Abstract 1. Large male seaweed flies (Diptera: Coelopidae) are more likely to mate than smaller ... more Abstract 1. Large male seaweed flies (Diptera: Coelopidae) are more likely to mate than smaller males. This is due to sexual conflict over mating, by which females physically resist male attempts to copulate. In some species, large males are simply more efficient at overpowering female resistance.
Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neurona... more Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. This manuscript provides an overview of the drug-drug interaction potential of retigabine with other AEDs, using data collated from both in vitro work and clinical studies, either previously published or from relevant information collated during the development of retigabine. Retigabine is not a substrate for the major CYP enzymes and at clinically relevant concentrations there is little or no potential for retigabine to inhibit or induce the CYP enzymes or to inhibit the major renal drug transporters. The addition of retigabine to a range of existing AEDs showed little or no effect on the AED trough concentrations apart from a 20% decrease in lamotrigine concentrations. Results from a small phase II study showed that co-administration of valproic acid and topiramate had no impact on the PK of retigabine whereas carbamazepine and phenytoin increased the clearance of retigabine by approximately 27% and 36%, respectively. Conversely, a population PK analysis of combined data from phase I, II and III studies showed that none of the coadministered AEDs affected retigabine clearance apart from lamotrigine which lowered retigabine clearance by 6.7%. Retigabine is not metabolized by CYP isozymes and does not induce or inhibit these isozymes at clinically relevant concentrations. Therefore, retigabine is associated with a low potential for PK interactions with other drugs via CYP450. Overall, there was little or no potential for retigabine to interact with other available AEDs. Although some PK interactions were observed with lamotrigine, these are unlikely to be clinically relevant.
Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium cha... more Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity. This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures. Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N-glucuronidation. In vitro and in vivo studies have shown that the drug-interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients. Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment.
Shortly after admission with facial space infection, ultrasound-guided needle aspiration of later... more Shortly after admission with facial space infection, ultrasound-guided needle aspiration of lateral masticator space abscess was carried out in 2 adult patients. One abscess was associated with pericoronitis and the other with post-extraction infection. Successful aspiration of pus was followed by an instantaneous improvement in the ability to open the mouth for a period of at least 24 hours. This obviated the need for conscious nasoendoscopic intubation and allowed orotracheal intubation for conventional drainage. We concluded that ultrasonography can be beneficial in the management of orofacial infections.
Background: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that... more Background: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that opens voltage-dependent K+(K v) channels in peripheral arteries. We studied the role of KCNQ-type K v channels and tested the hypothesis that hydrogen sulfide (H 2 S ...
Background: Retigabine (international nonproprietary name)/ezogabine (United States adopted name)... more Background: Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (K v 7) potassium channel activity. Objectives: The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials. Methods: Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC 0-τ during the 12week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partialseizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated. Results: AUC 0-τ values increased linearly over the 600-to 1200-mg/d dose range. Over the entire AUC 0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC 0-τ. Conclusions: Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC 0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.
The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopu... more The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are G i ␣ protein coupled. MCP-1 induced a transient Ca 2؉ flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca 2؉ flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca 2؉ mobilization, Ca 2؉ flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
... church and received Protestant wisdom. Here are long philosophic ruminations about the sermon... more ... church and received Protestant wisdom. Here are long philosophic ruminations about the sermons of the men whom she sought out as spiritual guides: Raja Singh, Garland Anderson and Clem Davies. Almost as long but more ...
In adults the bone marrow is the sole microenvironment that supports all activities of normal hae... more In adults the bone marrow is the sole microenvironment that supports all activities of normal haematopoiesis. Haematopoietic stem cells (HSCs) home to bone marrow during development and transplantation where pluripotency is maintained and maturity is facilitated (Nelissen et al, 2000). Both of these activities are likely to require different growth factors and cellular contexts. Bone marrow stromal cells are comprised of several different cellular populations including fibroblasts, endothelial and reticular cells, adipocytes and osteoblasts (OB) which serve as a rich source of growth factors (
• Acute dental pain may be severe and result in large quantities of 'over the counter' (OTC) medi... more • Acute dental pain may be severe and result in large quantities of 'over the counter' (OTC) medications being taken by patients for symptomatic relief. • Two cases of unintentional paracetamol overdose, arising as a result of dental pain, requiring anti-toxicity treatment are presented. • Emphasis is placed on the description of the signs, symptoms and management of paracetamol overdose.
