Novel bisquinoline antimalarials. Synthesis, antimalarial activity, and inhibition of haem polymerisation

We report the synthesis of two series of novel bisquinoline compounds that inhibit the growth of both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. To study the molecular basis of the action of these novel antimalarial drugs, we examined their ability to inhibit haem polymerisation in the presence and absence of parasite extracts. The level of antimalarial potency was correlated with the level of inhibition of haem polymerisation, suggesting that these bisquinolines exert their antimalarial activity by antagonising the sequestration of toxic haem moieties.     

Cyclophosphamide and 4-Hydroxycyclophosphamide/aldophosphamide kinetics in patients receiving high-dose cyclophosphamide chemotherapy

Using a recently developed gas chromatography and mass spectrometry method to determine whole-blood cyclophosphamide (CP) and 4-hydroxycyclophosphamide/aldophosphamide (4-HO-CP/AP) concentrations, we investigated their pharmacokinetics in women receiving CP therapy. Patients (n = 18) received one or two courses of CP: (a) a 90-min i.v. infusion (4 g/m2) followed by a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa; or (b) a 96-h i.v. infusion (6 g/m2) in combination with high-dose thiotepa. Whole-blood exposures to CP [area under the whole blood concentration versus time curve (AUCCP)] and 4-HO-CP/AP (AUC4HOCP) between courses 1 and 2 were compared after normalization to dose (g/m2). A nonproportional increase was observed for the AUCCP between the first course [1112 micrometer. h/g/m2 +/- 14% coefficient of variation (CV)] and the second course (1579 micrometer . h/g/m2 +/- 28% CV) (P < 0.001). In contrast, the AUC4HOCP (27 micrometer . h/g/m2 +/- 25% CV) determined for the first course was 29% higher than the AUC4HOCP (21 micrometer . h/g/m2 +/- 26% CV) for the second course (P < 0.01). The interpatient whole-blood exposures to both CP and 4-HO-CP/AP were remarkably consistent in this patient population with percent CVs ranging from 14 to 28%. Because thiotepa (800 mg/m2) was administered simultaneously with CP during the second course of treatment, possible inhibition of CP metabolism by thiotepa was investigated using human liver microsomes in vitro. IC50 values determined for inhibition of CP metabolism in three individual liver donors ranged from 1.0 to 40 micrometer. However, the clinical relevance of this observation has not been established.     

Organization of projections from the basomedial nucleus of the amygdala: a PHAL study in the rat

The organization of axonal projections from the basomedial nucleus of the amygdala (BMA) was examined with the Phaseolus vulgaris leucoagglutinin (PHAL) method in adult male rats. The anterior and posterior parts of the BMA, recognized on cytoarchitectonic grounds, display very different projection patterns. Within the amygdala, the anterior basomedial nucleus (BMAa) heavily innervates the central, medial, and anterior cortical nuclei. In contrast, the posterior basomedial nucleus (BMAp) sends a dense projection to the lateral nucleus, and to restricted parts of the central and medial nuclei. Extra-amygdalar projections from the BMA are divided into ascending and descending components. The former end in the cerebral cortex, striatum, and septum. The BMAa mainly innervates olfactory (piriform, transitional) and insular areas, whereas the BMAp also innervates inferior temporal (perirhinal, ectorhinal) and medial prefrontal (infralimbic, prelimbic) areas and the hippocampal formation. Within the striatum, the BMAa densely innervates the striatal fundus, whereas the nucleus accumbens receives a heavy input from the BMAp. Both parts of the BMA send massive projections to distinct regions of the bed nuclei of the stria terminalis. Descending projections from the BMA end primarily in the hypothalamus. The BMAa sends a major input to the lateral hypothalamic area, whereas the BMAp innervates the ventromedial nucleus particularly heavily. Injections were also placed in the anterior cortical nucleus (COAa), a cell group superficially adjacent to the BMAa. PHAL-labeled axons from this cell group mainly ascend into the amygdala and olfactory areas, and descend into the thalamus and lateral hypothalamic area. Based on connections, the COAa and BMAa are part of the same functional system. The results suggest that cytoarchitectonically distinct anterior and posterior parts of the BMA are also hodologically distinct and form parts of distinct anatomical circuits probably involved in mediating different behaviors (for example, feeding and social behaviors vs. emotion-related learning, respectively).     

