Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer

Epidemiologic and experimental data support a role for 1,25-dihydroxyvitamin D₃ in the growth regulation of prostate cancer. We conducted a phase II clinical trial evaluating calcitriol (1,25(OH)₂D₃) in patients with hormone refractory prostate cancer. We enrolled 14 patients in this study. 1,25(OH)₂D₃ was initiated at a daily oral dose of 0.5 μg and escalated to 1.5 μg daily. No objective responses were observed. However, in two patients decreases of 25% and 45% in prostate specific antigen levels were seen. Hypercalcemia was the predominant toxicity. We conclude that 1,25(OH)₂D₃ given in this manner is inactive in advanced prostate cancer. Dose escalation of oral 1,25(OH)₂D₃ is limited by hypercalcemia.     

Clues for the development of food-based dietary guidelines: how are dietary targets being achieved by UK consumers?

Expert scientific advice to the UK Government has been translated into eight general dietary guidelines, which form the core of population-based dietary advice in the UK and are supplemented by a food selection guide showing the types and proportions of foods needed for a balanced and healthy diet. Data from the Dietary and Nutritional Survey of British Adults were used to identify statistically significant differences between subgroups of the study population that met, or failed to meet, population nutritional goals for intakes of total fat, saturated fat and dietary fibre. Several eating habits--including greater consumption of starchy foods (particularly wholemeal varieties), greater consumption of fruit and the substitution of reduced-fat milk for whole-fat milk--were shared by the subgroups that met each of the nutritional goals. This analysis provides clues for any future refinement of food-based dietary guidelines.     

Publication rates of abstracts presented at the 1993 annual Academy meeting

What percent of abstracts presented at the American Academy of Orthopaedic Surgeons annual meeting are submitted, survive peer review, and eventually are published? The answer to this fundamental question is important because many national meeting attendees use the unscrutinized information that is presented to alter their surgical practices. At the 1993 American Academy of Orthopaedic Surgeons meeting, 573 abstracts were presented. After a 5-year period, 44% of abstracts presented were published as papers in a peer reviewed journal. The results suggest that for various reasons, the majority of presented material at the Academy meeting has not been authenticated scientifically to be as accurate as papers that survive the rigors of peer review.     

Extended transbasal approach: anatomy, technique, and indications

Appropriate indications for the transbasal approach have not been clearly established. The focus of this study is to determine the feasibility of maximal exposure of the clivus and surrounding regions via this strategy. Further, we sought to determine the key anatomical landmarks and morphometric data necessary for safe, radical exposure. In 20 injected cadaveric specimens, anatomical observations were made grossly and microscopically with 4-40 x magnification. The three basic variations of the transbasal craniotomy were compared with regard to surgical exposure. Maximum exposure of the ventral clivus could be obtained by total ethmoidectomy and sphenoidectomy through the extensive transbasal craniotomy. The lateral limits of exposure were found to be the optic nerves, intracavernous carotid arteries, and hypoglossal canals. Inferiorly, the foramen magnum is the limit of exposure. Morphometric measurements were determined between the key landmarks and were found helpful in subsequent dissections due to the lack of bony structures in relation to neural and vascular structures within the bone. The keys to optimizing the transbasal approach are beyond the simple initial steps of the craniotomy. Maximal exposure from the suprasellar compartment to the foramen magnum is possible via the extended transbasal approach.     

NTS catecholamine cell recruitment by hemorrhage and hypoxia

Immunolabelling for Fos and tyrosine hydroxylase was used to determine the patterns of activation of nucleus tractus solitarius catecholamine cells in response to graded levels of hemorrhage (0, 4, 8, 12 and 16 ml/kg) and systemic hypoxia (21, 14, 12, 10 and 8% O2) in conscious rats. Both stimuli elicited graded catecholamine cell recruitment with thresholds of 8 ml/kg and 12% O2. The majority of responsive neurons were A2 noradrenergic rather than C2 adrenergic cells. After hemorrhage most Fos-positive catecholamine cells were found below obex whereas most hypoxia-responsive cells were rostral to obex. These distinctive patterns of catecholamine cell recruitment may explain the differences in neuroendocrine responses to these stimuli.     