Sexual selection is known to operate at medfly leks with a few males gainiig a high proportion of... more Sexual selection is known to operate at medfly leks with a few males gainiig a high proportion of matings. However, specific male characteristics subject to sexual selection have not been identified. Here we report laboratory studies indicating that directional sexual selection operates on the level of fluctuating asymmetry (FA) in the superior frontal orbital setae (sex setae), with symmetrical males gaining more matings. Studies relating mating success with FA in a male trait have generally been taken as evidence of the operation of indirect sexual selection. For a male trait to acts as a reliable indicator of fitness, FA in the male trait should be negatively associated with trait size and females should mate with the males with the most exaggerated form of the trait. However no association was found between seta FA and mean seta length. In addition sexual selection did not appear to operate on mean trait size, although males with an intermediate sex seta to wing length ratio did achieve higher mating success, indicating that stabilizing sexual selection operates on this relative dimension. It is suggested that differences in male competitive ability may provide an alternative explanation of how such associations between mating success and FA in male characteristics can arise.
KikuchiFujimoto disease, also known as histiocytic necrotising lymphadenitis, is a self-limiting... more KikuchiFujimoto disease, also known as histiocytic necrotising lymphadenitis, is a self-limiting condition of uncertain aetiology characterised by lymphadenopathy, pyrexia, and neutropenia. Some reported cases have been associated with systemic lupus ...
Objective To identify potential tolerability issues for a novel selective p38 Mitogen-activated P... more Objective To identify potential tolerability issues for a novel selective p38 Mitogen-activated Protein Kinases (p38MAPK) inhibitor, we performed a systematic review of published studies and abstracts reporting safety outcomes for indirect inhibitors of p38MAPK. Methods A ...
The US apparel industry employed over 1 million workers as late as 1980, but today it employs onl... more The US apparel industry employed over 1 million workers as late as 1980, but today it employs only about one-third of that number. The common explanation for this collapse is the delocalization of production to low wage countries, but this neglects advantages of speed, flexibility and ...
Results of this systematic literature review suggest that the overall incidence of CMs in childre... more Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without ...
... " Stevie Cameron. ... This book belongs to them too: Laurie Edwards, Susan G. Cole,... more ... " Stevie Cameron. ... This book belongs to them too: Laurie Edwards, Susan G. Cole, Sandy Duncan, Lynne Fernie, Kate Hamilton, Barbara Hehner, Carol Mclntyre, Susan Rockman, Dell Texmo, Eve Zaremba, Arnold Rockman, Keith Maillard, Ed Carson, the This Magazine ...
Abstract 1. Large male seaweed flies (Diptera: Coelopidae) are more likely to mate than smaller ... more Abstract 1. Large male seaweed flies (Diptera: Coelopidae) are more likely to mate than smaller males. This is due to sexual conflict over mating, by which females physically resist male attempts to copulate. In some species, large males are simply more efficient at overpowering female resistance.
Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neurona... more Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. This manuscript provides an overview of the drug-drug interaction potential of retigabine with other AEDs, using data collated from both in vitro work and clinical studies, either previously published or from relevant information collated during the development of retigabine. Retigabine is not a substrate for the major CYP enzymes and at clinically relevant concentrations there is little or no potential for retigabine to inhibit or induce the CYP enzymes or to inhibit the major renal drug transporters. The addition of retigabine to a range of existing AEDs showed little or no effect on the AED trough concentrations apart from a 20% decrease in lamotrigine concentrations. Results from a small phase II study showed that co-administration of valproic acid and topiramate had no impact on the PK of retigabine whereas carbamazepine and phenytoin increased the clearance of retigabine by approximately 27% and 36%, respectively. Conversely, a population PK analysis of combined data from phase I, II and III studies showed that none of the coadministered AEDs affected retigabine clearance apart from lamotrigine which lowered retigabine clearance by 6.7%. Retigabine is not metabolized by CYP isozymes and does not induce or inhibit these isozymes at clinically relevant concentrations. Therefore, retigabine is associated with a low potential for PK interactions with other drugs via CYP450. Overall, there was little or no potential for retigabine to interact with other available AEDs. Although some PK interactions were observed with lamotrigine, these are unlikely to be clinically relevant.
Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium cha... more Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity. This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures. Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N-glucuronidation. In vitro and in vivo studies have shown that the drug-interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients. Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment.
Shortly after admission with facial space infection, ultrasound-guided needle aspiration of later... more Shortly after admission with facial space infection, ultrasound-guided needle aspiration of lateral masticator space abscess was carried out in 2 adult patients. One abscess was associated with pericoronitis and the other with post-extraction infection. Successful aspiration of pus was followed by an instantaneous improvement in the ability to open the mouth for a period of at least 24 hours. This obviated the need for conscious nasoendoscopic intubation and allowed orotracheal intubation for conventional drainage. We concluded that ultrasonography can be beneficial in the management of orofacial infections.
