Synthesis and neuroleptic activity of benzamides. Cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide and related compounds.

Three series of benzamides of N,N-disubstituted ethylenediamines (linear alkane-1,2-diamines), 1-substituted 2-(aminomethyl)pyrrolidines, and 1-substituted 3-aminopyrrolidines (cyclic alkane-1,2-diamines) were designed and synthesized as potential neuroleptics. All target compounds were evaluated for their inhibitory effects on apomorphine-induced stereotyped behavior in rats, and a good correlation between structure and activity was found throughout the series. In the linear series (analogues of metoclopramide), introduction of a benzyl group on the terminal nitrogen, rather than an ethyl group, and a methyl group on the p-amino group of metoclopramide both enhanced the activity. The resulting N-[2-(N-benzyl-N-methylamino)ethyl]-5-chloro-2-methoxy-4-(methylamino) benzamide(23) was about 15 times more active than metoclopramide. In the cyclic series, particularly among the benzamides of 1-benzyl-3-aminopyrrolidine, most of the compounds tested were more active than the corresponding linear benzamides. cis-N-(1-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino) benzamide (YM-09151-2, 55) was the most active among all of the compounds tested, being 13 and 408 times more potent than haloperidol and metoclopramide, respectively. Moreover, compound 55 exhibited a fairly high ratio of antistereotypic activity to cataleptogenicity compared with haloperidol and metoclopramide. It is expected that compound 55 may be used as a potent drug with few side effects in the treatment of psychosis.

Quantitative computed tomographic evaluation of femoral bone mineral content in renal osteodystrophy compared with radial photon absorptiometry.

The computed tomography (CT) numbers of cortical bone at the level of 20 cm (CT20) and of spongiosa in the lateral condyle at the level of 2 cm (CT02) from the distal end of the femur were obtained by a quantitative CT method and compared with the bone mineral density of mostly cortical bone within the radius (BMD) by photon absorptiometry. The study included 47 patients with chronic renal failure not dialyzed or induced to regular hemodialysis within 4 weeks of the study (group 1), 28 patients on regular hemodialysis for more than one month (group 2), and ten healthy volunteers (group 3). The measures of bone mineral content (BMC), namely CT20, CT02, and BMD, were compared in terms of their abilities to distinguish members in the various groups. For group 1 and group 3, the greatest variation in BMC was in the difference in CT02, which was primarily a measurement of the BMC of spongiosa. For groups 1 and 2, the greatest variation was in the difference in BMD, which was primarily a measurement of the BMC of cortex. The reproducibility of CT02 was estimated as almost equal to the difference in CT02 values at intervals of 10 months' duration of hemodialysis. The results indicated that CT02 was a useful measurement for evaluating the progress in the early stage of the renal osteodystrophy, and it is recommended that the bone mineral measurement with this QCT method should be performed once or twice a year.

Theory of survival of bacteria exposed to ionizing radiation. I. X and gamma rays.

A new model for the survival of bacteria exposed to ionizing radiation is constructed in the framework of a target theory based on microdosimetric concepts, where single- and double-strand breaks of DNA and their repair in vivo can be described consistently in terms of the microdosimetric quantity j (number of effective primary events per track per target). In this model, the ability of cells to repair DNA damage is taken into consideration in terms of the repair capacities for single- and double-strand breaks of DNA, xi 1 and xi 2 (0 less than or equal to xi 1, xi 2 less than or equal to 1). To apply this model to Escherichia coli K-12 strains with different repair abilities, values of the repair capacity for single-strand breaks, xi 1, were derived from experimental survival curves. The theoretical survival curves for 60Co gamma rays were found to be effectively insensitive to the value of xi 2. Experimental survival curves for the wild-type, uvr, and rec strains of E. coli K-12 were well reproduced in this model. From these results, it is concluded that the theoretical formulation for the survival fraction of bacteria can afford a quantitative method for analysis of the repair process for radiation-induced single-strand breaks in DNA in vivo.

Microdosimetric distributions for nanometer-size targets in water irradiated with 60Co gamma rays: frequency distributions of effective primary events by individual tracks of electrons.

A calculation method of frequency distributions for the microdosimetric quantity j (number of effective primary events per track per target), fj , is presented. fj distributions are calculated for nanometer-size targets in water irradiated with 60Co gamma rays, using degradation spectra of total electrons in water, phi t(E). Further, fractional total electron differential fluences effective to produce j effective primary events, phi t(E, j), are calculated. It is found that the frequency for occurrence of no effective primary event tracks (tracks traversing the target without any effective primary event inside the target) is very large for nanometer-size targets, and that the delta-ray effect on the fj distribution becomes more significant with the decrease of the target size and especially j effective primary events (j greater than or equal to 1) for very small targets are due mostly to delta rays.

Theory of relative biological effectiveness (RBE) of tritium beta rays: bacteria killing effects of tritiated water.

A new model is applied to bacteria exposed to tritiated water. In this model, the relation between the radiation quality, induction of single- and double-strand breaks in DNA and their repair in vivo can be reasonably described in terms of the microdosimetric distribution and the modification factors for single- and double-strand breaks in DNA. First, a mathematical formulation of RBE of tritium beta rays relative to an arbitrary reference radiation for killing effect on bacteria is derived on this model. Typical theoretical results on the survival curve parameters for bacteria exposed to tritiated water and RBE of tritium beta rays relative to 60Co gamma rays are presented. It is found that RBE of tritium beta rays depends on the ability of the cell to repair DNA damage. The present model is applied to the survival of Escherichia coli Bs-1 exposed to tritiated water and 7 MeV electrons. Although the average LET of tritium beta rays is remarkably higher than that of 7 MeV electrons, the experimental result that RBE of tritium beta rays relative to 7 MeV electrons is close to unity, is reasonably explained by the present model.

