Group purchasing of pharmaceuticals and medical supplies by the Gulf Cooperation Council states.

An important issue in health care today is the cost of essential pharmaceuticals and medical supplies. To control the increase of health care expenses, in 1976 the Gulf Cooperation Council states began to study the idea of establishing a group purchasing programme for pharmaceuticals and medical supplies. This paper demonstrates the elements of the programme, how it works, what obstacles it faces and how other countries can profit from this experience. It also discusses the future of the group purchasing programme in the light of globalization and how the international changes under the World Trade Organization agreements will affect the programme in future.

Isoniazid acetylation phenotyping in Saudi Arabs.

AIMS: The present study is designed to investigate the acetylator status in Saudi Arabs. METHODS: Isoniazid (INH) acetylation phenotyping was studied in 136 Saudi Arabs in Riyadh, Saudi Arabia, using a single plasma sample taken 3 h post-INH oral dose of 200 mg. Metabolic ratio (MR) of plasma acetyl-INH (Ac-INH) to INH was used to determine the acetylation phenotype. RESULTS: The MR had a bimodal distribution with an antimode of 1.0. The frequency distribution of slow acetylators (MR < 1.0) was 94.9% (n = 129). Using Hardy-Weinberg Law, the gene frequency (q) of the recessive allele determining slow acetylator phenotype was found to be 0.97. CONCLUSION: INH phenotyping suggests a high frequency of slow acetylators among Saudi Arabs. There was no association between the MR of plasma Ac-INH/INH and age or gender.

Effect of lamotrigine on the pharmacokinetics of carbamazepine and its active metabolite in dogs.

The effect of lamotrigine (LTG) on the pharmacokinetics of carbamazepine (CBZ) and its active metabolite; carbamazepine-epoxine (CBZ-E), was investigated in dogs. Five male dogs received CBZ (2 x 200 mg tab, p.o.) daily for a period of 1 week. After the end of this period, blood samples were collected serially for up to 24 hrs. After a wash-out period of I week, LTG (100 mg tab, p.o.) was coadministered with the CBZ dose (2 x 200 mg tab, p.o.) for 7 days. Blood samples were again serially collected and plasma levels of CBZ and CBZ-E were analysed by high performance liquid chromatography (HPLC). Concurrent administration of LTG with CBZ did not have any significant effect on the pharmacokinetic parameters of CBZ. There was also no significant difference between the plasma concentration ratio (CBZ-E to CBZ) vs time profiles in the two schedules of drug administration signifying the absence of pharmacokinetic interaction between LTG and CBZ or its active metabolite in this animal model.

Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog.

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT (12 mgkg(-1)i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB (60 mgkg(-1)) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mgkg(-1), i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n= 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug's kinetics, as evidenced by a 31% (P= 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life (t(1/2)), (P= 0.013) and area under the plasma PT concentration-time curve (AUC), (P= 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.

Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog.

The study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parental PT. VGB, however markedly changed the drug's kinetics as evidenced by a 31% (P = 0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P = 0.013) and area under the plasma PT concentration-time curve (AUC), (P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.

Liquid chromatographic determination of six antiepileptic drugs and two metabolites in microsamples of human plasma.

A simple, rapid, sensitive, and reproducible high-performance liquid chromatographic (HPLC) method for simultaneous determination of the antiepileptic drugs (ethosuximide, primidone, lamotrigine, phenobarbital, phenytoin, and carbamazepine) and two metabolites (carbamazepine-diol and carbamazepine-epoxide) in human plasma is described. The procedure involves extraction of the drugs from human plasma (100 microL) with ether using 9-hydroxymethyl-10-carbamyl acridan as an internal standard. The extract was evaporated and reconstituted with mobile phase and then injected onto the chromatograph. The drugs and the internal standard were eluted from a Supelcosil LC-18 stainless steel column at ambient temperature with a mobile phase consisting of a 0.01M phosphate buffer/methanol/acetonitrile (65/18/17, v/v/v) adjusted to a pH of 7.5 with phosphoric acid and a flow rate of 1 mL/min. The effluent was monitored at 220 nm. Quantitation was achieved by using peak area ratio of each drug to the internal standard. The intraassay and interassay coefficients of variation (CV) ranged from 2.43% to 6.25% and from 3.02% to 5.85%, respectively. The absolute (extraction) and relative (analytical) recoveries for the drugs ranged from 70.7% to 104.4% and from 88.3% to 106.1%, respectively. Stability tests showed that the drugs were stable in plasma for at least 4 weeks when stored at -20 degrees C. The method was applied clinically for monitoring the AEDs in epileptic patients.

Effects of pregnancy on the pharmacokinetics of lamotrigine in dogs.

PURPOSE: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG). METHODS: Five pregnant dogs were given a daily dose of LTG (100 mg) for a period of 1 week. Two months after parturition, the same subjects were given the LTG dose (100 mg) over the same period. On both occasions, plasma LTG concentrations were determined by a sensitive, high-performance liquid chromatographic (HPLC) method, over a 30-h period after the last dose. RESULTS: The mean maximum plasma concentration (Cmax), volume of distribution (Vd/F), and oral body clearance (Cl/F) for LTG (+/- SD) during pregnancy were 7.63+/-2.46 microg/ml 1.74+/-0.29 L/kg, and 0.19+/-0.04 L/h/kg, respectively. After pregnancy, the same variables were 6.12+/-2.24 microg/ml, 2.36+/-1.10 L/kg, and 0.30+/-0.13 L/h/kg, respectively. None of these pharmacokinetic parameters was found to be significantly different between the two groups. CONCLUSIONS: The apparent lack of change in the relevant pharmacokinetic parameters of LTG during pregnancy may indicate that pregnancy has little or no effect on glucuronidation; the principal pathway for the drug's elimination.

Effect of valproic acid on the pharmacokinetic profile of oxcarbazepine in the rat.

The pharmacokinetics of oxcarbazepine (30 mg kg-1, po), administered for 1 week, was studied in rats pre-treated for 2 weeks with valproic acid (100 mg kg-1, po). Oxcarbazepine (OXC) plasma levels were measured over a period of 24 h from dosing, using a sensitive HPLC method. No significant changes were observed in the mean values of OXC pharmacokinetic parameters (Cmax, Tmax, t1/2 and AUC0-infinity) between the control and the pre-treated groups. The findings of this study suggest that OXC metabolism in the rat is apparently not affected by valproic acid, and the lack of effect may be attributed to the different pathways of biotransformation of the two drugs.

High-performance liquid chromatographic determination of furosemide in plasma and urine and its use in bioavailability studies.

A sensitive, selective and efficient reversed-phase high-performance liquid chromatographic (HPLC) method is reported for the determination of furosemide in human plasma and urine. The method has a sensitivity limit of 5 ng/ml in plasma, with acceptable within- and between-day reproducibilities and good linearity (r2>0.99) over a concentration range from 0.05 to 2.00 microg/ml. The one-step extract of furosemide and the internal standard (warfarin) from acidified plasma or urine was eluted through a muBondapak C18 column with a mobile phase composed of 0.01 M potassium dihydrogenphosphate and acetonitrile (62:38, v/v) adjusted to pH 3.0. Within-day coefficients of variation (C.V.s) ranged from 1.08 to 8.63% for plasma and from 2.52 to 3.10% for urine, whereas between-day C.V.s ranged from 4.25 to 10.77% for plasma and from 5.15 to 6.81% for urine at three different concentrations. The minimum quantifiable concentration of furosemide was determined to be 5 ng/ml. The HPLC method described has the capability of rapid and reproducible measurement of low levels of furosemide in small amounts of plasma and urine. This method was utilized in bioavailability/pharmacokinetic studies for the routine monitoring of furosemide levels in adults, children and neonate patients.

A rapid liquid chromatographic method for the determination of lamotrigine in plasma.

A rapid sensitive and simple high-performance liquid chromatographic (HPLC) method for the determination of lamotrigine in plasma is described. The drug was extracted from 100 microliters of plasma with chloroform:isopropanol (95:5% v/v) in the presence of 100 microliters of phosphate buffer (10 mM). The extract was evaporated and the residue was reconstituted with mobile phase and injected onto the HPLC system. The drug and the internal standard (chloramphenicol) were eluted from a Symmetry C18 stainless steel column at ambient temperature with a mobile phase consisting of 0.01 M potassium-acetonitrile-methanol (70.20:10% v/v/v), adjusted to pH 6.7, at a flow rate of 1.3 ml min-1 and the detector was monitored at 214 nm. Quantitation was achieved by measurement of the peak-area ratio of the drug to the internal standard and the lower limit of detection for lamotrigine in plasma was 20 ng ml-1. The intraday precision ranged from 3.34 to 6.12% coefficient of variation (CV) and the interday precision ranged from 2.15 to 8.34% CV. The absolute and relative recoveries of lamotrigine ranged from 86.93 to 90.71% and from 95.18 to 107.13%, respectively. The method was applied in studying the pharmacokinetics of lamotrigine administered orally to rabbits. This reliable micro-method would have application in pharmacokinetic studies of lamotrigine where only small sample sizes are available, e.g. paediatric patients.

Comparative bioavailability of two tablet formulations of ranitidine hydrochloride in healthy volunteers.

This investigation was carried out to evaluate the bioavailability of a new tablet formulation of ranitidine HCl (300 mg), Ranid, relative to the reference product, Zantac, (300 mg) tablets. The bioavailability was carried out on 24 healthy male volunteers who received a single dose (300 mg) of the test (T) and the reference (R) products in the fasting state, in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 16 hours. Plasma harvested from blood was analyzed for ranitidine by a sensitive and validated high-performance liquid chromatographic assay. The maximum plasma concentration (Cmax), area under the plasma concentration time curve up to the last measurable concentration (AUC0-t), and to infinity (AUC0-infinity) and the absorption rate (Cmax/AUC0-infinity) were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (Tmax) was analyzed assuming an additive model. The parametric confidence intervals (90%) of the mean values of the pharmacokinetic characteristics (AUC0-t, AUC0-infinity), Cmax and Cmax/AUC0-infinity) for T/R ratio were in each case well within the bioequivalence acceptable range of 80-125%. The test formulation was found bioequivalent to the reference formulation by the Schuirmann's two one-sided t-tests and by Wilcoxon Mann Whitney two one-sided tests procedure. Therefore, the 2 formulations were considered to be bioequivalent.

Comparative bioavailability of two tablet formulations of acyclovir in healthy volunteers.

This investigation was carried out to evaluate the bioavailability of a new tablet formulation of acyclovir (400 mg), Clovir, relative to reference product, Zovirax (400 mg) tablets. The 2 brands were found to be similar in weight variation, disintegration time, dissolution, and assay as stipulated by the USPXXIII, as well as by the manufacturer. The bioavailability was carried out on 24 healthy male volunteers who received a single dose (400 mg) of the test (T) and the reference (R) products in the fasting state, in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 16 hours. Plasma harvested from blood was analyzed for acyclovir by a sensitive and validated high-performance liquid chromatographic assay. The maximum plasma concentration (Cmax), area under the plasma concentration-time curve up to the last measurable concentration (AUC0-t), and to infinity (AUC0-infinity), and the absorption rate (Cmax/AUC0-infinity) were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (Tmax) was analyzed assuming an additive model. The parametric confidence intervals (90%) of the mean values of the pharmacokinetic characteristics (AUC0-t, AUC0-infinity, Cmax, Cmax/AUC0-infinity) for T/R ratio were in each case, well within the bioequivalence acceptable range of 80-125%. The test formulation was found bioequivalent to the reference formulation by the Schuirmann's two 1-sided t tests and by Wilcoxon Mann Whitney two 1-sided tests procedure. Therefore, the 2 formulations were considered to be bioequivalent.

Effect of famotidine on ciprofloxacin pharmacokinetics after single intravenous and oral doses in rats.

The effect of intravenous (3.5 mg/kg) and oral (5 mg/kg) famotidine on ciprofloxacin pharmacokinetics after single (i.v.) intravenous (5 mg/kg) and oral (20 mg/kg) doses were examined in the rat. Famotidine co-administration significantly increased the terminal elimination half-life of ciprofloxacin (54% and 29% following i.v. and oral administration, respectively) and tended to reduce the total body clearance by 27% and 34% following i.v. and oral routes, respectively. The area under the plasma concentration-time curve and the mean residence time in the body after i.v. and oral doses were significantly increased following famotidine co-administration. No changes in the steady-state apparent volume of distribution was observed after i.v. administration. The maximum plasma concentration and the time to peak concentration after oral dosing were also unaffected. These results suggest a possible reduction in the total clearance of ciprofloxacin, owing to inhibition of its renal tubular excretion by famotidine. Further studies are warranted to determine whether this interaction occurs in humans.

Prescribing patterns of ambulatory care physicians in Saudi Arabia.

The drugs prescribing patterns of ambulatory care physicians in the Ministry of Health (MOH) hospitals were studied by examining 10,291 systematically prescriptions obtained from 22 general hospitals covering the various health regions within Saudi Arabia. An audit of prescription information revealed that documentation was not generally complete. Information relating to patient age and diagnosis was missing in 18.6% and 9.8% of the prescriptions, respectively. The average number of drugs per prescription was 2.1 +/- 0.95. The most frequently prescribed drug categories were systemic anti-infectives, analgesics/antipyretics, and vitamin preparations, respectively. Paracetamol, ampicillin, antacid preparations, and vitamin B complex were the specific drugs that ranked high in the frequency of prescription. The patterns of drug use observed in this study indicate a trend for the overprescribing of certain categories of drugs. The need to improve current drug policy and drug prescribing is discussed with a recommendation for the establishment of a Pharmacoepidemiology Unit to monitor drug use in Saudi Arabia.

Comparative study of Saudi-marketed products and US drug labeling.

Drug package inserts from ten nonsteroidal antiinflammatory drugs marketed in Saudi Arabia were compared with their corresponding US labels to determine possible differences in their information content. These variations were assessed with special regard to the number of words used and the type of the information provided. The study showed that inserts of Saudi-marketed products generally conveyed limited and incomplete information. Possible adverse reactions, drug--drug interactions, and date of revision often were not included, although this information was present on the corresponding US labels. Comparisons of the package inserts of the same product from various pharmaceutical companies show wide variations in the amount of information provided. Determining the minimal level of information that must be included by the manufacturer in the package insert and the establishment of firm international guidelines by the World Health Organization could effectively reduce such variations.

The effect of domperidone on theophylline disposition in the rat.

The effect of domperidone (2 mg kg-1) on the pharmacokinetics of a single oral dose of theophylline (25 mg kg-1) was studied in the rat. Theophylline concentrations were measured serially for 12 h using an HPLC technique. Domperidone did not have any significant effect on any of the four parameters studied: peak plasma levels (Cpmax), the time these were attained (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC). Our data preliminarily suggests that domperidone may be safely coadministered with theophylline but clearly further studies in patients or relevant animal models of gastric motility disturbances are needed to reliably rule out any potential interaction between these agents.

Assessment of pharmacokinetic interaction between theophylline and loperamide in the rat.

The effect of loparamide (1 mgkg-1, p.o.) on the pharma-cokinetics of theophylline was studied in the rat. Theophylline (as aminophylline-25 mgkg-1, p.o.) was administered either alone, in combination with, or 1 hr after loperamide. Plasma levels of theophylline were serially measured over a period of 12 hr using HPLC. The disposition kinetics of theophylline was markedly altered by loperamide. This was evident from the significant differences obtained between the control and drug combination groups in most of the parameters studied (Cpmax, tmax, Ka, t1/2 and AUC). Allowing for the limitations of single dose studies, the data presented here suggest that pharma-cokinetic interaction between theophylline and loperamide is possible during their concomitant use.