Background: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that... more Background: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that opens voltage-dependent K+(K v) channels in peripheral arteries. We studied the role of KCNQ-type K v channels and tested the hypothesis that hydrogen sulfide (H 2 S ...
Background: Retigabine (international nonproprietary name)/ezogabine (United States adopted name)... more Background: Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (K v 7) potassium channel activity. Objectives: The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials. Methods: Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC 0-τ during the 12week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partialseizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated. Results: AUC 0-τ values increased linearly over the 600-to 1200-mg/d dose range. Over the entire AUC 0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC 0-τ. Conclusions: Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC 0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.
The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopu... more The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are G i ␣ protein coupled. MCP-1 induced a transient Ca 2؉ flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca 2؉ flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca 2؉ mobilization, Ca 2؉ flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
... church and received Protestant wisdom. Here are long philosophic ruminations about the sermon... more ... church and received Protestant wisdom. Here are long philosophic ruminations about the sermons of the men whom she sought out as spiritual guides: Raja Singh, Garland Anderson and Clem Davies. Almost as long but more ...
In adults the bone marrow is the sole microenvironment that supports all activities of normal hae... more In adults the bone marrow is the sole microenvironment that supports all activities of normal haematopoiesis. Haematopoietic stem cells (HSCs) home to bone marrow during development and transplantation where pluripotency is maintained and maturity is facilitated (Nelissen et al, 2000). Both of these activities are likely to require different growth factors and cellular contexts. Bone marrow stromal cells are comprised of several different cellular populations including fibroblasts, endothelial and reticular cells, adipocytes and osteoblasts (OB) which serve as a rich source of growth factors (
• Acute dental pain may be severe and result in large quantities of 'over the counter' (OTC) medi... more • Acute dental pain may be severe and result in large quantities of 'over the counter' (OTC) medications being taken by patients for symptomatic relief. • Two cases of unintentional paracetamol overdose, arising as a result of dental pain, requiring anti-toxicity treatment are presented. • Emphasis is placed on the description of the signs, symptoms and management of paracetamol overdose.
Sexual selection is known to operate at medfly leks with a few males gainiig a high proportion of... more Sexual selection is known to operate at medfly leks with a few males gainiig a high proportion of matings. However, specific male characteristics subject to sexual selection have not been identified. Here we report laboratory studies indicating that directional sexual selection operates on the level of fluctuating asymmetry (FA) in the superior frontal orbital setae (sex setae), with symmetrical males gaining more matings. Studies relating mating success with FA in a male trait have generally been taken as evidence of the operation of indirect sexual selection. For a male trait to acts as a reliable indicator of fitness, FA in the male trait should be negatively associated with trait size and females should mate with the males with the most exaggerated form of the trait. However no association was found between seta FA and mean seta length. In addition sexual selection did not appear to operate on mean trait size, although males with an intermediate sex seta to wing length ratio did achieve higher mating success, indicating that stabilizing sexual selection operates on this relative dimension. It is suggested that differences in male competitive ability may provide an alternative explanation of how such associations between mating success and FA in male characteristics can arise.
KikuchiFujimoto disease, also known as histiocytic necrotising lymphadenitis, is a self-limiting... more KikuchiFujimoto disease, also known as histiocytic necrotising lymphadenitis, is a self-limiting condition of uncertain aetiology characterised by lymphadenopathy, pyrexia, and neutropenia. Some reported cases have been associated with systemic lupus ...
Objective To identify potential tolerability issues for a novel selective p38 Mitogen-activated P... more Objective To identify potential tolerability issues for a novel selective p38 Mitogen-activated Protein Kinases (p38MAPK) inhibitor, we performed a systematic review of published studies and abstracts reporting safety outcomes for indirect inhibitors of p38MAPK. Methods A ...
The US apparel industry employed over 1 million workers as late as 1980, but today it employs onl... more The US apparel industry employed over 1 million workers as late as 1980, but today it employs only about one-third of that number. The common explanation for this collapse is the delocalization of production to low wage countries, but this neglects advantages of speed, flexibility and ...
Results of this systematic literature review suggest that the overall incidence of CMs in childre... more Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without ...
... " Stevie Cameron. ... This book belongs to them too: Laurie Edwards, Susan G. Cole,... more ... " Stevie Cameron. ... This book belongs to them too: Laurie Edwards, Susan G. Cole, Sandy Duncan, Lynne Fernie, Kate Hamilton, Barbara Hehner, Carol Mclntyre, Susan Rockman, Dell Texmo, Eve Zaremba, Arnold Rockman, Keith Maillard, Ed Carson, the This Magazine ...
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