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F Jamali

Publications and source records attributed to F Jamali.

At least 37 records · Page 2Linked to original sources
PubMed1998

Motion detection and correction using multi-rotation 180 degrees single-photon emission tomography for thallium myocardial imaging.

Patient and organ motion is a potentially limiting factor in gamma camera single-photon emission tomography (SPET) imaging, as highlighted in stress thallium myocardial SPET, where the heart may exhibit a systematic axial motion (cardiac creep) following stress. Multi-rotation SPET has previously been described as a means of obtaining better raw data for motion detection and correction. This study describes the validation of a computerised motion detection algorithm applied to multi-rotation SPET, and reports measured motions in thallium myocardial stress SPET studies from a single-headed gamma camera. Forty-two patients underwent pharmacological stress (dipyridamole) with leg raising, with injection of 75 MBq thallium-201 and imaging after a 10-min delay to detect or evaluate coronary artery disease. Multi-rotation gamma camera SPET was performed with a single-headed gamma camera, with five sequential rapid (4.5 min) continuous SPET mode rotations over 180 degrees. A one-dimensional cross-correlation alignment technique was applied to the projection images to perform motion detection and correction in the axial direction prior to combining the five data sets for tomographic reconstruction. Validation of the cross-correlation alignment analysis was carried out by performing imaging with measured whole-body axial motions in nine subjects, and by reproducibility measurements on multi-rotation data sets. The effect of the applied motion correction was evaluated by calculating mean differences between image pairs before and after shifting, and the general reliability of the automatic motion detection was checked to within one pixel by visual assessment of 160 image pairs. Validation measurements of the cross-correlation technique gave a mean absolute error of 1.5+/-0.4 mm (0.24+/-0.06pixels) with a maximum error of 3.7 mm (0.6 pixels). In 40 subjects undergoing pharmacological stress 201Tl myocardial SPET imaging, the mean cardiac axial creep movement was calculated as 3.1+/-0.7 mm (0. 49+/-0.11 pixels), with 13 out of 40 (32%) having a calculated motion of 1 pixel (6.3 mm) or more. The automatic image shift was visually judged to be within 1 pixel in all 160 image pair analyses, and the mean pixel value difference between image pairs was reduced following image shifting. It is concluded that multi-rotation 180 degrees SPET imaging provides raw data which allow objective and accurate motion detection of cardiac motion in thallium stress myocardial imaging, whilst the one-dimensional cross-correlation technique demonstrates adequate accuracy and reliability to be applied as an automatic motion screening technique on these data.

Dipyridamole↗
PubMed1998

Effect of experimental diabetes mellitus and arthritis on the pharmacokinetics of hydroxychloroquine enantiomers in rats.

PURPOSE: To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. METHODS: The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. RESULTS: Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 +/- 0.15 and 1.3 +/- 0.19 l/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 +/- 0.32 and 1.93 +/- 0.34 l/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. CONCLUSIONS: Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.

Animals↗
PubMed1997

Stereospecific determination of mefloquine in biological fluids by high-performance liquid chromatography.

A sensitive stereoselective HPLC method was developed for determination of mefloquine (MFQ) enantiomers in plasma, urine and whole blood. The assay involved liquid-liquid extraction of MFQ from biological fluids with a mixture of hexane and isopropanol in the presence of sodium hydroxide and derivatization of the residue by (+)-(S)-naphthylethylisocyanate (NEIC) as chiral derivatizing reagent. Separation of the resulting diastereomers was performed on a silica normal-phase column using chloroform-hexane-methanol (25:74:1) as the mobile phase with a flow-rate of 1 ml/min. Using 200 microl of plasma or whole blood, the limit of determination was 0.2 microg/ml with UV detection for both enantiomers. The limit of determination in 500 microl of urine was 0.08 microg/ml with UV detection.

Animals↗
PubMed1997

Pharmacokinetics and multiple peaking of acebutolol enantiomers in rats.

