A 15-vertex heteroborane.
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Journal Article↗
Biomedical subjects
David Ellis
Publications and source records attributed to David Ellis.
Loading rat heart myocytes with Mg2+ using low-[Na+] solutions.
The objective of our study was to investigate how Mg2+ enters mammalian cardiac cells. During this work, we found evidence for a previously undescribed route for Mg2+ entry, and now provide a preliminary account of its properties. Changes in Mg2+ influx into rat ventricular myocytes were deduced from changes in intracellular ionized Mg2+ concentration ([fMg2+]i) measured from the fluorescence of mag-fura-2 loaded into isolated cells. Superfusion of myocytes at 37 degrees C with Ca2+-free solutions with both reduced [Na+] and raised [Mg2+] caused myocytes to load with Mg2+. Uptake was seen with solutions containing 5 mm Mg2+ and 95 mm Na+, and increased linearly with increasing extracellular [Mg2+] or decreasing extracellular [Na+]. It was very sensitive to temperature (Q(10) > 9, 25--37 degrees C), was observed even in myocytes with very low Na+ contents, and stopped abruptly when external [Na+] was returned to normal. Uptake was greatly reduced by imipramine or KB-R7943 if these were added when [fMg2+]i was close to the physiological level, but was unaffected if they were applied when [fMg2+]i was above 2 mm. Uptake was also reduced by depolarizing the membrane potential by increasing extracellular [K+] or voltage clamp to 0 mV. We suggest that initial Mg2+ uptake may involve several transporters, including reversed Na+-Mg2+ antiport and, depending on the exact conditions, reversed Na+-Ca2+ antiport. The ensuing rise of [fMg2+]i, in conjunction with reduced [Na+], may then activate a new Mg2+ transporter that is highly sensitive to temperature, is insensitive to imipramine or KB-R7943, but is inactivated by depolarization.
Adrenergic Uptake Inhibitors↗
Design, synthesis, and biological evaluations of novel quinolones as HIV-1 non-nucleoside reverse transcriptase inhibitors.
A novel series of quinolones was discovered as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a structure-based approach. The lead quinolones exhibited single digit nanomolar potency in the HIV-1 replication assays. The preliminary SAR of these quinolones was also established via systematic structural modifications. These novel and potent quinolones could serve as advanced leads for further optimization.
Binding Sites↗
A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.
Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
3',5'-Cyclic-GMP Phosphodiesterases↗
Low prevalence of BRCA1 exon rearrangements in familial and young sporadic breast cancer patients.
BRCA1 exon deletions and duplications have been reported in a number of studies, and in order to design an effective mutation screening strategy in a diagnostic setting it is import to determine the frequency of this type of mutation in breast and ovarian cancer patients. We have designed and applied quantitative fluorescent PCR (QF-PCR) assays to screen for BRCA1 exon rearrangements in breast cancer patients both with and without a family history. A panel of 182 familial patients was screened, and an exon 3-7 deletion mutation was detected in a patient with a family history of breast and ovarian cancer. Additionally, we detected a duplication of exons 18-19 in an early onset sporadic breast cancer patient from a panel of 100 patients tested. These data indicate that in the absence of any founder mutations, screening for BRCA1 exon rearrangements does not significantly increase the overall BRCA1 mutation detection rate in patients referred to a genetics clinic because of either a family history and/or an early onset of disease.
Adult↗
BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives.
Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.
Adenocarcinoma↗
Synthesis and evaluation of N-aryl pyrrolidinones as novel anti-HIV-1 agents. Part 1.
The synthesis and preliminary structure-activity relationship of a series of pyrrolidinones are described. These pyrrolidinones have been characterized as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) which are highly potent against wild-type and drug-resistant human immunodeficiency viruses (HIV-1).
Anti-HIV Agents↗
A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain.
Safety and efficacy data from a study of slow intrathecal (IT) ziconotide titration for the management of severe chronic pain are presented. Patients randomized to ziconotide (n = 112) or placebo (n = 108) started IT infusion at 0.1 microg/hour (2.4 microg/day), increasing gradually (0.05-0.1 microg/hour increments) over 3 weeks. The ziconotide mean dose at termination was 0.29 microg/hour (6.96 microg/day). Patients' baseline Visual Analogue Scale of Pain Intensity (VASPI) score was 80.7 (SD 15). Statistical significance was noted for VASPI mean percentage improvement, baseline to Week 3 (ziconotide [14.7%] vs. placebo [7.2%; P = 0.036]) and many of the secondary efficacy outcomes measures. Significant adverse events (AEs) reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Discontinuation rates for AEs and serious AEs were comparable for both groups. Slow titration of ziconotide, a nonopioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials that used a faster titration to a higher mean dose.
Adult↗
Cardiac autonomic modulation following high-intensity static muscle contractions.
