW and iCNV in controls, whereas participants with aphasia showed smaller anterior and larger left-posterior amplitudes. The centroparietal terminal CNV (tCNV; 1 s pre-S2) was smaller in participants with aphasia than in controls, but similar in topography. Results suggest left-anterior activation for those language processes that were presumably provoked in the present tasks, like lexical access, or phonological encoding. The pattern of participants with aphasia may indicate effects of language impairment and recovery, but also consequences of the brain damage.