Acebutolol (AC) is a chiral beta-blocker which is extensively metabolized to an active, chiral metabolite, diacetolol (DC). Similar to some other beta-adrenoceptors, AC exhibits multiple peaks in plasma concentration-time curves after oral doses to humans. We examined the suitability of the rat as an animal model and studied the effect of various factors including the route of administration, food, and bile on the pharmacokinetics of AC enantiomers. Pharmacokinetics of AC were delineated after oral (fed and fasted), i.v., and i.p. doses, and after oral and i.v. doses, to intact and bile-duct-ligated female Sprague-Dawley rats, respectively. The possibility of intestinal metabolism or saturable absorption was studied in vitro using everted rat gut. Multiple peaks were present but only after oral doses independent of food intake, suggestive of gastrointestinal tract involvement. Oral absorption of AC enantiomers was incomplete as bioavailability was lower after oral (R, 0.59; S, 0.63) as compared to i.p. off(R, 0.86; S, 0.84) doses. Food reduced bioavailability by 60%. A 250-fold increase in the dose did not alter the absorption kinetics of AC through the everted gut, ruling out the possibility of saturable absorption. No intestinal metabolism was detected in vitro. Enterohepatic recirculation cannot be responsible as ligation of the bile duct did not alter the pattern or route dependence of the multiple peaking. The rat appears to be a suitable animal model; a bile- and food-independent erratic absorption is probably responsible for the observed multiple peaking of AC.

Acebutolol↗
PubMed1997

Bi-directional chiral inversion of ketoprofen in CD-1 mice.

The R enantiomers of some of the 2-arylpropionic acid non-steroidal antiinflammatory drugs (NSAIDs) are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. The S to R chiral inversion, on the other hand, is rare and has been observed, in substantial extents, only for ibuprofen in guinea pigs and 2-phenylpropionic acid in dogs. After i.p. administration of single doses of racemic ketoprofen or its optically pure enantiomers to male CD-1 mice and subsequent study of the concentration time-course of the enantiomers, we noticed substantial chiral inversion in both directions. Following racemic doses, no stereoselectivity in the plasma-concentration time courses was observed. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated during the absorption phase. During the terminal elimination phase, however, the enantiomers had the same concentrations. Our observation is suggestive of a rapid and reversible chiral inversion for ketoprofen enantiomers in mice.

Animals↗
PubMed1997

Toxicokinetics of indomethacin-induced intestinal permeability in the rat.

Numerous studies in humans have demonstrated increases in intestinal permeability resulting from the administration of non-steroidal anti-inflammatory drugs (NSAIDs). The increased permeability correlates well with ulceration. The time course of the changes in intestinal permeability, however, has not been studied, which makes comparative studies between different NSAIDs or different formulations of the same drug difficult. In the present study we have administered single doses of indomethacin to examine both the time course and pharmacokinetic/pharmacodynamic relationships of intestinal permeability in rats estimated by following the urinary excretion of [51Cr]-EDTA. The change in intestinal permeability was both time- and dose-dependent. Following both 10 mg kg-1 and 20 mg kg-1 oral doses of indomethacin, there was a rapid rise in intestinal permeability to a maximum level, after at least 12 h post-dose, which is longer than those previously observed for ibuprofen, ketoprofen, flurbiprofen and naproxen. The maximal effect lasted 12 and 36 h following 10 and 20 mg kg-1 doses, respectively. The side-effect-plasma concentration relationship demonstrated a counter-clockwise hysteresis. The relationship between the observed side-effect and the estimated deep effect compartment concentration was, on the other hand, linear. In comparative permeability studies of NSAIDs the time of administration, concentration and drug dependencies should be considered.

Animals↗
PubMed1997

Influence of dosage form on the gastroenteropathy of flurbiprofen in the rat: evidence of shift in the toxicity site.

PURPOSE: Gastroduodenal and intestinal permeability were compared after single doses of sustained release and regular release flurbiprofen in the rat to assess possible site-specific formulation-dependent toxicity. METHODS: Pharmacokinetics was assessed and gastrointestinal permeability was evaluated using sucrose and 51Cr-EDTA as gastroduodenal and intestinal permeability probes, respectively. RESULTS: The two formulations demonstrated equal areas under the flurbiprofen concentration-time curve. The sustained release formulation peaked 2-3 h slower with 57-74% lower concentrations than regular release formulation. In comparison, the regular release powder induced greater gastroduodenal permeability while sustained release granules induced greater intestinal permeability. When S-flurbiprofen concentrations were plotted versus intestinal permeability, a linear relationship and an anti-clockwise hysteresis were obtained for regular and sustained release formulations, respectively. CONCLUSIONS: Sustained release formulations of flurbiprofen demonstrate reduced gastroduodenal permeability but shift the site of this side-effect to the more distal intestine.

Administration, Oral↗
PubMed1997

Application of a neural network for gentamicin concentration prediction in a general hospital population.

Neural network (NN) computation is computer modeling based in part on simulation of the structure and function of the brain. These modeling techniques have been found useful as pattern recognition tools. In the present study, data including age, sex, height, weight, serum creatinine concentration, dose, dosing interval, and time of measurement were collected from 240 patients with various diseases being treated with gentamicin in a general hospital setting. The patient records were randomly divided into two sets: a training set of 220 patients used to develop relationships between input and output variables (peak and trough plasma concentrations) and a testing set (blinded from the NN) of 20 to test the NN. The network model was the back-propagation, feed-forward model. Various networks were tested, and the most accurate networks for peak and trough (calculated as mean percent error, root mean squared error of the testing group, and tau value between observed and predicted values) were reported. The results indicate that NNs can predict gentamicin serum concentrations accurately from various input data over a range of patient ages and renal function and may offer advantages over traditional dose prediction methods for gentamicin.

Adolescent↗
PubMed1997

Pharmacological protection of NSAID-induced intestinal permeability in the rat: effect of tempo and metronidazole as potential free radical scavengers.

Recently, NSAID-induced changes in both the structure and function of the distal intestine have been found to occur more frequently and with greater toxicological significance than previously thought. We have previously validated a suitable animal model to evaluate intestinal permeability changes using orally administered 51Cr-EDTA that correlates with intestinal ulceration. In this study we investigated the suitability of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal permeability. Male Sprague-Dawley rats were dosed with two doses of metronidazole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tempo 1 h prior to NSAIDs. The urinary excretion of the orally administered marker 51Cr-EDTA was measured. Both tempo and metronidazole dramatically reduced indomethacin (20 mg/kg) and flurbiprofen (10 mg/kg)-induced intestinal permeability. All the animals exposed to indomethacin alone died within 48-96 h and presented with histological evidence of drug-induced enteropathy, ulceration and frank peritonitis. Protection by tempo and metronidazole suggests that free radicals and/or bacteria may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomitantly with NSAIDs may protect gastrointestinal tract.

Administration, Oral↗
PubMed1997

Bioequivalence of chiral drugs. Stereospecific versus non-stereospecific methods.

Guidelines for bioequivalence of non-racemic pharmaceuticals are abundant in the literature. However, few guidelines exist for the bioequivalence of racemic drugs which consist of 2 or more stereoisomers. The aim of this article is to address the question of whether the bioequivalence of racemic drugs should be based on the measurement of the individual enantiomers or that of the total drug. Several pharmacokinetic-pharmacodynamic cases are examined to test the validity of extrapolating the bioequivalence of racemic drugs to that of their individual enantiomers after administration of the racemate; simulation and experimental data are presented to support these cases. It is shown that for drugs which exhibit non-linear pharmacokinetics, the results of bioequivalence studies based on the total drug may differ from those based on the individual enantiomers. Similar discrepancies can be shown for a racemic drug with linear pharmacokinetics whose enantiomers substantially differ from each other in their pharmacokinetic parameters. Therefore, it is suggested that stereospecific assays be used for these drugs. Additionally, it is recommended that for racemic drugs which undergo chiral inversion, and for most products with modified release characteristics, the bioequivalence be assessed using stereospecific assays. Conversely, for racemic drugs with linear pharmacokinetics and minimal to modest stereoselectivity in their kinetic parameters, and for those with non-stereoselective pharmacodynamics, the use of stereospecific analytical methods are not warranted. Finally, the limited, controversial literature in favour of or against the use of stereospecific assays in bioequivalence of chiral drugs are reviewed and a preliminary guideline is proposed.

Adrenergic Uptake Inhibitors↗
PubMed1996

Rapid, sensitive and direct chiral high-performance liquid chromatographic method for ketoprofen enantiomers.

