Fakhreddin Jamali | University of Alberta (original) (raw)
Papers by Fakhreddin Jamali
Journal of Pharmacy and Pharmaceutical Sciences, Feb 6, 2023
Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora o... more Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora of studies has revealed that inflammation and inflammatory mediators such as cytokines and chemokines are associated with altered expression and activity of various proteins such as those involved in drug metabolism, specifically cytochrome P450 enzymes (CYPs). Emphasis of most available reports is on the inflammationinduced downregulation of CYPs, subsequently an increase in their substrate concentrations, and the link between the condition and the inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha. However, reports also suggest that inflammation influences expression and/or activity of other proteins such as those involved in the drug-receptor interaction. These multifaced involvements render the clinical consequence of the inflammation unexpected. Such changes are shown in many inflammatory conditions including rheumatoid arthritis, Crohn's disease, acute respiratory illnesses as well as natural processes such as aging, among others. For example, some commonly used cardiovascular drugs lose their efficacy when patients get afflicted with inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Interestingly, this is despite increased concentration subsequent to reduced clearance. The observation is attributed to a simultaneous reduction in the expression of target receptor proteins such as the calcium and potassium channel and β-adrenergic receptor as well as the metabolic enzymes. This narrative review summarizes the current understanding and clinical implications of the inflammatory effects on both CYPs and drug-receptor target proteins.
European Journal of Drug Metabolism and Pharmacokinetics, Oct 1, 1985
Journal of Pharmacy and Pharmaceutical Sciences, Jul 30, 2020
COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory resp... more COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory responses with cytokine storm. This plays a major role in COVID-19 severity and poor disease prognosis, even death. Higher levels of inflammatory hallmarks including C-reactive protein, ferritin, D-dimers, and cytokines such as interleukin (IL) -6, IL-10 and tumor necrosis factor-α (TNF-α) have been reported. Many anti-viral drugs have been tried, but none were proven fully effective. Supportive care and management of the complications that are caused mainly by inflammation might be the key to greater survival rates and shorter hospitalization (e.g., the use of remdesivir, lopinavir, ritonavir, umifenovir (arbidol), oseltamivir, ganciclovir, favipiravir, darunavir, hydroxychloroquine, chloroquine, colchicine, azithromycin, anakinra, canakinumab, tocilizumab, siltuximab, sarilumab, Type 1 interferon, interferon β-1a, interferon α-2b, baricitinib, ruxolitinib, fedratinib, methylprednisolone and dexamethasone). However, the efficacy of these treatments still needs well-planned clinical trials. In such trials, careful attention must be paid to the duration of the treatment, the onset of beneficial effects, and the severity of the disease, otherwise, the outcomes may still remain inconclusive. Herein, we present a review of the current drugs, which are being used in the management of the disease and their anti-inflammatory properties. We also investigated if these drugs directly interact with Angiotensin-Converting Enzyme (ACE 2), which is a crucial component of the virus entry to the cells.
Value in Health, Oct 1, 2017
that NSAIDs use can cause cardiovascular (CV) complications. Studies have suggested that NSAIDs t... more that NSAIDs use can cause cardiovascular (CV) complications. Studies have suggested that NSAIDs tissue distribution may be associated with differences in their CV risk profiles. The purpose of this systematic review was to assess the overall CV risks while stratified into different categories of coronary, vascular and renal outcomes based on different tissue compartments. Meloxicam for instance is known for its limited tissue distribution, owing to zwitterion nature of its molecule, and hence its use exhibits least renal and CV implications. Methods: We conducted an online search in selected healthcare database (till June 2013) looking for comparative observational studies or randomized clinical trial, having meloxicam in their comparisons and reporting coronary outcome (upon > 90 days exposure) or vascular/ renal outcomes (upon any exposure). Our search recruited 2106 studies out of which 17 were eligible, reporting coronary (n= 5), vascular (n= 6) and renal (n= 6) outcomes. The odd ratio (OR, 95% CI) and relative risk (RR, 95% CI) data was abstracted and pooled using fixed effect inverse variance model Results: Meloxicam caused moderate but significant overall CV risk 1. 15 [1.05, 1.25] mainly due to an elevated vascular 1. 37 [1.21, 1.55] risk; however, the coronary 1. 00 [0.87, 1.14 and renal 0.83 [0.63, 1.11] risks were not increased. Rofecoxib causes the highest overall CV risk 1. 38 [1.29, 1.46] that includes higher coronary 1. 46 [1.10, 1.93], vascular 1.31 [1.21, 1.41] and renal 1.51 [1.35, 1.68] risks. Other NSAIDs increased the overall risk in the following order indomethacin> diclofenac> naproxen> celecoxib> ibuprofen. ConClusions: NSAIDs are heterogeneous in causing CV/renal risks in terms of both extent and the nature of their adverse effects. Meloxicam causes limited risk and its side effects are mainly of vascular in nature, hence, clinically manageable.