Can heavy charged particles really be regarded as high-LET radiations with respect to their radiobiological actions? I: LETs and fluences of heavy charged particles and associated delta-rays.

The structures of the energy transfer of heavy charged particles (HCP) to nm-size targets have been investigated, taking account of delta-ray generation by HCP as well as associated delta-rays. From the microdosimetric viewpoint, the radiobiological effects of HCP have to be analysed in terms of the microdosimetric quantities based on the local energy transfer (LET) to the target, that is the restricted linear energy transfer (Ldelta), and the fluences or the degradation spectra of charged particles including delta-rays. Ldelta of HCP and delta-rays, and the fluences of delta-rays have been calculated for various HCP (H-Ar) with energies 1, 10 and 100 MeV amu(-1). From the results obtained, it is concluded that heavy ions (HI) should be expressed as two-component radiations which are composed of high-Ldelta heavy ion tracks of low fluence and low-Ldelta delta-rays of high fluence; in other words, the currently used expression 'HI are high-LET radiations' is not valid.

Multiple space-occupying lesions of the spleen in a case of Gaucher's disease.

A 50-year-old female patient was admitted because of an enormously enlarged spleen and thrombocytopenia. Ultrasonography and magnetic resonance imaging revealed multiple space-occupying lesions in the spleen. She was diagnosed as having Gaucher's disease based on the low level of beta-glucosidase activity in leukocytes and Gaucher's cells present in bone marrow aspirate. Severe hypersplenism necessitated splenectomy. Pathological studies of the excised spleen, including ultrastructural examinations, demonstrated that multiple space-occupying lesions in the spleen were composed of typical Gaucher cells.

Deranged mineral content in the bone of patients with chronic renal failure, estimated by computed tomography.

To evaluate the extent of renal osteodystrophy in patients with chronic renal failure, the CT numbers of the lateral condylus and mid-shaft of the femur were measured. To adjust for variation due to measurement conditions, calibration phantom was simultaneously scanned with the femur. The CT numbers of the lateral condylus were significantly lower than the control in both nondialyzed (p less than 0.005) and dialyzed patients (p less than 0.05). The CT numbers of the mid-shaft of the femur in dialyzed patients correlated significantly to the duration of hemodialysis (r = 0.807, p less than 0.001). In 15 patients subjected to both CT scan and the photon absorptiometry, the CT numbers of the lateral condylus positively correlated to the mineral content of the radial (r = 0.57) and ulnar (r = 0.69) bones as calculated by photon absorptiometry. These results indicate that the CT scan can be used to estimate bone mineral content quantitatively, and is useful tool for evaluating renal osteodystrophy in patients with chronic renal failure.

Deranged Ca, Al and Mg content in the tissues of patients with chronic renal failure, as measured by non-destructive neutron activation analysis.

Ca, Al and Mg content in the bone, aorta, skin and hair of 55 persons was measured by non-destructive neutron activation analysis. The Ca content in the bone of nondialyzed and dialyzed patients was found to decrease. Al and Mg were relatively higher than Ca in the patients compared to the controls. The present study suggests that fluctuation in the content of Al and Mg may have some relation to renal osteodystrophy such as osteomalacia as well as similar and related disorders. Al and Mg content in the aorta, and that of Ca in the hair of uremic patients, were higher than the controls. The mean Ca content in the skin of the patients was 25% higher than the controls. These findings indicate 1) that Al and Mg are possibly related to the advance of osteodystrophy, and 2) that Ca, Al and Mg deposits in the organs of uremic patients are a reflection of metabolic disorders in chronic renal failure.

Radiation quality of tritium beta-rays: microdosimetric distributions for nanometer-size targets in a medium containing tritiated water.

To elucidate the characteristics of the action of tritium beta-rays, the following parameters are derived: electron slowing down spectra of primary electrons (beta-rays) and delta-rays in a medium containing tritiated water; and frequency distributions for the microdosimetric quantity j (number of effective primary events per track per target), fj, for nanometer-size targets exposed to tritiated water. Features of the radiation quality of tritium beta-rays are discussed by comparing the present results with those for 60Co gamma-rays and 7 MeV electrons. It is concluded that, although tritium beta-rays, 60Co gamma-rays, and 7 MeV electrons are classified as the same low l.e.t. radiation, the radiation quality of tritium beta-rays is considerably different from those of 60Co gamma-rays and 7 MeV electrons, and has specific features such as a high average l.e.t., a small total electron fluence per unit absorbed dose, and a different microdosimetric distribution, fj, for nanometer-size targets.

Disturbances of trace element concentrations in plasma of patients with chronic renal failure.

Plasma concentrations of 6 essential trace elements were measured in undialyzed and hemodialyzed patients with chronic renal failure (CRF) and in healthy volunteers by tube-excited X-ray fluorescence analysis and atomic absorption analysis. The influences of hemodialysis on plasma concentrations of Al, Zn, Cu and Br were also studied. High plasma concentrations of Al and Cu and low concentrations of plasma Zn were found in nondialyzed patients with CRF. Plasma concentrations of Al and Cu increased and Zn and Br decreased in the hemodialyzed patients with CRF. An elevated concentration of plasma Al may be primarily caused by permeation from dialysate across the dialyzer membrane. The use of water produced by reverse osmosis will prevent the elevation of plasma Al concentration in patients with CRF.