Comparison of conventional single echo and multi-echo sequences with a fast spin-echo sequence for quantitative T2 mapping: application to the prostate

The accuracy of water T2 maps generated from a fast spin-echo (FSE) sequence was compared with data obtained by conventional single and multi-echo spin-echo pulse sequences using a commercial gel phantom. Spatially localized stimulated echo acquisition mode (STEAM) proton spectroscopy was also used to confirm the reported water T2 values of the gels contained in the phantom. The FSE sequence was shown to be superior in accuracy to both the single and multi-echo spin echo sequences and comparable to STEAM, producing results that were within 10% of known values. The effectiveness of the FSE sequence was further demonstrated by generating T2 maps of the normal and diseased prostate in clinically acceptable imaging times, resulting in comparable T2 values to those obtained using STEAM. Accurate quantitative T2 maps can be produced with the FSE sequence.     

Surgery for primary hyperparathyroidism 1962-1996: indications and outcomes

Twenty-two cases of ameloblastoma and ten cases of adenomatoid odontogenic tumour (AOT) were analyzed comparatively by the AgNOR technique. Ameloblastomas were distributed into three groups according to their clinical behaviour: primary lesions without recurrences (PLWTR), 5 cases; primary lesions with recurrences (PLWR), 4 cases; and recurrences, 13 cases. The cases were also regrouped according to their histological pattern: follicular (9 cases), plexiform (7 cases), acanthomatous (4 cases) and unicystic (2 cases). Considering histological patterns, there was a significant statistical difference only between follicular and plexiform types. There were no significant differences between the group of ameloblastomas and the group of AOTs or between the three groups of ameloblastomas with different clinical behaviour. Our results strongly suggest that the distinct clinical behaviour of ameloblastomas and AOT is not correlated with their cellular proliferation ratio. Thus, the infiltrative ability of the ameloblastomas is probably not related to the cellular proliferation index of these tumours.     

A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy

Maternal serum concentrations of inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC-related inhibin forms, total follistatin, steroids and gonadotrophins were measured longitudinally in six normal singleton pregnancies. Maternal venous blood was collected randomly during a spontaneous follicular phase prior to donor insemination, at 5, 7, 9, 11, 16, 20, 24, 28, 32 and 36 weeks after the first missed menses and in the early puerperium. Steroid and gonadotrophin profiles conformed to previous reports. While at week 5 of gestation inhibin-A, activin-A and follistatin concentrations were similar to those at the follicular phase, all three increased progressively (P < 0.001) to maximal concentrations in week 36: approximately 48-fold (3740 +/- 1349 ng inhibin-A/ml), approximately 22-fold (6109 +/- 1443 ng activin-A/ml) and approximately 10-fold (3563 +/- 418 ng follistatin/ml) higher. Pro-alphaC concentrations reached a maximum in weeks 5 (approximately 5-fold, P < 0.001) and 36 (1027 +/- 174 pg/ml, P < 0.01). Inhibin-B (71 +/- 23 pg/ml prior to pregnancy) was undetectable (<12 pg/ml) between week 5-16 of gestation but increased slightly in the third trimester (26 +/- 7 pg/ml in week 36). Activin-AB was undetectable throughout pregnancy. Post-partum concentrations of inhibin-A (41 +/- 12 ng/ml), inhibin-B (<12 pg/ml), activin-A (950 +/- 149 pg/ml), pro-alphaC (128 +/- 22 pg/ml) and follistatin (990 +/- 79 ng/ml) were substantially lower than at week 36 of gestation. The activin-A:follistatin ratio increased from 0.5 in week 5 to 1.8 in week 36, suggesting that more free activin-A is available in the maternal circulation during late pregnancy.     

