Biomedical subjects

I Mahmood

Publications and source records attributed to I Mahmood.

At least 55 records · Page 3Linked to original sources

PubMed1997

A limited sampling approach in bioequivalence studies.

A limited sampling model (LSM) has been developed for an antidepressant immediate-release product (Drug A) and an antiepileptic controlled release product (Drug B) to predict the area under the curve (AUC) and the maximum plasma concentration (Cmax) and to compare the bioequivalence of two formulations of each drug using predicted versus observed AUC and Cmax after a single oral dose. The LSM for drug A was developed using data from 10 healthy people. The correlation between plasma concentration (independent variable) at selected time points with the AUC or Cmax (dependent variable) was evaluated by simple regression analysis. The linear regression that gave the best correlation coefficient (r) for a single sampling time versus AUC or Cmax was chosen as the LSM. The model provided good estimates of AUC and Cmax for drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were as follows: AUC observed = 100% to 118%, AUC predicted = 101% to 117%, Cmax observed = 99% to 125%, and Cmax predicted = 100% to 131%. The LSM for drug B was developed using a similar approach to drug A. The 90% confidence interval on log transformed observed and predicted AUC and Cmax were: AUC observed = 99% to 110%, AUC predicted = 99% to 118%, Cmax observed = 107% to 120%, and Cmax predicted = 99% to 111%. Although the predicted Cmax did not meet the 90% confidence interval for drug A, the method described here may be used to estimate AUC and Cmax for a drug in bioequivalence studies without detailed blood sampling. More research is needed in this direction.

Anticonvulsants↗

PubMed1997

Clinical pharmacokinetics and pharmacodynamics of selegiline. An update.

Selegiline is a selective inhibitor of monoamine oxidase-B (MAO-B) at a dose of 10 mg/day and is given to patients with Parkinson's disease as an adjunct to levodopa therapy. By inhibiting MAO-B, selegiline increases the dopamine levels in the substantia nigra. Selegiline also blocks dopamine re-uptake from the synaptic cleft, thus increasing the dopamine concentrations in the brain. At a dose of 10 mg/day, selegiline is devoid of 'cheese effect'. The pharmacokinetics of selegiline are highly variable. Following an oral dose of selegiline 10 mg, it is rapidly absorbed and metabolised to desmethylselegiline, levoamphetamine and levomethamphetamine. The mean peak plasma concentration (Cmax) is approximately 2 micrograms/L and the time to reach the peak is under an hour. The absolute bioavailability of selegiline is approximately 10%. It has an apparent volume of distribution of 1854 L. The oral clearance of selegiline (59 L/min) is many fold higher than the liver blood flow (1.5 L/min), indicating that extrahepatic processes are involved in the elimination of selegiline. The elimination half-life of selegiline is about 1.5 hours. Following multiple administration of selegiline 10 mg/day, the accumulation of both the parent compound and its metabolites have been reported. At least a 4-fold increase in the half-lives of selegiline and desmethylselegiline has been reported. There is at least a 3-fold increase in the Cmax and area under the concentration-time curve of selegiline with food. One of the metabolites of selegiline, desmethylselegiline, is believed to posses some MAO-B inhibitory property, though to a lesser extent than that of selegiline. Within 2 to 4 hours of an oral dose of selegiline 10 mg, 86% of the platelet MAO-B activity was inhibited and it took almost 2 weeks for platelet MAO-B activity to return to the baseline values. Transdermal administration of selegiline resulted in an increase in the plasma concentrations of selegiline and a decrease in the formation of its metabolites, indicating that the extensive first-pass effect is avoided when selegiline is given transdermally.

Administration, Cutaneous↗

PubMed1996

Interspecies scaling: a comparative study for the prediction of clearance and volume using two or more than two species.

