Showing papers in "Pharmacy World & Science in 1993"
TL;DR: In this review a generally accepted definition of quality of life, existing of three components, is presented and the interrelationship betweenquality of life and all the different variables used in assessing disease activity in rheumatoid arthritis is discussed.
Abstract: It has increasingly been recognized that for the evaluation of interventions in patients with rheumatoid arthritis not only physician-oriented variables, like laboratory or radiographic assessments but also patient-oriented variables such as quality of life are of importance. Many different arthritis-specific quality of life instruments have been developed in recent years using different or no definition at all about the concept ‘quality of life’. In this review a generally accepted definition of quality of life, existing of three components, is presented. The interrelationship between quality of life and all the different variables used in assessing disease activity in rheumatoid arthritis is discussed.
256 citations
TL;DR: Economic analyses can help ensure the efficient use of health care dollars in areas such as drug therapy and can assist care providers in determining which treatments are most cost-effective.
Abstract: In 1990, health care expenditures in the United States reached $666.2 billion, 12.2% of the gross domestic product (GDP). It is projected for the year 2000, the USA will spend $1.6 trillion for health care which will be comparable to 16.4% of that year's GDP. As a result of the rapid increase in costs of health care and limited resources available, patients/third-party payers and the government have initiated and implemented more rigid cost control measures. Economic analyses can help ensure the efficient use of health care dollars in areas such as drug therapy. The four methodologies available are cost-benefit analysis, cost-effectiveness analysis, cost-minimization analysis and cost-utility analysis. This article reviews methods and provides examples from the medical literature. These tools can assist care providers in determining which treatments are most cost-effective.
113 citations
TL;DR: The program of this meeting reveals the contnming interest in tile hasic and clinical aspects cff purine und pyrinlidine nletuboJisnl and several of the ntost prln)llslng new anticancer and anti-HIV agents which are contlnl.
Abstract: The important role of purines and pyrimidines in man is evident. It has been recognized fnr a ltmg time that any disturbance in the synthesis of these building blocks of D N A and RNA, can lead to serious clinical symptoms. Classical in this aspect is the deficiency in hypoxanthine-guanine phosphoribosyltransferase leading to the Lesch-Nyhan syndrome, while some forms of gout are associated with a partial deficiency of this enzyme. Other classical examples of inborn errors of lnetabolism are deficiencies of :ldenosme deaminuse, purinr nucleoside phosphoL'ylase and 5'-nuclentidase, which are associated wuh immunodeficiency. The recognition of these and other rare inborn errors of metabolism has led to new concepts with respect to the regulation of purine and pyrimidine illetaholism. In turn. tills knowledge has resulted in new approaches for the treatment of leukenl[as, other malignancies, und viral infections. More recently, correction of adenosine dc;lnlinase deficiency became o n e of tile first targets for gene therapy. Ftlllowmg the ln[tlU[ design of nlIopurinol f~,u\" tile treatment of gout, some O[ tile most ~,ucce.,,sfu[ untiltletabolite~, have emerged from the purine and pyrimidine field. These agents include uzuthloprinc (also used R)r gout), 6nlercaptopurhle, lind cytosine ;(rubinosidc. used in the treatment of Icukemi;.l, 5fluoro-urucil in (hut ~,lf stllid tumors, and more recently acyclovir for the treutntcnt of herpes ntfections and Y-uzido-Ydec~xythymidine (AZT) R~r the care of AIDS patient.',. Several of the ntost prln)llslng new anticancer and anti-HIV agents which are contlnl.nlusly intlt*duccci in the c[inic, such as 2-chlorodeoxyadenoxine in the treuunem tit\" huu)~ cell leukcntkl, find dide~lxyinoxine (ddI) and dMeox_vcytldme (ddC} Ior the ileHtnlent tit AIDS. rentum analogues of niltural purlne fllttl p'r This 4th syntpoMuln ill\" the Etlrcllleiln Sociely hn tile Study Im Purine find Pyrimidine Metabohsm in Man (ESSPPMM} lbcuses on all the above-mentioned aspects of the t~eld, h ha,', been recognized that it is e.',~,ential to have reliable ntcthods Ik)r detection tlf inborn errors of metaholism, hut a thorough understanding of tile bk)chenlicu[ and molecular hum5 is equully necessary both in model systems and even niobe importantly in tile clinic. The program of this meeting reveals the contnming interest in tile hasic and clinical aspects cff purine und pyrinlidine nletuboJisnl. {Hid the uni1 [o transhlte new acquisitions into therapeutic progress.