Structure/Enthalpy of Formation Relationships for Hydrocarbons Containing Benzene Rings

Simple protocols to convert molecular mechanics (MMX/PCMODEL), semiempirical PM3, and HF ab initio energies to accurate heats of formation for hydrocarbons with benzene rings are described. The data set consists of every hydrocarbon benzene derivative with an experimentally determined ΔH_f^o (g), and the ΔH_f^o (g)'s cover a range of -140 to +410 kJ/mol. The molecular structures are comprised of numerous structural types. Hierarchical sets of molecular structure parameters are defined to describe these molecules. The independent variables include atom types (level 1), group and ring terms (level 2), nonbonded atom interactions (level 3), and the calculated MMX, PM3 or ab initio HF energies, which contribute a final level 4 parameter for rectification of the ΔH_f^o (g) data. The additivity, level 1-3 parameters give an excellent correlation of the experimental ΔH_f^o (g)'s, average error = 3.4 kJ, and maximum error = 12.1 kJ. However, the correlations are further enhanced by addition of any level 4 parameter, with maximum improvement coming at the 6-31G*//STO-3G HF level of calculation.     

Periodic limb movement in sleep in children with Williams syndrome

Difficulty differentiating physiologic genu varum from early Blount's disease persists. Drennan's metaphyseal-diaphyseal (MD) angle remains the most consistently valuable radiographic parameter despite measurement error. Clinical risk factors also should be considered. All patients receiving orthoses for genu varum since 1985 were reviewed. The focus of the study was those patients with an MD angle of >16 degrees or between 9 and 16 degrees with a clinical risk factor for progression. Risk factors considered were ligamentous instability, obesity, asymmetry, and being female, black, or Hispanic. Thirty-eight patients with 60 tibiae were included. The success rate was 90%. Risk factors for failure (six cases) were instability, obesity, and delayed bracing. In cases with MD angles >16 degrees, the success rate was 86%. The results of orthotic treatment, restricted to patients meeting the stated parameters, represent improvement on the reported natural history.     

Growth hormone treatment in pediatric burns: a safe therapeutic approach

In the recovery period after strenuous exercise, there is increased O2 uptake, termed the excess postexercise O2 consumption (EPOC). One of the mechanisms suggested to explain EPOC is activation of the triglyceride/fatty acid (TG/FA) cycle by catecholamines. The purpose of this study was to determine the effect of selective beta1- and nonselective beta-adrenoceptor blockade on EPOC and the TG/FA cycle. Seven healthy young men each participated in three control and three exercise experiments in a randomized and balanced sequence. In the exercise experiments, subjects exercised for 90 minutes at 58% +/- 2% (mean +/- SD) of maximal O2 uptake on a cycle ergometer, followed by a 4.5-hour bedrest. The control experiments followed the same protocol, but without exercise. In one control and one exercise experiment, the selective beta1-adrenoceptor antagonist atenolol (0.062 mg.kg(-1) body weight) was administered intravenously immediately after the exercise (EXAT) and at the corresponding time in the rest-control experiment (REAT). In a second set of control and exercise experiments, the nonselective beta-adrenoceptor antagonist propranolol (0.15 mg.kg(-1) body weight) was administered (REPRO and EXPRO). In a third set of rest and exercise experiments, an injection of saline was given instead of beta-antagonist (RE and EX). TG/FA cycling was calculated by combining results obtained with a two-stage glycerol infusion and indirect calorimetry. O2 uptake was significantly increased above control levels throughout the recovery period after exercise with the nonselective beta-adrenoceptor antagonist, beta1-adrenoceptor antagonist, and saline. However, there was no difference between the time course or magnitude of EPOC in the three situations. After 4.5 hours of bedrest, the mean increase in O2 uptake was 8% to 9% in all three conditions. TG/FA cycling was increased after exercise, but no effects of beta-antagonists were observed. We conclude that EPOC and the rate of TG/FA cycling are not attenuated by selective beta1- or nonselective beta-adrenoceptor blockade after an acute prolonged exercise protocol.