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5,292 results on '"White, H. A."'

248. The ups and downs of alkyl-carbamates in epilepsy therapy: How does cenobamate differ?

Author

Löscher, Wolfgang, Sills, Graeme J., and White, H. Steve

Abstract

Since 1955, several alkyl‐carbamates have been developed for the treatment of anxiety and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, and cenobamate. They have each enjoyed varying levels of success as antiseizure drugs; however, they have all been plagued by the emergence of serious and sometimes life‐threatening adverse events. In this review, we compare and contrast their predominant molecular mechanisms of action, their antiseizure profile, and where possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of the prototypical γ‐aminobutyric acidergic (GABAergic) modulator phenobarbital is included for comparison. Like phenobarbital, all of the clinically approved alkyl‐carbamates share an ability to enhance inhibitory neurotransmission through modulation of the GABAA receptor, although the specific mechanism of interaction differs among the different drugs discussed. In addition, several alkyl‐carbamates have been shown to interact with voltage‐gated ion channels. Flupirtine and retigabine share an ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl‐carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl‐carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno‐bamate's mechanistic profile is unique among the alkyl‐carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate.

Published
2021

249. Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Author

Schwartz G, Szarek M, Bittner V, Bhatt D, Diaz R, Goodman S, Jukema J, Loy M, Manvelian G, Pordy R, White H, Steg P, ODYSSEY OUTCOMES Comm Investigator, and ODYSSEY OUTCOMES Committees and Investigators

Abstract

OBJECTIVE In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

Published
2021

250. Clinical care of pregnant and postpartum women with COVID-19: Living recommendations from the National COVID-19 Clinical Evidence Taskforce.