Pediatrics, 1987
Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminoph... more Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminophylline were treated with incremental doses of doxapram beginning at 0.5 mg/kg/h. Continuous recording of heart rate, thoracic impedance, and transcutaneous Po2 demonstrated that 47% of the infants satisfied objective response criteria at the lowest dose, 53% responded at 1.0 mg/kg/h, 65% at 1.5 mg/kg/h, 82% at 2.0 mg/kg/h, and 89% at the highest allowed dose of 2.5 mg/kg/h. The mean serum doxapram concentration at the response dose was 2.9 ± 1.3 µg/mL, and all infants who responded had levels greater than 1.5 µg/mL. BP was significantly elevated at doses higher than 1.5 mg/kg/h (P < .05). Minute ventilation significantly increased and Pco2 significantly decreased as the doxapram dosage was increased (P = .02). Terminal elimination half-life was 9.9 ± 2.9 hours. When doxapram is used for treatment of refractory neonatal apnea the starting dosage should be no more than 0.5 mg/kg/h.
Clinical Pharmacology & Therapeutics, 2004
Inflammatory conditions decrease cardiovascular response to β and Ca2+ channel blockers despite e... more Inflammatory conditions decrease cardiovascular response to β and Ca2+ channel blockers despite elevated drug levels due to downregulation of the receptors by inflammatory mediators. Whether downregulation is also evident with AT1R antagonists in RA was tested. The subjects were 14 active RA, 12 controlled RA and 12 healthy. Joint swelling, NO and C-reactive protein were measured. Valsartan (VAL) or losartan
Inflammopharmacology, 2015
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (... more Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (CV) and renal incidences, especially at higher doses and upon long term use. However, the available reports are criticized for lack of specificity, grouping of vastly different outcomes together and ignoring the heterogeneity among NSAIDs. In this systematic review, we are reporting CV/renal risks associated with meloxicam, stratified into myocardial, vascular, renal risk categories, to address the differential nature of NSAIDs effects on different body systems. We are also reporting composite CV/renal risk to present overall risk associated with various covariates. We searched the online healthcare databases for observational studies or randomized controlled trials, reporting myocardial or all-cause mortality outcome (>90 days exposure) and/or vascular/renal outcomes (any exposure) after meloxicam use, published until April 2014. The combined odd ratio values (OR'; 95% CI) were c...
Xenobiotica, 1991
1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed ... more 1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry. 2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts. 3. Significant inter-individual differences in the metabolic pathways of doxapram were observed. 4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog. 5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2- pyrrolidinone (VII), 1-ethyl-4-[2-(4-morpholin-2-onyl)ethyl]-3,3-diphenyl-2-pyrro lidinone (IX) and 4-ethenyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).
Journal of Pharmaceutical Sciences, 1991
The chiral p-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major meta... more The chiral p-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major metabolite, diacetotol (DC), are chiral, the Senantiorner possessing p-blocking activity. The pharmacokinetics of AC and DC enantiomers was determined in 12 healthy subjects following oral administration of 200 mg of AC. Plasma and urine were collected over a 24-hr period and both AC and DC enantiomers were measured utilizing a stereospecific HPLC assay. Concentrations of S A C were predominant in both plasma and urine [AUC S:R, 1.20 2 0.1 ; cumulative urinary excretion (ZX,,) S:R, 1.17 ? 0.05), which corresponded to a significantly greater oral clearance of R-AC (106 ? 30 Uh) than S A C (87 t 22 Uh). The C,, of R-DC was significantly greater than for S D C (SIR 0.7 * 0.1). The half-life (t,,J of R-DC (6.4 * 1.6 h) was significantly shorter than that of S D C (8.8 ? 2.4 h). The observed AUC values for R-and S D C were not significantly different. Renal clearance of R-DC (70 2 34 mumin) was significantly greater than that of S D C (53 k 29 mumin). The data suggest that the first-pass metabolism of R-AC to R-DC is stereoselective. This metabolism, coupled with the stereoselective renal excretion of R-DC is likely a major contributor to the observed stereoselective disposition of AC and its major metabolite in humans.