57 citations
TL;DR: It is concluded that fosfomycin trometamol is a reasonable alternative to 7 days nitrofurantoin 50 mg four times a day in the treatment of women with symptoms of acute uncomplicated urinary tract infections in general practice.
Abstract: In general practice acute uncomplicated urinary tract infections in women are treated with different courses of antibiotics. In this study the efficacy and tolerability of a single dose of 3 g fosfomycin trometamol and the conventional treatment with nitrofurantoin 50 mg four times daily for seven days were compared. In a randomized, double-blind, double-dummy trial in 31 general practices in the Netherlands 231 patients with symptoms of acute dysuria, stranguria and/or urinary frequency received treatment. Evaluation was based on resolution of symptoms, dipslide results and side-effects at 4, 9 and 42 days after starting the treatment. The clinical cure rates and bacteriological cure rates were not significantly different between the treatment groups. Side-effects were reported at day 4 by 43% of the women receiving single-dose treatment, compared with 25% of the women in the seven-day treatment group, a significant difference. At day 9 the groups did not significantly differ in the number of patients with side-effects. Almost all side-effects were mild and gastro-intestinal complaints were reported most. Taking into account the convenience of taking a single dose we conclude that fosfomycin trometamol is a reasonable alternative to 7 days nitrofurantoin 50 mg four times a day in the treatment of women with symptoms of acute uncomplicated urinary tract infections in general practice.
45 citations
TL;DR: Although the calcium phosphates are usually stable substances, the role of crystal water in the case of dibasic calcium phosphate dihydrate and monobasiccium phosphate monohydrate is problematic due to possible interactions with active ingredients.
Abstract: Ten commercially available calcium phosphates used for direct tableting were evaluated. The particle size distributions, powder properties, Sorption isotherms and pH values of aqueous slurries were compared. All samples showed good or at least sufficient flowability. Scanning electron micrographs illustrated the different kinds of manufacturing and gave hints on their expectable behaviour under compaction pressure. The sorption isotherms of identical chemical substances, which had been manufactured by different methods, differed strongly. This can be related to their specific surface areas. Most of the hydroxylapatites have large surface areas and can absorb up to more than 15% water at 93% relative humidity. Dibasic calcium phosphate dihydrate was non-hygroscopic and absorbed less than 1% water. With the exception of monobasic calcium phosphate monohydrate all calcium phosphates behaved quite neutral in water. Monobasic calcium phosphate monohydrate can be regarded as a solid acid. Although the calcium phosphates are usually stable substances, the role of crystal water in the case of dibasic calcium phosphate dihydrate and monobasic calcium phosphate monohydrate is problematic due to possible interactions with active ingredients.
40 citations
TL;DR: It is concluded that sufentanil in portable pump reservoirs can be used under patient conditions at 32°C for 7 days when diluted with glucose 5% or 3 days in combination with bupivacaine hydrochloride.
Abstract: The stability of sufentanil (5 micrograms/ml as citrate) in admixtures with glucose 5% or bupivacaine hydrochloride (2 mg/ml) in 100 ml polyvinyl chloride portable pump reservoirs was investigated during simulated infusion by an epidural catheter at 32 degrees C for 48 h and during storage at 4 degrees C and 32 degrees C for 30 days. During both experiments a small decrease (< 5%) in concentration of sufentanil and bupivacaine was observed. No loss of sufentanil or bupivacaine could be detected (in both experiments) in the portable pump reservoirs when stored at 4 degrees C for 30 days. A significant decrease of sufentanil was observed when stored at 32 degrees C after 30 days when diluted with glucose (9.2%) or in combination with bupivacaine (8.9%); also, the bupivacaine concentration decreased significantly (4.1%). It is concluded that sufentanil in portable pump reservoirs can be used under patient conditions at 32 degrees C for 7 days when diluted with glucose 5% or 3 days in combination with bupivacaine hydrochloride.
35 citations
TL;DR: The absence of a clear policy regarding chirality causes a great deal of confusion and frustration at various levels and is not in the interest of industries developing newer and more beneficial drugs.