Author

Burgess P., Morphet J., Nou S., Russo P., Sarson M., Young A., Norris S., Morris-Donovan B., Gurry S., Hudson E., Hurley S., Primmer D., Timms S., Whicker S., Mukherjee S., Booth K., Cameron P., Cooper M., Cheng A., Fowler P., Frydenberg M., McGloughlin S., McPhee E., Mitchell B., O'Donnell C., Parr M., Phillips J., Varndell W., Whyte I., Randall R., Brightwell R., Condon L., Deshpande A., Ehm A., Ferrie M., Muller J., Pullin L., Robinson E., Witt A., Larkins S., Morgan M., Taylor G., Agostino J., Douglas K., Ewald B., Fornasier D., Knight S., Nelson C., Peachey L., Peiris D., Driel M., Walters L., Weaver I., Burr L., Hendel S., Shekar K., Avard B., Cairns K., Glanville A., Gilroy N., Myles P., O'Sullivan R., Robinson O., Sharland C., McCarthy S., Wark P., McGoughlin S., Hodgson C., Ankravs M., Hansen K., Huckson S., Iredell J., Janerka C., Jaspers R., Litton E., Macdonald S., Peake S., Bowen A., McMullan B., Tingay D., Vasilunas N., Anderson L., Best J., Burns P., Erickson S., Fancourt N., Goff Z., Kapuya V., Keyte C., Malyon L., Wurzel D., Agar M., Lindley R., Smallwood N., Callary M., Chapman M., Good P., Jenkin P., Morgan D., Naganathan V., Srikanth V., Tuffin P., Whiting E., William L., Yates P., Barber B., Davies J., Davis J., Gwee A., Leder K., Matthews G., McMahon J., Peel T., Raftery C., Rees M., Roberts J., Seppelt I., Wibrow B., Baker R., Curnow J., Cutts B., Enjeti A., Forbes A., Ho P., Holyoak A., Liley H., McFadyen J., McQuilten Z., Merriman E., Savoia H., Tan C.W., Tran H., Ward C., Williams K., Ballard N., Bendall S., Bhanderi N., Byers L., Craig S., Ellis D., Ewald D., Fairley C., Hoggard B., Cong M.L., Morley P., Nair P., Pearce A., Turner T., Callesen H., Campbell S., Ring J., Wilson A., Henry D., Pearson S., Boyle D., Chidwick K., Chapman W., French C., Pearce C., Snelling T., Bero L., Grundy Q., Lexchin J., Mintzes B., Vogel J.P., Tendal B., Giles M., Whitehead C., Burton W., Chakraborty S., Cheyne S., Downton T., Fraile Navarro D., Gleeson G., Gordon A., Hunt J., Kitschke J., McDonald S., McDonnell N., Middleton P., Millard T., Murano M., Oats J., Tate R., White H., Elliott J., Roach V., Homer C.S.E., McGowan S., Ballenden N., Barrett T.-L., Beavis V., Saunders J.B., Buchanan T., Buchanan-Grey M., Casey D., Cowie M., Doyle J., Gnjidic D., Green S., Greenland R., Griffin K., Groombridge S., Hardy L., Hodak A., Holley A., Jovanovska V., Michaels K., Burgess P., Morphet J., Nou S., Russo P., Sarson M., Young A., Norris S., Morris-Donovan B., Gurry S., Hudson E., Hurley S., Primmer D., Timms S., Whicker S., Mukherjee S., Booth K., Cameron P., Cooper M., Cheng A., Fowler P., Frydenberg M., McGloughlin S., McPhee E., Mitchell B., O'Donnell C., Parr M., Phillips J., Varndell W., Whyte I., Randall R., Brightwell R., Condon L., Deshpande A., Ehm A., Ferrie M., Muller J., Pullin L., Robinson E., Witt A., Larkins S., Morgan M., Taylor G., Agostino J., Douglas K., Ewald B., Fornasier D., Knight S., Nelson C., Peachey L., Peiris D., Driel M., Walters L., Weaver I., Burr L., Hendel S., Shekar K., Avard B., Cairns K., Glanville A., Gilroy N., Myles P., O'Sullivan R., Robinson O., Sharland C., McCarthy S., Wark P., McGoughlin S., Hodgson C., Ankravs M., Hansen K., Huckson S., Iredell J., Janerka C., Jaspers R., Litton E., Macdonald S., Peake S., Bowen A., McMullan B., Tingay D., Vasilunas N., Anderson L., Best J., Burns P., Erickson S., Fancourt N., Goff Z., Kapuya V., Keyte C., Malyon L., Wurzel D., Agar M., Lindley R., Smallwood N., Callary M., Chapman M., Good P., Jenkin P., Morgan D., Naganathan V., Srikanth V., Tuffin P., Whiting E., William L., Yates P., Barber B., Davies J., Davis J., Gwee A., Leder K., Matthews G., McMahon J., Peel T., Raftery C., Rees M., Roberts J., Seppelt I., Wibrow B., Baker R., Curnow J., Cutts B., Enjeti A., Forbes A., Ho P., Holyoak A., Liley H., McFadyen J., McQuilten Z., Merriman E., Savoia H., Tan C.W., Tran H., Ward C., Williams K., Ballard N., Bendall S., Bhanderi N., Byers L., Craig S., Ellis D., Ewald D., Fairley C., Hoggard B., Cong M.L., Morley P., Nair P., Pearce A., Turner T., Callesen H., Campbell S., Ring J., Wilson A., Henry D., Pearson S., Boyle D., Chidwick K., Chapman W., French C., Pearce C., Snelling T., Bero L., Grundy Q., Lexchin J., Mintzes B., Vogel J.P., Tendal B., Giles M., Whitehead C., Burton W., Chakraborty S., Cheyne S., Downton T., Fraile Navarro D., Gleeson G., Gordon A., Hunt J., Kitschke J., McDonald S., McDonnell N., Middleton P., Millard T., Murano M., Oats J., Tate R., White H., Elliott J., Roach V., Homer C.S.E., McGowan S., Ballenden N., Barrett T.-L., Beavis V., Saunders J.B., Buchanan T., Buchanan-Grey M., Casey D., Cowie M., Doyle J., Gnjidic D., Green S., Greenland R., Griffin K., Groombridge S., Hardy L., Hodak A., Holley A., Jovanovska V., and Michaels K.

Abstract

To date, 18 living recommendations for the clinical care of pregnant and postpartum women with COVID-19 have been issued by the National COVID-19 Clinical Evidence Taskforce. This includes recommendations on mode of birth, delayed umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, antenatal corticosteroids, angiotensin-converting enzyme inhibitors, disease-modifying treatments (including dexamethasone, remdesivir and hydroxychloroquine), venous thromboembolism prophylaxis and advanced respiratory support interventions (prone positioning and extracorporeal membrane oxygenation). Through continuous evidence surveillance, these living recommendations are updated in near real-time to ensure clinicians in Australia have reliable, evidence-based guidelines for clinical decision-making. Please visit https://covid19evidence.net.au/ for the latest recommendation updates.Copyright © 2020 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Published
2021

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