Journal of Pharmaceutical Sciences, 1990
The Journal of Clinical Pharmacology, 2004
Inflammatory conditions decrease the cardiovascular response to calcium channel and β‐adrenergics... more Inflammatory conditions decrease the cardiovascular response to calcium channel and β‐adrenergics blockers due, likely, to down‐regulation of the receptors mediated by pro‐inflammatory mediators such as C‐reactive protein (CRP), nitric oxide (NO), and tumor necrosis factor. The purpose of this investigation was to determine whether down‐regulation is also evident in angiotensin II type 1 receptors (AT1R) during varying inflammatory states. Normotensive subjects were divided into three groups according to the severity of disease: 14 with active rheumatoid arthritis, 12 with controlled rheumatoid arthritis, and 12 healthy control subjects. The AT1R antagonist valsartan (160 mg) was given to all the subjects, and blood samples were taken for pharmacokinetic analysis. The systolic, diastolic, and mean arterial pressures were determined at all blood collection times. The degree of inflammation was measured using joint swelling, NO, and CRP. Plasma valsartan concentration was measured usi...
The Journal of Clinical Pharmacology, 1992
Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed... more Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed as racemates (i.e., an equal proportion of two enantiomers). Although enantiomers of racemic drugs often differ from one another in their pharmacodynamic and pharmacokinetic properties, bioequivalence assessments are made using nonstereospecific assays. Such an approach may provide a poor assessment of therapeutic equality. This can be true particularly for drugs with complicated pharmacokinetics and those that exhibit extensive stereoselectivity in their disposition kinetics. Accordingly, examples of bioequivalence studies based on stereospecific assays have started to appear in the literature. Fortunately, facile stereospecific assays have become available in the last several years for many drugs. Consequently, regulatory agencies have started to take the issue of stereochemistry into consideration in the assessment of bioequivalence, particularly from the standpoint of generic substitution.
The Journal of Clinical Pharmacology, 1992
The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 ±... more The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 ± 3.3 years), 6 nonarthritic elderly subjects (ages 73 ± 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R‐etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S‐enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali‐labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers...
Int. Journal of Clinical Pharmacology and Therapeutics, 2008
Pain or its associated trauma impairs oral absorption of drugs due, perhaps, to a diminished disi... more Pain or its associated trauma impairs oral absorption of drugs due, perhaps, to a diminished disintegration and dissolution rate secondary to suppression of the vagal nervous system. We first examined whether ibuprofen absorption is impaired on suppressing vagus nerve activity in a rat model. Secondly, we examined if ibuprofen absorption in rats during vagal suppression and in humans experiencing dental pain is improved by enhancing disintegration and dissolution rate of the administered formulation. Vagal suppression was achieved in rats by administering 20 mg/kg propantheline i.p. 2 h and 1 h before gastric gavage of 20 mg/kg ibuprofen as small crushed pieces of a regular release and a fast-dissolving ibuprofen caplets. In humans, after surgical removal of wisdom teeth and emergence of pain, 2 A 200 mg ibuprofen as regular released (n = 14) and fast-dissolving (n = 12) caplets were administered. Serial blood sample were collected for bioavailability studies. Vagal suppression resulted in significantly decreased absorption rate of ibuprofen enantiomers following administration of the regular release but not after fast-dissolving formulation. Human dental pain was associated with significantly slower absorption of ibuprofen enantiomers from the regular released as compared with the fast-dissolving caplets. Within the first hour post-dose the area under the plasma drug concentration-time curve was raised to 2.7-fold (p < 0.05) after the fast-dissolving as compared with the regular release formulations. There was a 1-h difference in the peak concentration time (tmax) between the two caplets. Impaired drug absorption appears to be due to slow disintegration and dissolution encountered during pain episodes.
Inflammopharmacology, 2009
Aims To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non... more Aims To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non-steroidal antiinflammatory drugs (NSAIDs) with short t 1/2 , and duration of therapy of NSAIDs on gastrointestinal permeability. Methodology 2.5 mg/(kg 12 h) flurbiprofen was administered as repeated oral and interperitoneal (i.p) doses or as i.p. osmotic pump (once implanted to mimic long t 1/2 ) for 7 days to healthy rats. Urinary excretion of 51 Cr-EDTA (days 0, 1, 4 and 7 during all regimens) and sucrose (days 0, 1 and 7 for i.p. doses) were measured as markers of gastroduodenal and intestinal permeability, respectively. Results Both i.p. regimens elevated 51 Cr-EDTA permeability suggestive of a systemic effect. There was no significant difference between the i.p regimens in 51 Cr-EDTA permeability. The first day 51 Cr-EDTA permeability was significantly higher for the oral than for the i.p. doses suggestive of a topcal effect. The effect became less potent with time despite continuous dosing indicating adaptation for both topical and systemic effects. None of the i.p. regimen altered sucrose permeability. Conclusion NSAID's potency to increase permeability reduces with time despite continuous dosing. Topical effect following oral dosing, and not the frequent peaking differentiates regimens from each other in elevating 51 Cr-EDTA permeability. The repeated dosing rather than the magnitude of t 1/2 may influence the gut safety profile of NSAIDs.
Equine Veterinary Journal, 2010
Clinical and Experimental Pharmacology and Physiology, 2006
SUMMARY Non‐steroidal anti‐inflammatory drugs (NSAIDs) cause renal side‐effects. In the present s... more SUMMARY Non‐steroidal anti‐inflammatory drugs (NSAIDs) cause renal side‐effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo‐oxygenase (COX)‐2‐selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration–time curve (AUC0−24) of rofecoxib and the change in sodium (r = –0.65; P < 0.02) and potassium (r = –0.82; P < 0.0006) excretion. The AUC0−24 of celecoxib was correlated with sodium (r = –0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.1...
British Journal of Pharmacology, 2003
Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of t... more Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of the drug. This coincides with reduced drug effects through an unknown mechanism. The effect of interferon‐induced acute inflammation on the pharmacokinetics and electrocardiogram of verapamil (20 mg kg−1, p.o.) and nifedipine (0.1 mg kg−1, i.v.) was studied in Sprague–Dawley rats. The effect of both acute and chronic inflammation on radioligand binding to cardiac L‐type calcium channels was also investigated. Acute inflammation resulted in increased plasma concentration of verapamil but had no effect on that of nifedipine. Verapamil binding to plasma proteins was unaffected. As has been reported for humans, the increased verapamil concentration coincided with a reduction in the degree to which PR interval is prolonged by the drug. The effect of nifedipine on PR interval was also reduced by inflammation. Maximum binding of 3H‐nitrendipine to cardiac cell membrane was significantly reduced ...
Biopharmaceutics & Drug Disposition, 1987
The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients afte... more The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day−1 Pharmacokinetic indices were found to be independent of the dose administered. The half‐life, volume of distribution and oral clearance of metronidazole were 9.5 ± 2.1 h, 0.732 ± 0.0941 kg−1 and 0.921 ± 0.175 (ml min−1) kg−1 (mean ± SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 ± 7.4 to 58.9 ± 5.2. Both plasma and urine data exhibited very large inter‐patient variations. However, intra‐patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations...
Journal of Pharmacy and Pharmaceutical Sciences, Feb 6, 2023
Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora o... more Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora of studies has revealed that inflammation and inflammatory mediators such as cytokines and chemokines are associated with altered expression and activity of various proteins such as those involved in drug metabolism, specifically cytochrome P450 enzymes (CYPs). Emphasis of most available reports is on the inflammationinduced downregulation of CYPs, subsequently an increase in their substrate concentrations, and the link between the condition and the inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha. However, reports also suggest that inflammation influences expression and/or activity of other proteins such as those involved in the drug-receptor interaction. These multifaced involvements render the clinical consequence of the inflammation unexpected. Such changes are shown in many inflammatory conditions including rheumatoid arthritis, Crohn's disease, acute respiratory illnesses as well as natural processes such as aging, among others. For example, some commonly used cardiovascular drugs lose their efficacy when patients get afflicted with inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Interestingly, this is despite increased concentration subsequent to reduced clearance. The observation is attributed to a simultaneous reduction in the expression of target receptor proteins such as the calcium and potassium channel and β-adrenergic receptor as well as the metabolic enzymes. This narrative review summarizes the current understanding and clinical implications of the inflammatory effects on both CYPs and drug-receptor target proteins.