Abstract: In this review we describe the impact of chirality on drug development and registration in the United States, Japan and the European Community. Enantiomers may have differences in their pharmacological profiles, and, therefore, chiral drugs ask for special analytical and pharmacological attention during their development. However, the registration authorities have no clear policy towards the registration of chiral drugs. The absence of a clear policy regarding chirality causes a great deal of confusion and frustration at various levels and is not in the interest of industries developing newer and more beneficial drugs.
31 citations
TL;DR: This third part focuses specifically on the mechanisms that are involved in drug transport across the blood-brain barrier and the opportunities to improve drug transport into the brain.
Abstract: This is the third part of a review on the transport of drugs across the blood-brain barrier. In the first two parts, the anatomical and physiological aspects and the various techniques that can be used to study blood-brain transport have been discussed and reviewed. This third part focuses specifically on the mechanisms that are involved in drug transport across the blood-brain barrier. In addition, the opportunities to improve drug transport into the brain will be reviewed. Emphasis is on the transport of peptides.
31 citations
TL;DR: A considerable effect of the particle size on the tensile strength of the tablets was found and the ejection forces and residual pressures were high in general, but critical only in the case of hydroxylapatites.
Abstract: Ten calcium phosphates suitable for direct compression (dibasic calcium phosphate dihydrate, dibasic calcium phosphate anhydrous and hydroxylapatite) were investigated with respect to their compressional behaviour. Except for Di-Cafos A all products gave tablets with sufficient to good mechanical strength. Nevertheless, there were differences between the products. All tablets prepared from the different products showed a high friability. This seems to be a problem of the calcium phosphates in general. On the other hand, the influence of magnesium stearate on the mechanical strength of the tablets was negligible for all products investigated. Moreover, a considerable effect of the particle size on the tensile strength of the tablets was found. The ejection forces and residual pressures were high in general, but critical only in the case of hydroxylapatites. Heckel plots were used to differentiate between plastic deformation and brittle fracture of the particles. In the case of calcium phosphates the slope of the Heckel plots indicated the hardness of the particles rather than their deformation behaviour.
30 citations
TL;DR: Routinely grown cell suspension cultures of Mucuna pruriens L. (Fabaceae) were able to endogenously accumulate the anti-Parkinson drug L-dihydroxyphenylalanine in the range between 0.2 and 2% on a dry weight (DW) basis.
Abstract: Routinely grown cell suspension cultures of Mucuna pruriens L. (Fabaceae) were able to endogenously accumulate the anti-Parkinson drug L-dihydroxyphenylalanine (L-dopa) in the range between 0.2 and 2% on a dry weight (DW) basis. The green colour that developed in light-exposed cultures, appeared to be a suitable marker to select cells with an increased L-dopa biosynthesis and/or phenoloxidase activity. For this purpose, saccharose concentrations from 0 to 4% (w/v), and light intensities of 1,000 and 2,000 lux, were involved in the selection procedure. After 6 months, photomixotrophic callus cultures with a rapid growth and a high L-dopa content of 0.9% (DW) were obtained on 2% saccharose and under 1,000 lux. The cell suspensions, derived from these calli, accumulated up to 6% (DW) L-dopa, which was the highest stable content ever measured in cultures of M. pruriens. An L-dopa yield of approximately 1.2 g/l was calculated after 6 days of growth. In contrast, compared wtih the standard-grown parent cell line, the phenoloxidase activity, and consequently the bioconversion capacity as measured after entrapment in calcium alginate, of these high-producing cultures was approximately threefold lower.
29 citations
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TL;DR: In this article, a 7.5-kb cDNA clone of the NADH-GOGAT enzyme was isolated from an alfalfa root nodule cDNA library.
Abstract: Glutamate synthase (NADH-GOGAT) is one of several proteins whose expression is either enhanced in, or specific to developing legume root nodules induced by (Brady)Rhizobium infection. This enzyme catalyzes the second committed step in the assimilation of symbiotically fixed nitrogen; the transamidation of 2-oxoglutarate by glutamine to yield two moles of glutamate. We have previously purifed alfalfa root nodule NADH-GOGAT and raised antibodies against this protein. To investigate the regulation of the gene encoding this enzyme, we have isolated a full length cDNA clone for NADH-GOGAT from an alfalfa nodule cDNA library. This 7.5 kb cDNA includes the sequence encoding the mature 210 kd protein (the amino terminus of which has been sequenced), as well as an apparent transit peptide. Northern blots indicate that mRNA levels are developmentally regulated in the nodule, showing a similar pattern to that of previously characterized genes encoding aspartate aminotransferase and phosphoenoylpyruvate carboxylase.