BACKGROUND: The purpose of this investigation was to examine cardiac autonomic modulation, as measured by wavelet analysis of heart rate variability, following a series of high-intensity static muscle contractions. METHODS: After 10 minutes of rest, electrocardiograms (ECGs) were collected in 17 participants (age, 24.5 +/- 1 yr) 2.5 minutes before (REST) and 10 minutes after a series of static contractions of the knee extensors. Participants performed contractions with the nondominant leg (knee fixed at 90 degrees) at either 70% or 85% (randomized order) of their maximal voluntary contraction (MVC) on two separate visits. The postexercise ECGs were further divided into four consecutive 2.5-minute segments (POST 1-POST 4) to evaluate the time course of any possible autonomic changes after exercise. Each 2.5-minute segment was evaluated for the standard deviation of normal RR intervals (SDNN) and the percentage of successive RR intervals that differed by more than 50 ms (pNN50). Frequency-domain indices were obtained via wavelet transformation giving coefficients that reflected high- and low-frequency fluctuations in heart period (HFw and LFw). RESULTS: SDNN was elevated during POST-1 and pNN50 was reduced during POST-3 and POST-4 (P < 0.05) compared to REST for both intensities. Furthermore, HFw and LFw were increased during POST-1 and reduced during POST-3 and POST-4 compared to REST for both intensities (P < 0.05). CONCLUSION: These data suggest that complex alterations cardiac autonomic modulation exist for at least 10 minutes following a series of high-intensity static contractions performed at either 70% or 85% of MVC.
Adult↗
Cyclomyces tabacinus as a cause of deep tissue infection: the first case report.
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Aged↗
Active surveillance for candidemia, Australia.
Population-based surveillance for candidemia in Australia from 2001 to 2004 identified 1,095 cases. Annual overall and hospital-specific incidences were 1.81/100,000 and 0.21/1,000 separations (completed admissions), respectively. Predisposing factors included malignancy (32.1%), indwelling vascular catheters (72.6%), use of antimicrobial agents (77%), and surgery (37.1%). Of 919 episodes, 81.5% were inpatient healthcare associated (IHCA), 11.6% were outpatient healthcare associated (OHCA), and 6.9% were community acquired (CA). Concomitant illnesses and risk factors were similar in IHCA and OHCA candidemia. IHCA candidemia was associated with sepsis at diagnosis (p<0.001), death <30 days after infection (p<0.001), and prolonged hospital admission (p<0.001). Non-Candida albicans species (52.7%) caused 60.5% of cases acquired outside hospitals and 49.9% of IHCA candidemia (p = 0.02). The 30-day death rate was 27.7% in those > or =65 years of age. Adult critical care stay, sepsis syndrome, and corticosteroid therapy were associated with the greatest risk for death. Systematic epidemiologic studies that use standardized definitions for IHCA, OHCA, and CA candidemia are indicated.
Adolescent↗
Elks Lodge building collapse.
Of the 50 patients we anticipated, we evaluated 14 victims, two firefighters and two people in the crowd who developed anxiety-related symptoms in reaction to the incident. Forty-eight people escaped the building in various ways, with the most amazing being when rubble created a hole in the wall that led to a stairwell where people were able to get out. We transported 11 patients to the local hospital, four were flown to trauma centers in Kansas City, and four refused to be transported. Of those four, one later went to the ED, where he was diagnosed as having an AMI and was flown to a cardiac center in Kansas City.
Disasters↗
Sodium-dependent recovery of ionised magnesium concentration following magnesium load in rat heart myocytes.
Our objectives were to investigate regulation of intracellular ionised Mg2+ concentration ([fMg2+]i) in cardiac muscle and cardiac Na+/Mg2+ antiport stoichiometry. [fMg2+]i was measured at 37 degrees C in isolated rat ventricular myocytes with mag-fura-2. Superfusion of myocytes with Na+ and Ca2+ free solutions containing 30 mM Mg2+ for 15 min more than doubled [fMg2+]i from its basal level (0.75 mM). Re-addition of Na+ caused [fMg2+]i to fall exponentially with time to basal level, the rate increasing linearly with [Na+]. Log(recovery rate) increased linearly with log([Na+]), the slope of 1.06 (95% confidence limits, 0.94-1.17) suggesting one Na+ ion is exchanged for each Mg2+. [fMg2+]i recovery was complete even if the membrane potential was depolarised to 0 mV or if superfusate [Mg2+] was increased to 3 mM. Recovery was rapid in normal Tyrode (0.3 min(-1)) with a Q10 of 2.2. It was completely inhibited by 200 microM imipramine but was unaffected by 20 microM KB-R7943 or 1 microM SEA0400, suggesting the Na+ /Ca2+ antiporter is not involved. Membrane depolarisation by increasing superfusate [K+] to 70 mM, or voltage clamp to 0 mV, increased recovery rate in Na+ containing solutions more than threefold. We conclude [fMg2+]i recovery is by Mg2+ efflux on a 1 Na+:1 Mg2+ antiport.
Adrenergic Uptake Inhibitors↗
The synthesis and characterisation of 4,1,2-MC2B10 metallacarboranes.