Relative medial and dorsal cortex volume in relation to foraging ecology in congeneric lizards

The need to locate distributed resources such as mates, food, and nests is correlated with an enlarged hippocampus in many mammalian and avian species. This correlation is believed to be a consequence of selection for spatial ability. Little is known about how such ecological needs affect non-mammalian, non-avian species. In lizards, the putative hippocampal homologues are the dorsal cortex (DC) and medial cortex (MC). We examined the relationship between foraging ecology and the size of the DC and MC in congeneric male lizards. We predicted based on the mammalian and avian literature that Acanthodactylus boskianus, an active forager that captures clumped, immobile prey would have a larger MC and DC than A. scutellatus, a sit-and-wait predator, that captures mobile prey. Our previous behavioral studies showed that A. boskianus did not differ from A. scutellatus on a spatial task but that A. boskianus was significantly better at the reversal of a visual discrimination, another task that is hippocampally dependent in mammals. In the current study, we found that, relative to telencephalon volume, the MC and DC were larger in the active forager whereas a control region, the lateral, olfactory, cortex, was similar in size between species. The current anatomical results suggest that MC and DC size is related to active foraging in lizards and, along with our previous behavioral studies, show that it is possible for this relationship to occur in the absence of evidence for species differences in spatial memory. Copyright (R) 2000 S.Karger AG, Basel     

Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region

The present study investigated the effects of naturally fluctuating endogenous levels of oestrogen on the induction and maintenance of long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. Using an anaesthetized in vivo preparation, the results showed that the induction of LTP was augmented during the pro-oestrous stage of the oestrous cycle. In contrast to LTP, however, the induction of paired-pulse LTD was severely attenuated during pro-oestrous, but was clearly manifested by rats during met/dioestrous and oestrous stages of the cycle. These findings are discussed with reference to: (i) the modulatory effects of oestrogen on N-methyl-D-aspartate (NMDA) receptor function and gamma-aminobutyric acid (GABA) neurotransmission in the hippocampus; and (ii) the functional implications that such cyclical changes in synaptic plasticity have for learning and memory processes supported by the hippocampus.     

Stereoselective and substrate-dependent inhibition of hepatic mitochondria beta-oxidation and oxidative phosphorylation by the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen, and ketorolac

Non-steroidal anti-inflammatory drugs (NSAIDs) cause a range of adverse effects, some of which have been associated with perturbances of lipid metabolic pathways. Previous data demonstrating stereoselective formation of the CoA thioester of R-ibuprofen in particular were suggestive of possible stereoselective effects on lipid metabolism. Our aim was to characterise the relative stereoselectivity of the effects of ibuprofen, flurbiprofen, and ketorolac (0.01-1.0 mM) on both the beta-oxidation of palmitate and oxidative phosphorylation in rat hepatic mitochondria as a means of dissecting prostaglandin related from non-prostaglandin-related events. Beta-oxidation was inhibited stereoselectively by R-ibuprofen (P = 0.015), non-stereoselectively by R- and S-flurbiprofen (P = 0.002 and P = 0.004, respectively), and was essentially unaffected by either enantiomer of ketorolac. At 0.25 mM, inhibition by R-ibuprofen and both flurbiprofen enantiomers was partially reversed by increasing CoA concentrations (0-200 microM). Mitochondrial respiration was moderately inhibited by both enantiomers of ibuprofen and flurbiprofen (P < 0.01), but only by high concentrations (> or = 1 mM) of the enantiomers of ketorolac (P < 0.01). Uncoupling of oxidative phosphorylation measured as stimulation of State 4 respiration contributed to these effects. The data support interactions involving both stereoselective CoA-dependent and non-CoA-dependent mechanisms. The plasma drug concentrations required to achieve these effects are not likely to be attained in the majority of patients, although these concentrations are achievable in the gastrointestinal tract and may contribute to the well-known spectrum of adverse effects in this organ. Some patients do experience systemic adverse events which may be mediated by these mechanisms.     

The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.