TL;DR: The citrate buffer at the optimum pH (4.6) has a low, acceptable buffer capacity for epidural administration and sufentanil was absorbed into the polyvinyl chloride, resulting in a reduction of 10.9% of the concentration after 48 h.
Abstract: Sufentanil (5μg/ml as citrate) was investigated for its stability when diluted with sodium chloride 0.9%, in 100 ml polyvinyl chloride portable pump reservoirs during administration under simulated epidural conditions at 32°C for 48 h. Sufentanil was absorbed into the polyvinyl chloride, resulting in a reduction of 10.9% of the concentration after 48 h. The absorption of sufentanil (5μg/ml as citrate), alone and in combination with bupivacaine hydrochloride (2 mg/ml), was investigated when diluted with sodium chloride 0.9% in combination with a citrate buffer (pH 4.6), in the same reservoirs under similar conditions. There was no loss of sufentanil after 48 h in both experiments. The effect of the pH on the absorption of sufentanil in polyvinyl chloride was investigated at different pH values. After storage for 21 days at 32°C there was 5.1% loss of sufentanil at pH 4 and 80.6% loss at pH 6. The citrate buffer at the optimum pH (4.6) has a low, acceptable buffer capacity for epidural administration.
TL;DR: It was inferred that probenecid acyl glucuronide is formed in the kidney during blood-to-lumen passage through the tubular cells and the plateau value in the renal excretion rate-time profile reflects itsVmax of formation.
Abstract: A dose of 1,000 mg probenecid was administered orally to 14 human volunteers in order to quantify the maximal rate of formation and excretion of probenecid acyl glucuronide in the urine. Probenecid showed dose-dependent pharmacokinetics. Plasma protein binding of probenecid was high, being somewhat higher in males (90.7±1.4%) than in females (87.9±1.4%; p=0.0019). It was shown that probenecid is metabolized by cytochrome P-450 into at least two phase I metabolites. Each of the metabolites accounted for less than 12% of the dose administered; the main metabolite probenecid acyl glucuronide, representing 42.9±13.2% of the dose, was only present in urine and not in plasma. The renal excretion rate-time profile of probenecid acyl glucuronide showed a plateau value in the presence of an acidic urine pH. This plateau value was maintained for about 10 h at the dose of 1,000 mg. The height of the plateau value depended on the individual and varied between 250 and 800μg/min (15–50 mg/h). It was inferred that probenecid acyl glucuronide is formed in the kidney during blood-to-lumen passage through the tubular cells. We conclude that the plateau value in the renal excretion rate of probenecid glucuronide reflects itsVmax of formation.
TL;DR: The treatment of generalized convulsive status epilepticus according to a protocol, including a time schedule, prevents unnecessary delay and improves outcome.
Abstract: The treatment of generalized convulsive status epilepticus according to a protocol, including a time schedule, prevents unnecessary delay and improves outcome. Based on a literature study and our own clinical experiences a treatment protocol is discussed with special emphasis on medical complications, choice of antiepileptic drugs, route of administration and a proper time schedule.
TL;DR: In this article, the authors propose a method to measure the quality of life of health care interventions by considering both clinical and economic data, which is a common concern of governments, clinicians, health insurance companies, policy makers, and the general public.
Abstract: Assessing the value of health care interventions is more and more a concern of governments, clinicians, health insurance companies, policy makers, and the general public. One dimension of the outcomes of such interventions that has received relatively little attention until recently is quality of life. However, during the last decade, measuring quality of life has become more frequent. Methodologies have also developed rapidly. At the same time, methodological problems continue to be troubling. In part, this explains the relative lack of use of validated measures of quality of life in clinical trials. In the future, measuring quality of life will certainly become more frequent. It may even be demanded by policy making bodies. Increasingly, too, economic costs will be part of such studies. This requires considering both clinical and economic data.
TL;DR: The results from a large double-blind, placebocontrolled clinical trial did not show any beneficial effect of vitamin E in Parkinson's disease, and it was suggested that vitamin E is able to slow the progression of the illness.