Reduction of the tethered carborane 1,2-(CH2)3-1,2-closo-C2B10H10 followed by treatment with CoCl2/NaCp, [(p-cymene)RuCl2]2(p-cymene=C6H4MeiPr-1,4), (PMe2Ph)2PtCl2 or (dppe)NiCl2(dppe=Ph2PCH2CH2PPh2) affords reasonable yields of the new 13-vertex metallacarboranes 1,2-(CH2)3-4-Cp-4,1,2-closo-CoC2B10H10 (1), 1,2-(CH2)3-4-(p-cymene)-4,1,2-closo-RuC2B10H10 (2), 1,2-(CH2)3-4,4-(PMe2Ph)2-4,1,2-closo-PtC2B10H10 (3) and 1,2-(CH2)3-4,4-(dppe)-4,1,2-closo-NiC2B10H10 (4), respectively. All compounds were characterised spectroscopically and crystallographically. The cobalt and ruthenium species 1 and 2 have Cs symmetry in both solution and the solid state, having henicosahedral cage structures featuring a trapezoidal C1C2B9B5 face. The platinum and nickel compounds 3 and 4 have asymmetric docosahedral cage structures in the crystal (the more so for 4 than for 3) although both appear, by 11B and 31P NMR spectroscopy, to have Cs symmetry in solution. Low-temperature experiments on the more soluble platinacarborane could not freeze out the diamond-trapezium-diamond fluctional process that we assume is operating in solution, and we therefore conclude that this process has a relatively low activation barrier, probably <35 kJ mol-1.
Journal Article↗
Synthetic, spectroscopic, computational and structural studies of some 13-vertex ruthenacarboranes.
Reduction of 1,2-closo-C2B10H12 followed by treatment with [RuCl2(p-cymene)]2(p-cymene = C6H4MeiPr-1,4) affords the 13-vertex ruthenacarborane 4-(p-cymene)-4,1,6-closo-RuC2B10H12, characterised both spectroscopically and, in two crystalline forms, crystallographically. Although asymmetric in the solid state, having a docosahedral cage architecture with cage C atoms at vertices 1 and 6, this species clearly has Cs symmetry on the NMR timescale at room temperature. However, the fluctional process in operation can be arrested at low temperature, and an activation energy of 43.1 kJ mol(-1) is estimated. A computational study of the related species 4-(eta-C6H6)-4,1,6-closo-RuC2B10H12 reveals that the fluctionality is due to a double diamond-square-diamond process, first suggested by Hawthorne et al for the analogous CpCo species. These calculations yield an activation energy of 40.4 kJ mol(-1), in excellent agreement with that derived from experiment. Reduction of 1,2-Ph(2)-1,2-closo-C2B10H10 followed by treatment with [RuCl2(eta-C6H6)]2 or [RuCl2(p-cymene)]2 yields the analogous species 1,6-Ph2-4-(eta-C6H6)-4,1,6-closo-RuC2B10H10 and 1,6-Ph2-4-(p-cymene)-4,1,6-closo-RuC2B10H10, respectively. These C,C-diphenyl compounds were again studied spectroscopically and crystallographically, the p-cymene species again showing two crystalline modifications. In contrast to their CpCo and Cp*Co analogues all three ruthenacarboranes do not undergo isomerisation in refluxing toluene.
Journal Article↗
Fourteen-vertex homo- and heterobimetallic metallacarboranes.
Reduction of 4-(p-cymene)-4,1,12-closo-RuC2B10H12 followed by metallation with {M'} fragments (M' = {CpCo2+}, {(arene)Ru2+} or {(dppe)Ni2+}) affords 14-vertex bimetallic 1,14,2,10-RuM'C2B10 species having bicapped hexagonal antiprismatic structures.
Journal Article↗
The first 4,1,10-MC2B10 supraicosahedral metallacarboranes and a route to previously inaccessible 4,1,12-ruthenium arene species.
Reduction of 1,12-closo-C2B10H12 or its C,C-dimethyl analogue with sodium in liquid ammonia followed by metallation with {CpCo}2+, {(arene)Ru}2+ or {(dppe)Ni}2+ fragments affords the first examples of 4,1,10-MC2B10 species; thermolysis of these yields the appropriate 4,1,12-MC2B10 isomers, unavailable for (arene)Ru metallacarboranes by similar thermolysis of known 4,1,6-MC2B10 compounds.
Journal Article↗
Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial.
CONTEXT: Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive calcium channels and may be effective in patients with pain that is refractory to opioid therapy or those with intolerable opioid-related adverse effects. OBJECTIVE: To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment. DESIGN, SETTING, AND PATIENTS: Double-blind, placebo-controlled, randomized trial conducted from March 12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia, and the Netherlands. Patients were 111 individuals ages 24 to 85 years with cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment. INTERVENTIONS: Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of nonresponders to the opposite treatment group. MAIN OUTCOME MEASURE: Mean percentage change in VASPI score from baseline to the end of the initial titration period. RESULTS: Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/d for the ziconotide group and 600 mg/d for the placebo group; P =.63, based on mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo group (P =.18). Mean VASPI scores improved 53.1% (95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the placebo group (P<.001), with no loss of efficacy of ziconotide in the maintenance phase. Pain relief was moderate to complete in 52.9% of patients in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five patients receiving ziconotide achieved complete pain relief, and 50.0% of patients receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001). CONCLUSION: Intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.
Acquired Immunodeficiency Syndrome↗