The stereospecific HPLC assays reported for ketoprofen (KT) mainly utilize indirect approaches. These assays involve the formation of amide diastereomeric derivatives, which are then separated by chromatography. The advantages of indirect methods include versatility, good sensitivity and cost effectiveness; however, lengthy preparation time is often required. Therefore, we have developed a new direct stereospecific HPLC assay for KT enantiomers to improve preparation time and sensitivity. The KT enantiomers and indomethacin, internal standard (I.S.), were resolved using a Chiralpac AD column attached to 5 cm Supelcosil LC-SI at constant temperature (30 degrees C). The mobile phase consisted of hexane-isopropanol-trifluoroacetic acid (90:10:0.1). Under chromatographic conditions employed R-KT, S-KT and I.S. were eluted at 12, 14 and 16 min, respectively. A linear concentration response relationship was found (0.05-5.0 micrograms/ml of enantiomers) which covered normally observed concentrations in plasma after conventional doses of KT. The minimum quantifiable concentration of the assay was found to be 0.025 or 0.25 microgram/ml based on 1 ml of human or 0.1 ml of rat plasma samples, respectively. This direct HPLC method is suitable for pharmacokinetic studies of KT enantiomers and offers the advantages of shorter sample preparation and run time. This method is at least as sensitive as assays currently in use.

Animals↗
PubMed1996

Nonsteroidal antiinflammatory drug-induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis.

This report describes the case of a woman who was admitted to the hospital with severe anemia and refractory rheumatoid arthritis. She had been transfusion dependent for 8 years and was receiving a combination of indomethacin and naproxen. An indium-111 white blood cell scan revealed small bowel inflammation. Salsalate was substituted for her previous nonsteroidal antiinflammatory drugs (NSAIDs), and metronidazole was initiated. This resulted in maintenance of a normal hemoglobin level for at least 1 year after discharge. Small intestine inflammation and bleeding (enteropathy) due to NSAIDs must be considered in the evaluation of anemia in patients with arthritis.

Aged↗
PubMed1996

Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation.

A case involving a 27-year-old woman who ingested an overdose of acebutolol is presented. Extracorporeal membrane oxygenation was initiated to stabilize the patient's condition before commencing hemodialysis. S-diacetolol (the N-acetelation product of acebutolol) was cleared with hemodialysis. It is suggested that extracorporeal membrane oxygenation may be of short-term benefit in the treatment of overdoses with beta-adrenergic agents such as acebutolol when accelerated clearance with hemodialysis is anticipated.

Acebutolol↗
PubMed1996

Pharmacokinetics of tiaprofenic acid in humans: lack of stereoselectivity in plasma using both direct and precolumn derivatization methods.

A new direct stereospecific HPLC method was developed to assay tiaprofenic acid (TA) enantiomers in plasma. It has been reported previously that TA exhibits nonstereoselective pharmacokinetics in humans using an indirect stereospecific HPLC assay. The indirect assay involves formation of diastereomers through reaction of the carboxylic acid moiety with a coupling reagent, 2,2,2-trichloroethyl chloroformate, to form a mixed anhydride, followed by formation of an amide using L-leucinamide. A recent report suggests the possibility of the existence of a small but significant difference between the pharmacokinetics of TA enantiomers in humans when a direct HPLC method was used for analysis of plasma samples. The discrepancy between the two reports may be explained by partial or complete chiral conversion during derivatization. We have studied the possibility of racemization using both direct and indirect methods. In addition, the pharmacokinetics of TA enantiomers were compared after single oral doses of 300 mg of TA administered to 4 healthy volunteers as a conventional tablet and a sustained release formulation using both assays. The reported direct HPLC assay is suitable for analysis of plasma samples as reflected from small intra- and interday coefficients of variation (< 10%) and suitable sensitivity (0.025 micrograms/mL). There was no chiral conversion when a stereochemically pure (> 98.6%) enantiomer was subjected to the direct method. The derivatization of the enantiomers with L-leucinamide, however, resulted in approximately 7% chiral conversion. Nevertheless, the plasma concentration--time profiles of (R)- and (S)-TA were not significantly different using either methods. This finding indicates that both direct and indirect HPLC methods are suitable for pharmacokinetic study of TA enantiomers. There is no evidence for the existence of stereoselectivity in the disposition kinetics of TA enantiomers in humans.

Adult↗
PubMed1996

Effect of the enantiomers of flurbiprofen, ibuprofen, and ketoprofen on intestinal permeability.