Abstract: In this article the effect of vitamin E on two extrapyramidal disorders, tardive dyskinesia and Parkinson's disease, is reviewed. After a brief description of the symptoms, the current hypotheses for the pathogenesis of these diseases are described. A summary of the clinical research that has been done to establish the effectiveness of vitamin E is given. In tardive dyskinesia four clinical trials (double-blind, placebo-controlled) showed improvement in the symptoms with vitamin E in doses of up to 1,600 IU/day. Preliminary studies concerning Parkinson's disease suggested that vitamin E (2,000 IU/day) probably cannot prevent the development of the disease. It was suggested that vitamin E is able to slow the progression of the illness. The results from a large double-blind, placebo-controlled clinical trial, however, did not show any beneficial effect of vitamin E in Parkinson's disease.
TL;DR: The stability of cisplatin in sodium chloride 0.9% intravenous solutions contained in glass bottles, polyvinyl chloride bags, polyethylene and polypropylene containers was studied and no precipitation at 4°C was observed within the time period studied.
Abstract: The stability of cisplatin in sodium chloride 0.9% intravenous solutions contained in glass bottles, polyvinyl chloride bags, polyethylene and polypropylene containers was studied over two weeks. The solubility of cisplatin at 4°C was also studied for possible precipitation. The type of container had no effect on cisplatin decomposition. No precipitation at 4°C was observed within the time period studied.
TL;DR: Serum carnitine increased slowly after cessation of therapy and reached normal concentrations after 6–12 months, and symptoms caused by carnitines depletion disappeared.
Abstract: Long-term treatment with pivampicillin and pivmecillinam for 6–24 months in five adults and one child reduced the total serum carnitine concentration to 3.7–14 μmol/l (reference value: 25–66 μmol/l). Muscle carnitine was reduced to 0.3–0.7μmol/g wet weight (reference value: 3–5μmol/g) in two cases. All patients had muscle symptoms with weakness, asthenia and pains. One showed signs of carnitine depletion in the liver with increased secretion of dicarboxylic acids (C6, C8, C10) in urine and limited ketone body formation during prolonged fasting. Serum carnitine increased slowly after cessation of therapy and reached normal concentrations after 6–12 months. All symptoms caused by carnitine depletion disappeared. This was achieved on a normal diet without carnitine supplementation.
TL;DR: The results of this study suggest that the choice of drugs for the treatment of cardiovascular co-morbidity in patients with diabetes mellitus can be improved.
Abstract: The medication of 582 patients taking insulin or oral hypoglycaemic agents has been analysed. A characterization is given of the patients and their antidiabetic medication. Subsequently, a description of the use of cardiovascular drugs, in comparison with an age-matched control group, is presented. The diabetic population investigated has an average age of 67 years. Most cardiovascular agents, with the exception of thiazide diuretics, are used to a larger extent in the diabetic group in comparison with the control group. Non-selective beta-blockers, possibly hazardous in patients with diabetes mellitus, appear to be prescribed without restriction in the diabetic patients investigated. The results of this study suggest that the choice of drugs for the treatment of cardiovascular co-morbidity in patients with diabetes mellitus can be improved.
TL;DR: The most common ocular complication in patients with the acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis, which can largely diminish the patient's quality of life as discussed by the authors.
Abstract: The most common ocular complication in patients with the acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis. Incidence figures vary from 20 to 76%. Patients with cytomegalovirus may suffer from mild visual impairment of one or both eyes, but as the disease progresses the retinitis will almost certainly lead to blindness. Although cytomegalovirus retinitis is not a life-threatening infection, it can largely diminish the patient's quality of life. Clinical trials for the treatment of cytomegalovirus retinitis with a number of antiviral drugs have resulted in two drugs of choice, ganciclovir and foscarnet. Both drugs have an initial efficacy with induction therapy of 80–90%, but maintenance therapy is always needed to prevent a relapse. To exclude systemic side-effects of ganciclovir, intravitreal administration has been investigated with good results. Combination therapy of foscarnet and ganciclovir may be worthwhile in resistant cytomegalovirus retinitis.
TL;DR: In this paper, the authors studied the risk of ventricular tachycardia due to terfenadine and cytochrome P-450 inhibitors, and showed that the risk has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
TL;DR: Undergraduate and postgraduate education of pharmacy personnel should aim more at satisfying the demand for information of the general public and focus more on the symptomatic treatment of fever and minor illness in general.