The prediction of pharmacokinetic parameters in humans from data obtained in lower animals can be of considerable importance in the process of drug development. Successful extrapolation will facilitate drug dosing transitions from animals to man and accelerate the drug testing process. Existing literature indicates that for the prediction of pharmacokinetic parameters, data from at least three animal species are used. Some investigators have used only two species to predict clearance and volume in humans. The objective of this paper is to investigate and try to determine if a two species scale-up model is as reliable as a three or more species model. Twelve compounds were chosen randomly from literature and clearance and volume of distribution were scaled-up from two species and compared to predictions obtained from more than two species. The findings in this study indicate that: (1) three or more species are needed for a reliable prediction of clearance; and (2) volume of distribution of a compound is predicted equally well using data from two species or more.

Animals↗

PubMed1996

Interspecies scaling: predicting pharmacokinetic parameters of antiepileptic drugs in humans from animals with special emphasis on clearance.

The objective of this study was to test the interspecies-scaling approach in a series of antiepileptic drugs. Clearance, volume of distribution, and elimination half-life were scaled up from animal data obtained from literature. Four different methods were utilized to generate plots to scale up the clearance values: (i) clearance vs body weight (simple allometric equation); (ii) the product of clearance and maximum life-span potential (MLP) vs body weight (an approach recommended in literature); (iii) the two-term power equation which incorporates both body weight and brain weight suggested by Boxenbaum; and (iv) the product of clearance and brain weight vs body weight (a new approach being introduced in this study). When the predicted values for clearance were qualitatively compared with the observed values in humans, it was found that our proposed method predicted the clearance better than the other three methods. Using the simple allometric equation, the prediction of volume of distribution as a function of body weight was found to be satisfactory. The elimination half-life could not be predicted from simple allometric equations for any of the drugs studied; however, utilizing the equation CL = VK, prediction for half-life was feasible. The results of this study indicate that it is possible to predict reliably the pharmacokinetic parameters of these antiepileptic drugs in humans from animal data using an allometric approach.

Animals↗

PubMed1996

Pharmacokinetic analysis of the absorption characteristics of diclofenac sodium in man by use of a multi-segment absorption model.

The pharmacokinetic analysis of an oral sustained-release preparation of diclofenac sodium has been investigated using multi-segment absorption models in which it has been assumed that the gastrointestinal tract can be divided into several segments in each of which the drug has its own lag-time and absorption rate constants. Plasma concentration-time data for sustained release diclofenac sodium in man were fitted both by a conventional pharmacokinetic method assuming first-order absorption and by a multi-segment absorption model. The plasma concentration of diclofenac sodium calculated on the basis of the multi-segment absorption model was found to correlate with the observed plasma concentration. It was concluded that diclofenac sodium data can be better described by a multi-segment absorption model than by a conventional pharmacokinetic model. The results also show that multi-segment absorption models are suitable for pharmacokinetic analysis of plasma drug-concentration data with irregular or multiple peaks in the absorption profiles, and also for the pharmacokinetic analysis of sustained-release preparations.

Adult↗

PubMed1996

Interspecies scaling: predicting clearance of drugs in humans. Three different approaches.

1. The interspecies scaling approach to predict clearance in humans from animal data was tested for a wide variety of drugs. 2. Three different methods were utilized to generate plots to scale-up the clearance values: (i) method I, clearance versus body weight (simple allometric equation); (ii) method II, product of clearance and maximum life-span potential; (iii) method III, product of clearance and brain weight versus body weight. 3. The circumstances under which the three methods can be applied to predict clearance in humans were evaluated. 4. If the exponent lies between 0.55 to 0.7 then method I predicts clearance reasonably well. 5. If the exponent lies between 0.71 to 1.0 clearance can be predicted reasonably well by method II. 6. If the exponent is > 1.0 clearance can be predicted using method III.

Animals↗

PubMed1995

Pharmacokinetics and relative bioavailability of selegiline in healthy volunteers.