European Journal of Drug Metabolism and Pharmacokinetics, Oct 1, 1985
Journal of Pharmacy and Pharmaceutical Sciences, Jul 30, 2020
COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory resp... more COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory responses with cytokine storm. This plays a major role in COVID-19 severity and poor disease prognosis, even death. Higher levels of inflammatory hallmarks including C-reactive protein, ferritin, D-dimers, and cytokines such as interleukin (IL) -6, IL-10 and tumor necrosis factor-α (TNF-α) have been reported. Many anti-viral drugs have been tried, but none were proven fully effective. Supportive care and management of the complications that are caused mainly by inflammation might be the key to greater survival rates and shorter hospitalization (e.g., the use of remdesivir, lopinavir, ritonavir, umifenovir (arbidol), oseltamivir, ganciclovir, favipiravir, darunavir, hydroxychloroquine, chloroquine, colchicine, azithromycin, anakinra, canakinumab, tocilizumab, siltuximab, sarilumab, Type 1 interferon, interferon β-1a, interferon α-2b, baricitinib, ruxolitinib, fedratinib, methylprednisolone and dexamethasone). However, the efficacy of these treatments still needs well-planned clinical trials. In such trials, careful attention must be paid to the duration of the treatment, the onset of beneficial effects, and the severity of the disease, otherwise, the outcomes may still remain inconclusive. Herein, we present a review of the current drugs, which are being used in the management of the disease and their anti-inflammatory properties. We also investigated if these drugs directly interact with Angiotensin-Converting Enzyme (ACE 2), which is a crucial component of the virus entry to the cells.
Value in Health, Oct 1, 2017
that NSAIDs use can cause cardiovascular (CV) complications. Studies have suggested that NSAIDs t... more that NSAIDs use can cause cardiovascular (CV) complications. Studies have suggested that NSAIDs tissue distribution may be associated with differences in their CV risk profiles. The purpose of this systematic review was to assess the overall CV risks while stratified into different categories of coronary, vascular and renal outcomes based on different tissue compartments. Meloxicam for instance is known for its limited tissue distribution, owing to zwitterion nature of its molecule, and hence its use exhibits least renal and CV implications. Methods: We conducted an online search in selected healthcare database (till June 2013) looking for comparative observational studies or randomized clinical trial, having meloxicam in their comparisons and reporting coronary outcome (upon > 90 days exposure) or vascular/ renal outcomes (upon any exposure). Our search recruited 2106 studies out of which 17 were eligible, reporting coronary (n= 5), vascular (n= 6) and renal (n= 6) outcomes. The odd ratio (OR, 95% CI) and relative risk (RR, 95% CI) data was abstracted and pooled using fixed effect inverse variance model Results: Meloxicam caused moderate but significant overall CV risk 1. 15 [1.05, 1.25] mainly due to an elevated vascular 1. 37 [1.21, 1.55] risk; however, the coronary 1. 00 [0.87, 1.14 and renal 0.83 [0.63, 1.11] risks were not increased. Rofecoxib causes the highest overall CV risk 1. 38 [1.29, 1.46] that includes higher coronary 1. 46 [1.10, 1.93], vascular 1.31 [1.21, 1.41] and renal 1.51 [1.35, 1.68] risks. Other NSAIDs increased the overall risk in the following order indomethacin> diclofenac> naproxen> celecoxib> ibuprofen. ConClusions: NSAIDs are heterogeneous in causing CV/renal risks in terms of both extent and the nature of their adverse effects. Meloxicam causes limited risk and its side effects are mainly of vascular in nature, hence, clinically manageable.
Pediatrics, 1987
Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminoph... more Eighteen infants with idiopathic apnea of prematurity refractory to therapeutic levels of aminophylline were treated with incremental doses of doxapram beginning at 0.5 mg/kg/h. Continuous recording of heart rate, thoracic impedance, and transcutaneous Po2 demonstrated that 47% of the infants satisfied objective response criteria at the lowest dose, 53% responded at 1.0 mg/kg/h, 65% at 1.5 mg/kg/h, 82% at 2.0 mg/kg/h, and 89% at the highest allowed dose of 2.5 mg/kg/h. The mean serum doxapram concentration at the response dose was 2.9 ± 1.3 µg/mL, and all infants who responded had levels greater than 1.5 µg/mL. BP was significantly elevated at doses higher than 1.5 mg/kg/h (P < .05). Minute ventilation significantly increased and Pco2 significantly decreased as the doxapram dosage was increased (P = .02). Terminal elimination half-life was 9.9 ± 2.9 hours. When doxapram is used for treatment of refractory neonatal apnea the starting dosage should be no more than 0.5 mg/kg/h.
Clinical Pharmacology & Therapeutics, 2004
Inflammatory conditions decrease cardiovascular response to β and Ca2+ channel blockers despite e... more Inflammatory conditions decrease cardiovascular response to β and Ca2+ channel blockers despite elevated drug levels due to downregulation of the receptors by inflammatory mediators. Whether downregulation is also evident with AT1R antagonists in RA was tested. The subjects were 14 active RA, 12 controlled RA and 12 healthy. Joint swelling, NO and C-reactive protein were measured. Valsartan (VAL) or losartan
Inflammopharmacology, 2015
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (... more Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (CV) and renal incidences, especially at higher doses and upon long term use. However, the available reports are criticized for lack of specificity, grouping of vastly different outcomes together and ignoring the heterogeneity among NSAIDs. In this systematic review, we are reporting CV/renal risks associated with meloxicam, stratified into myocardial, vascular, renal risk categories, to address the differential nature of NSAIDs effects on different body systems. We are also reporting composite CV/renal risk to present overall risk associated with various covariates. We searched the online healthcare databases for observational studies or randomized controlled trials, reporting myocardial or all-cause mortality outcome (>90 days exposure) and/or vascular/renal outcomes (any exposure) after meloxicam use, published until April 2014. The combined odd ratio values (OR'; 95% CI) were c...
Xenobiotica, 1991
1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed ... more 1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry. 2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts. 3. Significant inter-individual differences in the metabolic pathways of doxapram were observed. 4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog. 5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2- pyrrolidinone (VII), 1-ethyl-4-[2-(4-morpholin-2-onyl)ethyl]-3,3-diphenyl-2-pyrro lidinone (IX) and 4-ethenyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).
Journal of Pharmaceutical Sciences, 1991
The chiral p-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major meta... more The chiral p-blocker acebutolol (AC) is marketed as a racemic mixture. Both AC and its major metabolite, diacetotol (DC), are chiral, the Senantiorner possessing p-blocking activity. The pharmacokinetics of AC and DC enantiomers was determined in 12 healthy subjects following oral administration of 200 mg of AC. Plasma and urine were collected over a 24-hr period and both AC and DC enantiomers were measured utilizing a stereospecific HPLC assay. Concentrations of S A C were predominant in both plasma and urine [AUC S:R, 1.20 2 0.1 ; cumulative urinary excretion (ZX,,) S:R, 1.17 ? 0.05), which corresponded to a significantly greater oral clearance of R-AC (106 ? 30 Uh) than S A C (87 t 22 Uh). The C,, of R-DC was significantly greater than for S D C (SIR 0.7 * 0.1). The half-life (t,,J of R-DC (6.4 * 1.6 h) was significantly shorter than that of S D C (8.8 ? 2.4 h). The observed AUC values for R-and S D C were not significantly different. Renal clearance of R-DC (70 2 34 mumin) was significantly greater than that of S D C (53 k 29 mumin). The data suggest that the first-pass metabolism of R-AC to R-DC is stereoselective. This metabolism, coupled with the stereoselective renal excretion of R-DC is likely a major contributor to the observed stereoselective disposition of AC and its major metabolite in humans.
Journal of Pharmaceutical Sciences, 1990
The Journal of Clinical Pharmacology, 2004
Inflammatory conditions decrease the cardiovascular response to calcium channel and β‐adrenergics... more Inflammatory conditions decrease the cardiovascular response to calcium channel and β‐adrenergics blockers due, likely, to down‐regulation of the receptors mediated by pro‐inflammatory mediators such as C‐reactive protein (CRP), nitric oxide (NO), and tumor necrosis factor. The purpose of this investigation was to determine whether down‐regulation is also evident in angiotensin II type 1 receptors (AT1R) during varying inflammatory states. Normotensive subjects were divided into three groups according to the severity of disease: 14 with active rheumatoid arthritis, 12 with controlled rheumatoid arthritis, and 12 healthy control subjects. The AT1R antagonist valsartan (160 mg) was given to all the subjects, and blood samples were taken for pharmacokinetic analysis. The systolic, diastolic, and mean arterial pressures were determined at all blood collection times. The degree of inflammation was measured using joint swelling, NO, and CRP. Plasma valsartan concentration was measured usi...
The Journal of Clinical Pharmacology, 1992
Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed... more Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed as racemates (i.e., an equal proportion of two enantiomers). Although enantiomers of racemic drugs often differ from one another in their pharmacodynamic and pharmacokinetic properties, bioequivalence assessments are made using nonstereospecific assays. Such an approach may provide a poor assessment of therapeutic equality. This can be true particularly for drugs with complicated pharmacokinetics and those that exhibit extensive stereoselectivity in their disposition kinetics. Accordingly, examples of bioequivalence studies based on stereospecific assays have started to appear in the literature. Fortunately, facile stereospecific assays have become available in the last several years for many drugs. Consequently, regulatory agencies have started to take the issue of stereochemistry into consideration in the assessment of bioequivalence, particularly from the standpoint of generic substitution.
The Journal of Clinical Pharmacology, 1992
The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 ±... more The pharmacokinetics of the enantiomers of etodolac were studied in six young subjects (ages 28 ± 3.3 years), 6 nonarthritic elderly subjects (ages 73 ± 6.0 years), and in three cholecystectomy patients after single oral doses of the racemate (200 mg). In all subjects, the plasma concentrations of R‐etodolac, which is pharmacologically inactive, greatly exceeded those of the pharmacologically active S‐enantiomer. Stereoselectivity was reflected in the pharmacokinetics, with R > S for maximum peak plasma concentration and area under the concentration versus time curve, and S > R for apparent oral clearance and apparent volume of distribution. On average, less than 25% of the dose of each enantiomer was excreted in the urine within 24 hours as alkali‐labile conjugates; little or no unchanged drug was recovered. Bile constituted a minor route of elimination of etodolac as conjugated enantiomers. There were no significant differences in the pharmacokinetics of etodolac enantiomers...
Int. Journal of Clinical Pharmacology and Therapeutics, 2008
Pain or its associated trauma impairs oral absorption of drugs due, perhaps, to a diminished disi... more Pain or its associated trauma impairs oral absorption of drugs due, perhaps, to a diminished disintegration and dissolution rate secondary to suppression of the vagal nervous system. We first examined whether ibuprofen absorption is impaired on suppressing vagus nerve activity in a rat model. Secondly, we examined if ibuprofen absorption in rats during vagal suppression and in humans experiencing dental pain is improved by enhancing disintegration and dissolution rate of the administered formulation. Vagal suppression was achieved in rats by administering 20 mg/kg propantheline i.p. 2 h and 1 h before gastric gavage of 20 mg/kg ibuprofen as small crushed pieces of a regular release and a fast-dissolving ibuprofen caplets. In humans, after surgical removal of wisdom teeth and emergence of pain, 2 A 200 mg ibuprofen as regular released (n = 14) and fast-dissolving (n = 12) caplets were administered. Serial blood sample were collected for bioavailability studies. Vagal suppression resulted in significantly decreased absorption rate of ibuprofen enantiomers following administration of the regular release but not after fast-dissolving formulation. Human dental pain was associated with significantly slower absorption of ibuprofen enantiomers from the regular released as compared with the fast-dissolving caplets. Within the first hour post-dose the area under the plasma drug concentration-time curve was raised to 2.7-fold (p < 0.05) after the fast-dissolving as compared with the regular release formulations. There was a 1-h difference in the peak concentration time (tmax) between the two caplets. Impaired drug absorption appears to be due to slow disintegration and dissolution encountered during pain episodes.
Inflammopharmacology, 2009
Aims To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non... more Aims To test the influence of frequent concentration peaking, as occurs in multiple-dosing of non-steroidal antiinflammatory drugs (NSAIDs) with short t 1/2 , and duration of therapy of NSAIDs on gastrointestinal permeability. Methodology 2.5 mg/(kg 12 h) flurbiprofen was administered as repeated oral and interperitoneal (i.p) doses or as i.p. osmotic pump (once implanted to mimic long t 1/2 ) for 7 days to healthy rats. Urinary excretion of 51 Cr-EDTA (days 0, 1, 4 and 7 during all regimens) and sucrose (days 0, 1 and 7 for i.p. doses) were measured as markers of gastroduodenal and intestinal permeability, respectively. Results Both i.p. regimens elevated 51 Cr-EDTA permeability suggestive of a systemic effect. There was no significant difference between the i.p regimens in 51 Cr-EDTA permeability. The first day 51 Cr-EDTA permeability was significantly higher for the oral than for the i.p. doses suggestive of a topcal effect. The effect became less potent with time despite continuous dosing indicating adaptation for both topical and systemic effects. None of the i.p. regimen altered sucrose permeability. Conclusion NSAID's potency to increase permeability reduces with time despite continuous dosing. Topical effect following oral dosing, and not the frequent peaking differentiates regimens from each other in elevating 51 Cr-EDTA permeability. The repeated dosing rather than the magnitude of t 1/2 may influence the gut safety profile of NSAIDs.
Equine Veterinary Journal, 2010
Clinical and Experimental Pharmacology and Physiology, 2006
SUMMARY Non‐steroidal anti‐inflammatory drugs (NSAIDs) cause renal side‐effects. In the present s... more SUMMARY Non‐steroidal anti‐inflammatory drugs (NSAIDs) cause renal side‐effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo‐oxygenase (COX)‐2‐selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration–time curve (AUC0−24) of rofecoxib and the change in sodium (r = –0.65; P < 0.02) and potassium (r = –0.82; P < 0.0006) excretion. The AUC0−24 of celecoxib was correlated with sodium (r = –0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.1...
British Journal of Pharmacology, 2003
Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of t... more Rheumatoid arthritis reduces verapamil oral clearance thereby increases plasma concentration of the drug. This coincides with reduced drug effects through an unknown mechanism. The effect of interferon‐induced acute inflammation on the pharmacokinetics and electrocardiogram of verapamil (20 mg kg−1, p.o.) and nifedipine (0.1 mg kg−1, i.v.) was studied in Sprague–Dawley rats. The effect of both acute and chronic inflammation on radioligand binding to cardiac L‐type calcium channels was also investigated. Acute inflammation resulted in increased plasma concentration of verapamil but had no effect on that of nifedipine. Verapamil binding to plasma proteins was unaffected. As has been reported for humans, the increased verapamil concentration coincided with a reduction in the degree to which PR interval is prolonged by the drug. The effect of nifedipine on PR interval was also reduced by inflammation. Maximum binding of 3H‐nitrendipine to cardiac cell membrane was significantly reduced ...
Biopharmaceutics & Drug Disposition, 1987
The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients afte... more The pharmacokinetics of metronidazole (MTZ) were studied in six Crohn's disease patients after multiple oral daily doses of 250, 500, 750, and 1000 mg day−1 Pharmacokinetic indices were found to be independent of the dose administered. The half‐life, volume of distribution and oral clearance of metronidazole were 9.5 ± 2.1 h, 0.732 ± 0.0941 kg−1 and 0.921 ± 0.175 (ml min−1) kg−1 (mean ± SD), respectively. A strong linear correlation (r = 0.95) was found between the volume of distribution of MTZ and the patients' total body weight. The percentage of dose of metronidazole excreted in urine as the intact drug and metabolites as well as glucuronic acid conjugates ranged from 34.7 ± 7.4 to 58.9 ± 5.2. Both plasma and urine data exhibited very large inter‐patient variations. However, intra‐patient variations were negligible. Strong positive linear correlations were observed between the dose and the areas under the plasma concentration versus time curves, peak plasma concentrations...