Abstract: To study the fever perception and self-care of pharmacy personnel as well as the information given to customers about the management of fever problems, a random sample of 152 Norwegian pharmacists and 150 pharmacy technicians were interviewed, in 1989, by a national opinion poll company. One-third thought that body temperatures between 39.0°C and 40.5°C could be lifethreatening. Of all respondents 24% (33% of technicians, 16% of pharmacists) assumed body temperatures to be rising when sweating accompanied fever. In cases of common cold or influenza accompanied by fever 56% of the personnel would use antipyretics. 7% Of the staff (14% of technicians, 1% of pharmacists) believed penicillin to be effective against viral infections. Antipyretic drug preferences were consistent, but a wide range of perceptions was revealed, in particular with respect to start of antipyretic therapy and seeking medical care for children. Undergraduate and postgraduate education of pharmacy personnel should aim more at satisfying the demand for information of the general public and focus more on the symptomatic treatment of fever and minor illness in general. Pharmacists in charge have a special responsibility in counselling their assistants.
TL;DR: Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed and their side-effects on the central nervous system, calcium channel affinity and metabolism are analysed.
Abstract: Terfenadine was the first non-sedating histamine H1 receptor antagonist and one of the most frequently prescribed H1 antihistamines. Terfenadine has one asymmetric centre in the molecule and is currently used as a racemate. Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed in the present paper. Studies on antihistamine activity of the enantiomers, their side-effects on the central nervous system, calcium channel affinity and metabolism are also reviewed and analysed.
TL;DR: Both the indirect and the direct separation methods provide various options to achieve separation and quantitation of enantiomers and for reasons of practice and reliability direct separations should be preferred over indirect methods.
Abstract: The final conclusion is that both the indirect and the direct separation methods provide various options to achieve separation and quantitation of enantiomers. Which of the two methods would be the best choice is greatly dependent on the chemical structure of the solute. For reasons of practice and reliability direct separation methods — if available — should be preferred over indirect methods. For biological samples an exhaustive clean-up step is required before a direct and/or indirect separation method can be used. For direct methods this clean-up step is the only way to prevent the expensive column from being damaged. For indirect methods the clean-up step may be less exhaustive depending on the kind of chiral derivatizing agent applied.
TL;DR: The mixture optimization part of the formulation optimization and its robustness against errors in the mixture concentration settings were considered and should ideally be robust enough to be immune to the mentioned sources of error.
Abstract: In pharmaceutical technology one is often engaged with the design and analysis of formulations. A formulation of a solid dosage form is normally a mixture of components. This formulation usually consists of a number of components with fixed concentrations like the the medicinal substance(s) (drug), the lubricant, the glidant, possibly the disintegrant and components with variable concentrations like the fillerbinders. In the case of tablets, several physical demands can be set to the formulation like having certain (minimum or maximum) values for the crushing strength, the disintegration time, the friability, the weight variation, content uniformity, etc. The desired properties should be reached by changing the concentrations of the filler-binders, sometimes the disintegrant and/or by changing the manufacturing conditions. Another important property of a formulation is to keep the desired values of the physical demands as constant as possible during production or shelf-life despite (small) variations in the manufacturing conditions or in the concentrations of the components. In other words the fomulation should ideally be robust against the mentioned sources of error or a certain quality level should be maintained. This thesis considers only the mixture optimization part (changing filler-binderldisintegrant concentrations) of the formulation optimization and robustness against errors in the mixture concentration settings.
TL;DR: A gradient reversed-phase high pressure liquid chromatographic analysis was developed for the direct measurement of nalidixic acid with its acyl glucuronide, 7-hydroxymethylnalidixi acid withIts acyl and ether glucuronides, and 7-carboxynalidIXic acid in human plasma and urine.
Abstract: A gradient reversed-phase high pressure liquid chromatographic analysis was developed for the direct measurement of nalidixic acid with its acyl glucuronide, 7-hydroxymethylnalidixic acid with its acyl and ether glucuronides, and 7-carboxynalidixic acid in human plasma and urine. The glucuronides and 7-carboxynalidixic acid were not present in plasma after an oral dose of 1,000 mg nalidixic acid. The acyl glucuronides of 7-carboxynalidixic acid were not present in plasma and urine. The acyl glucuronides are stable in urine at pH 5.0–5.5. The subject's urine must therefore be acidified by the oral intake of 4×1 g of ammonium chloride per day. With acidic urine, hardly any nalidixic acid was excreted unchanged (0.2%). It was excreted as acyl glucuronide (53.4% of dose), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide (30.9%), and 7-carboxynalidixic acid (4.2%).