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. A sensitive flourimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to study the pharmacokinetics of selegiline. This method quantitates selegiline as low as 0.25 ng ml-1. The pharmacokinetics and relative bioavailability of selegiline were investigated in healthy volunteers following oral administration of 10 mg tablet or solution. A half-life of approximately 70 min was observed following the administration of either dosage form. Although the two dosage forms exhibited a lag time, the absorption was rapid and peak plasma concentrations were observed between 30 and 45 min for the solution and 30 and 90 min for the tablets. Statistically no significant difference was found between Cmax, Tmax, AUC0-infinity and MRT between the two dosage forms. Negligible renal clearance was found in both groups, but apparent oral plasma clearance was comparatively high and indicates rapid elimination of selegiline from the body.

Adult↗

PubMed1995

Differential suppression of serum prostatic acid phosphatase and prostate-specific antigen by 5-alpha-reductase inhibitor.

OBJECTIVE: To evaluate the effect of finasteride (Proscar) on the serum levels of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Thirty patients on finasteride therapy for BPH formed the study group. Serum PSA and PAP levels were monitored for 2 years while the patients were receiving finasteride. RESULTS: During 12 months of finasteride therapy the serum PSA was suppressed but serum PAP was unaffected. The baseline mean PAP value was 1.303 ng/mL prior to finasteride therapy; this changed to 1.510 ng/mL (P = 0.195) at 6 months and 1.166 ng/mL (P = 0.383) at 12 months. The serum PSA was 2.630 ng/mL at baseline, 1.757 ng/mL (P < 0.001) at 6 months and 1.545 ng/mL (P = 0.001) at 12 months. CONCLUSIONS: Further studies are warranted to determine if PAP has a role as a tumour marker in patients whose PSA is suppressed as a result of finasteride therapy.

Acid Phosphatase↗

PubMed1994

The pharmacokinetics and absolute bioavailability of selegiline in the dog.

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL-1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL-1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg-1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 +/- 9.56 min, 6.56 +/- 0.56 L kg-1, and 159.91 +/- 19.28 mL min-1 kg-1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a tmax and Cmax of 25 +/- 5.8 min and 5.2 +/- 1.36 ng mL-1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 +/- 3.31%.

Absorption↗

PubMed1994

An enzymatic assay for the MAO-B inhibitor selegiline in plasma.

A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been described. The procedure measures the inhibition of MAO activity produced by the addition of selegiline extracted from human plasma. This method uses the substrate kynuramine which is converted by MAO to the product 4-hydroxyquinoline which fluoresces in alkaline solution. Human plasma (500 microliters) containing different concentrations of selegiline was deproteinized and extracted with ethyl acetate-butyl chloride. After reconstitution with 200 microliters phosphate buffer, 50 microliters of rat brain homogenate was added to study the MAO-B inhibition. Selegiline metabolites, amphetamine and methamphetamine (50 ng ml-1), and desmethylselegiline (20 ng ml-1), showed no inhibitory effect on MAO-B inhibition. Selegiline concentrations as low as 0.25 ng ml-1 can be detected. The standard curve was linear from 125 pg (0.25 ng ml-1) to 4000 pg (8.0 ng ml-1) in the incubation tube. This method should be helpful to determine pharmacokinetic parameters of selegiline after i.v. or oral dosing.

Amphetamine↗

PubMed1994

Detection of phencyclidine in urine using a polarization fluoroimmunoassay.

A polarization fluoroimmunoassay was developed for the detection of phencyclidine in urine and the reagents were adapted for use on the Abbott TDx analyser. The assay was used to look for evidence of phencyclidine abuse, over a 6 month period, amongst patients attending drug abuse clinics in the East End of London. Although over 2000 patients' samples tested negative, the assay successfully detected phencyclidine in an external quality control scheme.

Animals↗

PubMed1992

Congenital dyserythropoietic anemia type II diagnosed in a 69-year-old patient with iron overload.

Congenital dyserythropoietic anemia type II is a rare disorder that is often diagnosed in patients before age 20 years. Patients with this disorder, which is also called hereditary erythroblastic multinuclearity associated with a positive acidified serum lysis test, may have symptoms of iron overload. The purpose of this case report is to alert physicians to consider the diagnosis of congenital dyserythropoietic anemia type II in elderly patients who have anemia and iron overload.

Aged↗

PubMed1989

The clinical implication of changing unbound quinidine levels.

Pharmacodynamic and pharmacokinetic aspects pertinent to the potential clinical application of unbound quinidine levels were studied. Following heparin administration during electrophysiologic testing in 10 patients receiving quinidine, there were significant increases in the mean (+/- SD) right ventricular effective refractory period (266 +/- 24 versus 279 +/- 23; p less than 0.025), free fatty acid concentration (515 +/- 213 versus 1071 +/- 359 mmol/L; p less than 0.001), and unbound quinidine concentration (0.3 +/- 0.1 to 0.6 +/- 0.1 microgram/ml; p less than 0.001) but no changes in heart rate, corrected QT interval, or total plasma quinidine concentration. Ten control patients showed no change in the right ventricular effective refractory period following heparin administration. These findings were consistent with a heparin-induced increase in unbound drug concentration and activity that was limited to the vascular compartment. Eleven patients studied on day 3 (+/- 1) and day 10 (+/- 3) during an acute myocardial infarction showed a significant decrease in unbound quinidine fraction (12 +/- 4% versus 9 +/- 4%; p less than 0.02) accompanied by a decrease, rather than the predicted increase, in half-life (7.1 +/- 2.7 versus 6.3 +/- 2.1 hours; p less than 0.02). Volumes of distribution remained stable while the mean quinidine clearance tended to increase. Half-life correlated with albumin changes (r = -0.71; p less than 0.02). Apparently, improvement in clinical status (assumed) and drug clearance (measured) negated the direct effects of the decrease in unbound quinidine fraction. Although unbound drug concentrations should correlate best with drug dynamic and kinetic information, full knowledge of the clinical context of such measurements is needed for appropriate interpretation.

Adult↗

PubMed1978

An improved method for the extraction of cholesterol and phospholipids from the bovine spinal cord.

A pharmacopoeial grade of cholesterol and a separate phospholipid fraction can be obtained by this simple extraction procedure of bovine spinal cord. The tissue is collected in 5% (Wt/V) formalin. It is then separated from the formalin solution, minced and dried in a hot-air oven at 105 degrees C. Total lipids are extracted with petroleum ether. The cholesterol is separated from the phospholipids by extraction with a mixture of petroleum ether and acetone. The method allows for not only the recovery of the phospholipids but also a high yield of cholesterol without using saponification or tedious purification procedures.

Animals↗

PubMedDate not supplied

A comparative study of uranyl nitrate and cisplatin-induced renal failure in rat.

Renal dysfunction can have substantial effects on the pharmacokinetics and pharmacodynamics of drugs. A wide variety of animal models have been developed in an attempt to mimic conditions seen in human renal failure. In reality, no single animal model would be completely satisfactory because the etiology and development of renal failure are diverse. During recent years injection of uranyl nitrate has been found to be the most effective and easiest method to produce renal dysfunction in laboratory animals. Changes over the last 10 years in government regulations on the production and use of radioactive substances make the compound less available. There is, therefore, a need for a more accessible compound comparable to uranyl nitrate as an inducer of renal failure. The present study compares the effects of another known nephrotoxin, cisplatin, with uranyl nitrate in the rat. Cisplatin was chosen because of its ability to produce kidney damage and its identical site and mechanism of action on the kidneys as uranyl nitrate. In the present study, rats were given different i.v. doses of uranyl nitrate or cisplatin dissolved in 0.9% of saline solution. The effects of nephrotoxins were evaluated on the basis of changes in body weight, creatinine and blood urea nitrogen (BUN) concentrations. It was found that the degree of renal damage produced by uranyl nitrate and cisplatin is a function of the administered dose. With increasing dose there is evidence of more severe kidney damage, as measured by substantially increased plasma concentrations of creatinine and BUN. The time required to return to normal creatinine and BUN concentrations was also a function of dose. Furthermore, plasma alanine aminotransferase (ALT) activity was measured as an index of hepatocellular damage. The ALT test showed that a single dose does not affect the liver function. From dose-response curves a dose of 4 mg/kg body weight of uranyl nitrate or cisplatin was chosen to produce acute renal failure in animals for pharmacokinetic study of barbital. Barbital (100 mg/kg) was administered on the fifth day (the day of maximum renal dysfunction) to uranyl nitrate, cisplatin-treated and control rats. The elimination rate constant (k), elimination half life (t1/2), volume of distribution at steady state (Vss), total (CLt) and renal clearance (CLr) were significantly different in treated groups of rats from control, however no such difference was detected between uranyl nitrate and cisplatin-treated group of rats. In short, cisplatin is comparable to uranyl nitrate in producing renal failure in the rat and can be considered a suitable alternative.

Acute Kidney Injury↗

PubMedDate not supplied

Interspecies scaling: predicting clearance of anticancer drugs in humans. A comparative study of three different approaches using body weight or body surface area.

From this study it is proposed that the clearance of anti-cancer drugs may be best estimated if they follow the following trend: (i) that if the exponent of the allometric equation (clearance vs body weight) lies between 0.55-0.75 (0.75 was chosen after Kleiber's power rule (18)), then a simple allometric equation can predict the clearance reasonably well; (ii) if the exponent of the allometric equation lies between 0.75 to approximately 0.90, clearance can be reasonably predicted using CL x MLP; and (iii) if the exponent of the allometric equation is > or = 0.90, the clearance can be predicted using the product of clearance and brain weight.

Animals↗

PubMedDate not supplied

Interspecies scaling of maximum tolerated dose of anticancer drugs: relevance to starting dose for phase I clinical trials.

This analysis was carried out to compare the predictive performance of two different approaches of allometry for the prediction of maximum tolerated dose (MTD) in humans from animal data. The two approaches used to predict MTD in humans in this analysis were (1) the use of a fixed exponent of 0.75 and the LD(10) in mice and (2) the use of the LD(10) or MTD data from at least three animal species (interspecies scaling). Twenty-five anticancer drugs were taken from the literature and used in this analysis. The results of the study indicate that MTD can be predicted more accurately using interspecies scaling than using a fixed exponent of 0.75. Incorporation of a correction factor known as mean life-span potential can also be used for the improved prediction of MTD for some drugs. One third of the predicted MTD from interspecies scaling can be used as a starting dose in humans. This approach will save time and avoid many unnecessary steps in attaining MTD in humans.

Animals↗

PubMedDate not supplied

Interspecies scaling of inhalational anesthetic potency minimum alveolar concentration (MAC): application of a correction factor for the prediction of MAC in humans.

The objective of this study was to predict minimum alveolar concentration (MAC) of inhalational anesthetics in humans from animal data. The MAC of 10 anesthetics was obtained from the literature. At least three animal species (excluding humans) were used in the scaling. Interspecies scaling of MAC was performed in two ways: (1) using the traditional allometric approach, the MAC of each drug was plotted against the body weight of the species on a log-log scale, and MAC in humans was predicted from the resultant equation; and (2) MAC in each species was multiplied by a correction factor obtained by adjusting the lung weight of the species based on per kg body weight. The product of the correction factor and the MAC was then plotted against body weight as described in the traditional approach. Predicted MAC values in humans from animal data using simple allometry produced comparatively more error than the prediction made by incorporating the correction factor into the scaling. The results of this study indicate that MAC may not be predicted in humans from animal data using simple allometry; however, applying a correction factor may significantly improve the prediction of MAC in humans from animal data.

Anesthetics, Inhalation↗