Numerous studies have demonstrated that the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) increases small intestinal permeability, and this has been suggested to be a prerequisite to enteropathy. It is believed that the inhibitory effect of chiral NSAIDs on the synthesis of prostaglandins and hence their efficacy and toxicity are mainly due to the S enantiomer. Using the urinary excretion of [51Cr]-EDTA, we have investigated the effects of three nonsteroidal anti-inflammatory drugs (flurbiprofen, ibuprofen, and ketoprofen) on small intestinal permeability in rats. Single doses of each NSAID were administered orally as either the racemate or the R or S enantiomer, the enantiomer dose being half that of the racemate. Each treatment caused a significant increase in intestinal permeability above that seen in untreated animals. The R enantiomers of all three NSAIDs increased small intestinal permeability significantly above base line, which was expected for (R)-ketoprofen and (R)-ibuprofen due to substantial chiral R to S inversion. The intestinal permeability for (R)-flurbiprofen, although minimal and likely due to 10% inversion, may also suggest prostaglandin-independent involvement. Furthermore, (S)-flurbiprofen, used at one-half the dose of the racemate, increased permeability to a similar magnitude as the racemate. This observation was similar to that previously reported for etodolac. A stereochemically pure enantiomer does not necessarily offer a safer alternative than its racemic form.

Animals↗
PubMed1996

The influence of renal function on the pharmacokinetics of unchanged and acyl-glucuroconjugated ketoprofen enantiomers after 50 and 100 mg racemic ketoprofen.

1. To study the effect of renal dysfunction on the pharmacokinetics of ketoprofen (KT), and the possibility of saturation of clearance with elevation of dose, single 50 and 100 mg doses of racemic ketoprofen were administered in a cross-over fashion to seven patients (creatinine clearance, CLCR, 6-72 ml min-1). 2. The stereospecific disposition kinetics of KT enantiomers and their acyl-glucuronide conjugates (KTconj) were determined in plasma and urine for 24 h post-dose. 3. Decreased renal function was associated with a reduced KT oral clearance (CLO) and terminal elimination rate constant (lambda z). Renal clearance of KT conj (CLrconj) was reduced with diminished renal function. 4. Following both 50 and 100 mg doses, there was significant stereoselectivity in the AUC of KT (mean S/R, 0.87 and 0.83, respectively), the AUC of KTconj (mean S/R, 3.4 and 5.2, respectively) and the cumulative urinary excretion of KTconj (mean S/R, 2.1 and 2.2, respectively). The stereoselectivity in renal dysfunction in contrast with the observations previously made in healthy subjects may suggest a disease-related process. 5. CLO remained constant after increasing the dose, indicating linearity in the pharmacokinetics of KT despite reduced CLCR. CLrconj, however, was significantly reduced after the 100 mg dose suggestive of saturation of the urinary clearance and existence of a compensatory pathway. 6. Renal impairment reduces CLrconj and this appears to be the rate-limiting step for clearance of KT due to the observed stronger correlations of CLO with CLrconj than with CLCR. 7. Dose reduction of ketoprofen is indicated only for patients with CLCR < 20 ml min-1.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Twice daily nizatidine or ranitidine is superior to once daily dosing in elevating 24 h intragastric pH in patients with duodenal ulcer disease.

The present study was performed in six asymptomatic patients with a history of resistant duodenal ulcers in whom 24 h intragastric pH, gastric juice pepsin and PGE2 concentrations, as well as serum gastrin concentrations, were measured. We wanted to compare the effects on these parameters of a single night time (q.h.s.) dose of nizatidine 300 mg (N1), nizatidine 300 mg b.i.d. (N2), ranitidine 300 mg q.h.s. (R1) or ranitidine 300 mg b.i.d. (R2) compared with placebo (P). During the night (22.00-08.00 h), all treatments gave a higher mean pH than P, but during the day (08.00-22.00 h) the mean pH was higher than P only for patients administered R2 and N2. Doubling the dose of nizatidine (N2 vs N1) or ranitidine (R2 vs R1) increased the mean daytime pH, but had no effect on night time pH. The daytime pepsin concentration was unaffected by H2-receptor antagonists, while night time pepsin was lower with R1 and R2, but not with N1 or N2. The night time gastrin concentration was unaffected by H2-receptor antagonists; doubling the dose of the H2-receptor antagonist (R2 vs R1 and N2 vs N1) increased daytime gastrin concentration. During the night, each treatment increased PGE2 concentration by at least six-fold compared with P. Thus, where it is therapeutically indicated to achieve greater suppression of acid secretion, doubling the total daily dose by dosing with twice daily versus once daily night time nizatidine or ranitidine is efficacious.

Adult↗