TL;DR: The results of an inquiry among Dutch hospital pharmacists on the monitoring of aminoglycosides are presented and the relevance of monitoring is discussed and the monitoring may be helpful to reduce the variability in serum levels after a standard dose.
Abstract: The results of an inquiry among Dutch hospital pharmacists on the monitoring of aminoglycosides are presented and the relevance of monitoring is discussed. The vast majority of Dutch hospitals (47 out of 65) use aminoglycosides in a twice-daily dosage regimen, whereas 12 hospitals use a once-daily dose. The timing of peak level sampling is usually 30 min after the end of an intravenous infusion of 20–30 min. Mean ’therapeutic’ peak levels of gentamicin were 7–13 mg/l in the once-daily group, 6.4–9.6 mg/l in the twice-daily group and 5–9 mg/l in the small thricedaily group. Little or no evidence has been published to substantiate a real therapeutic range for aminoglycosides, concerning a relationship between peak or trough levels of aminoglycosides and clinical efficacy, ototoxicity and nephrotoxicity. All studies have been performed with the conventional thrice-daily regimen. No therapeutic range can be defined yet for once-daily or twice-daily aminoglycosides. The monitoring of aminoglycosides may be helpful to reduce the variability in serum levels after a standard dose.
TL;DR: This thesis examines the manner in which drug utilization data obtained from community pharmacies can contribute to a safe and rational use of drugs shortly before and during pregnancy.
Abstract: This thesis examines the manner in which drug utilization data obtained from community pharmacies can contribute to a safe and rational use of drugs shortly before and during pregnancy. Three studies were performed with this goal in mind. The first study is based on data relating to 1,948 women obtained from 10 community pharmacies in the north of The Netherlands; it describes the use of prescribed drugs before, during and after pregnancy. In the second study 295 mothers were interviewed a few days after delivery about the medication which they had used during pregnancy. The third study describes the use of ovulation-stimulating drugs in the Dutch population.
TL;DR: Evaluated angiotensin-converting enzyme inhibitors selected for the hospital formulary due to its higher score, although the differences between the three are very small, and sensitivity analysis confirms this result.
Abstract: Decision analysis is applied to the group of angiotensin-converting enzyme inhibitors, in order to select those which should be included in the hospital formulary and to establish a research method which allows the reproduction of the process with new, related drugs. Captopril, enalapril and lisinopril were the alternatives considered. Evaluation criteria were efficacy, clinical experience, safety, dosage interval, hepatic bioactivation, interactions, dosage forms and cost. A relative weight was assigned through a survey among the hospital's staff. Each alternative was evaluated in relation to all criteria. Sensitivity analysis was applied to validate the method. Enalapril obtained the highest score, followed by lisinopril and captopril. The sensitivity analysis confirms this result. Enalapril is selected for the hospital formulary due to its higher score, although the differences between the three are very small.
TL;DR: Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide, and thein vitro protein binding of both acy glucuronides was increased, while noEffect on the unconjugated compounds was seen.
Abstract: The aim of this pilot study was to demonstrate the possible inhibitory effect of probenecid on the renal glucuronidation and on the renal clearance of nalidixic acid in a human volunteer. Under acidic urine conditions, hardly any nalidixic acid is excreted unchanged (0.2%). It is excreted as acyl glucuronide (53.4%), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide 30.9%, and 7-carboxynalidixic acid (4.2%). Under probenecid co-medication the renal glucuronidation of nalidixic acid is reduced from 53% to 16%; the renal clearance of both nalidixic acid and 7-hydroxymethylnalidixic acid are reduced (p <0.001); the intrinsict
1/2 of the metabolite 7-hydroxymethylnalidixic acid increased from 0.48 h to 4.24 h. The amount of acyl glucuronidation of 7-hydroxymethylnalidixic acid was not altered. Thein vitro protein binding of both acyl glucuronides was increased, while no effect on the unconjugated compounds was seen. Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide.