Garry Graham - Academia.edu (original) (raw)

Papers by Garry Graham

Research paper thumbnail of Population Pharmacokinetics of Metformin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus: Simulation of Doses According to Renal Function

Clinical Pharmacokinetics, 2013

Metformin is contraindicated in patients with renal impairment; however, there is poor adherence ... more Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.

Research paper thumbnail of 1H, 13C NMR, and electronic absorption spectroscopic studies of the interaction of cyanide with aurothiomalate

Journal of Inorganic Biochemistry, 1985

The reaction between cyanide and aurothiomalate (Autm) has been studied by 1H and 13C NMR spectro... more The reaction between cyanide and aurothiomalate (Autm) has been studied by 1H and 13C NMR spectroscopy and by uv spectroscopy. At cyanide:Autm ratios greater than or equal to 2, aurocyanide, [Au(CN)2]-, is the sole product but was also produced at lower ratios. Two intermediates were also identified. These were a mixed ligand complex, [tmAuCN]-, which accounted for over 80% of the gold at a ratio of cyanide to Autm of 1, and a bisthiomalato complex, [Autm2]-, which accounted for 6.8% of the total gold at this ratio of cyanide to Autm. The formation of these complexes may be significant in the antiarthritic activity of Autm since cyanide is produced by potential target cells such as polymorphonuclear leukocytes.

Research paper thumbnail of Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs

Inflammopharmacology, 1999

There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is com... more There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC50 values ranging from approximately 4/~M to 200/zM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100/~M and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOC1). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC50 value, derived from inhibition of the total production of HOCI by isolated myeloperoxidase, is 81 ~M. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.

Research paper thumbnail of Population Pharmacokinetics of Metformin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus: Simulation of Doses According to Renal Function

Clinical Pharmacokinetics, 2013

Metformin is contraindicated in patients with renal impairment; however, there is poor adherence ... more Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.

Research paper thumbnail of 1H, 13C NMR, and electronic absorption spectroscopic studies of the interaction of cyanide with aurothiomalate

Journal of Inorganic Biochemistry, 1985

The reaction between cyanide and aurothiomalate (Autm) has been studied by 1H and 13C NMR spectro... more The reaction between cyanide and aurothiomalate (Autm) has been studied by 1H and 13C NMR spectroscopy and by uv spectroscopy. At cyanide:Autm ratios greater than or equal to 2, aurocyanide, [Au(CN)2]-, is the sole product but was also produced at lower ratios. Two intermediates were also identified. These were a mixed ligand complex, [tmAuCN]-, which accounted for over 80% of the gold at a ratio of cyanide to Autm of 1, and a bisthiomalato complex, [Autm2]-, which accounted for 6.8% of the total gold at this ratio of cyanide to Autm. The formation of these complexes may be significant in the antiarthritic activity of Autm since cyanide is produced by potential target cells such as polymorphonuclear leukocytes.

Research paper thumbnail of Current concepts of the actions of paracetamol (acetaminophen) and NSAIDs

Inflammopharmacology, 1999

There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is com... more There is much uncertainty about the mechanism of action of paracetamol (acetaminophen). It is commonly stated that, unlike the non-steroidal anti-inflammatory drugs (NSAIDs), it is a weak inhibitor of the synthesis of prostaglandins. This conclusion is made largely from studies in which the synthesis of prostaglandins was measured in homogenized tissues. However, in several cellular systems, paracetamol is an inhibitor of the synthesis of prostaglandins with IC50 values ranging from approximately 4/~M to 200/zM. Paracetamol is not bound significantly to plasma proteins and therefore the concentrations in plasma can be equated directly with those used in in vitro experiments. After oral doses of 1 g, the peak plasma concentrations of paracetamol are approximately 100/~M and the plasma concentrations are therefore in the range where marked inhibition of the synthesis of prostaglandins should occur in some cells. Paracetamol is metabolized by the peroxidase component of prostaglandin H synthase but the relationship of this to inhibition of the cyclooxygenase or peroxidase activities of the enzyme is unclear. Paracetamol is also metabolized by several other peroxidases, including myeloperoxidase, the enzyme in neutrophils which is responsible for the production of hypochlorous acid (HOC1). The metabolism of paracetamol by myeloperoxidase leads to the decreased total production of HOC1 by both intact neutrophils and isolated myeloperoxidase, even though the initial rate of production of HOC1 is increased. The IC50 value, derived from inhibition of the total production of HOCI by isolated myeloperoxidase, is 81 ~M. Several NSAIDs inhibit functions of neutrophils in media containing low concentrations of protein but their effects, in contrast to that of paracetamol, are generally produced only at concentrations greater than those of the unbound drug in plasma during treatment with the NSAIDs. However, neutrophils isolated during treatment with NSAIDs, such as piroxicam, ibuprofen and indomethacin show decreased function. Paracetamol has little or no anti-inflammatory activity by itself but may potentiate the clinical activity of NSAIDs in the treatment of rheumatoid arthritis.