USP and the development of drug standards.
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Pharmaceutical Preparations↗
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A high performance liquid chromatographic system for the analysis of tetracycline drug standards, analogs, degradation products and other impurities.
This paper describes the high performance liquid chromatographic (HPLC) analysis of eight parent tetracycline standards: tetracycline, chlortetracycline, rolitetracycline, oxitetracycline, minocycline, doxycycline, democlocycline, methacycline; and three tetracycline epimers: epitetracycline, epianhydrotetracycline, and anhydrotetracycline. The HPLC system employs an octadecylsilane reverse phase column and an isopropanol-diethanolamine-phosphate-ammonium EDTA-water mobile phase. This system produced at least partial resolution of all eight parent compounds and many of their degradation products.
Chlortetracycline↗
Neurosurgical devices and drugs: standardizing intracranial shunts; CT scanning; unnecessary X-ray films of the skull.
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Economics, Medical↗
Drug standards--communication and revision.
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Pharmaceutical Preparations↗
[General and oral pharmacotherapeutic drug standards].
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Abnormalities, Drug-Induced↗
Interlaboratory variability in determination of plasma antiepileptic drug concentrations.
The usefulness of plasma antiepileptic drug concentrations in treatment of epilepsy has been established, and many laboratories provide this service. A "blind" survey utilizing pooled patient plasma samples was conducted among 197 laboratories in the United States and Canada to establish the interlaboratory reproducibility. Three "patient specimens" containing different amounts of phenobarbital, phenytoin (diphenylhydantoin), primidone, and ethosuximide were employed; 112 laboratories reported results within five weeks. The average cost for analyzing four drugs in a single sample was $43.27. Half of the laboratories reported results outside +/- 1 standard deviation of the mean of five reference laboratories. Wide interlaboratory variability must be considered by the practicing physician. Until certified antiepileptic drug standards in a biologic matrix are available from the National Bureau of Standards, a volunteer quality control program among laboratories is needed.
Anticonvulsants↗
A chemical ionization selected ion monitoring assay for methylphenidate and ritalinic acid.
A methane chemical ionization quantitative assay for methylphenidate and its major metabolite, ritalinic acid, is described. Methylphenidate and the internal standard, ethylphenidate, were extracted from plasma samples and derivatized to prevent thermal decomposition in the gas chromatography. Ritalinic acid was esterified with diazomethane and extracted as methylphenidate. The intensity of the protonated molecular ion of the derivatized drug and internal standard was measured by selected ion monitoring. Calibration curves were prepared from drug standards dissolved in drug-free plasma, and the lower limit of the curves extended to 0.5 ng methylphenidate per ml plasma. The method was used to generate plasma decay curves for pediatric patients undergoing methylphenidate therapy.
Child↗
Calculation of received dose intensity for combinations of drugs using small-cell lung carcinoma treatment regimens as examples.
Programs are presented for the calculation of received dose intensity in combination chemotherapy regimens. These provide methods for determining the final dose intensity, the mean cumulative dose intensity together with its standard error, and other tabular and graphic summaries. Two ways of dividing patients into high and low received-dose-intensity groups are proposed. Methods are illustrated using data from Mid-Atlantic Oncology Program (MAOP) 2183, a phase III evaluation of a six-drug alternating combination vs a three-drug "standard" combination treatment for extensive small-cell lung cancer. Comparisons of received dose intensity with demographic and outcome variables are presented.
Antineoplastic Combined Chemotherapy Protocols↗
A chromatography system for drug identification.
A classification system is described for drugs using thin-layer chromatography (TLC), gas-liquid chromatography (GLC) and ultraviolet (UV) spectrophotometry. The TLC classifications are based on division of the plate into zones relative to a set of mixed drug standards. The GLC classification is based on Kovats' retention indices. The procedure for classifying drugs is presented, together with a list of over 200 classified drugs.
Chromatography, Gas↗
Detection of diuretics in horse urine by GC/MS.
The use of diuretics in horses subject to doping control is prohibited. Thus, a sensitive screening procedure is required to identify the chemically different diuretics. We communicate here a method to detect three commonly employed acidic diuretics: bumetanide, ethacrynic acid, and furosemide. A liquid-liquid extraction on Extrelut 3 was performed at weak acidic and basic conditions using ethyl acetate as organic solvent. For analysis by GC, the diuretics were methylated on-column in the presence of MSTFA/TMAH, avoiding the commonly employed highly toxic derivatizing agent methyl iodide. For identification of diuretics, we used a mass selective detector operating in the SIM (selected ion monitoring) mode. Confirmation analysis may be obtained with a full scan run. Recoveries for the individual drugs ranged from 31 to 48% at the 100-ng/mL level for 3 mL urine, using calibration curves of drug standards with linearity from 2.5 to 20 ng injected. The limit of detection amounts to 40 ng/mL for the three diuretics. The method permits rapid and sensitive detection of diuretics in horse urine and is recommended for doping control.
Animals↗
Determination of free concentration of piroxicam and naproxen in plasma. The influence of experimental conditions in equilibrium dialysis.
An equilibrium dialysis method was established in order to investigate possible relationships between free drug concentrations of piroxicam and naproxen and clinical events. Therefore the influence of variations in pH, phosphate concentration and sodium azide concentration of the dialysis buffer on the free concentrations of piroxicam and naproxen was investigated. Piroxicam was found to have a pH-dependent protein binding. Therefore a good control of pH during the dialysis process is necessary. This has been achieved by increasing the buffer capacity of the dialysis buffer, by adding an antibacterial agent to the dialysis buffer and by cleansing the dialysis cells with 70% ethanol before use to prevent bacterial growth. Addition of 0.03% sodium azide as an antibacterial agent and the use of a 0.09 mol/l phosphate buffer gave good pH control. A method to correct for deviations of pH in measurements of free concentrations of piroxicam by a simple mathematical correction has been found. As naproxen was found to have a protein binding independent of pH, a pH-correction is not necessary for this drug. Standardized conditions in determination of protein binding of drugs by equilibrium dialysis are important, as composition of the dialysis buffer and pH of plasma compartment at equilibrium may influence the free concentration measurements. Comparisons of data from experiments using different methods are therefore difficult; the importance of pH-control is stressed. With the methods used in the present investigation, equilibrium dialysis in connection with HPLC, the coefficients of variation for piroxicam and naproxen free concentrations are 5.5% and 7.4%, respectively.
Azides↗
Addition of rifampin to combination antibiotic therapy for Pseudomonas aeruginosa bacteremia: prospective trial using the Zelen protocol.
A multicenter, prospective randomized trial was conducted to determine if the addition of rifampin to a combination therapy of an antipseudomonal beta-lactam agent and aminoglycoside improves the outcome of patients with Pseudomonas aeruginosa bacteremia. The Zelen protocol for randomized-consent design was used. Consent was sought only from patients randomized to the experimental therapy (rifampin+). If the experimental therapy was refused, the patient would then receive the standard combination therapy (control); however, when outcome was evaluated, all patients randomized to the rifampin+ group, including those that declined rifampin, were compared with the control group. One hundred twenty-one consecutive hospitalized patients with positive blood cultures for P. aeruginosa were enrolled. Entry was stratified for prior use of empiric antipseudomonal antibiotics, neutropenia, severity of illness, and presence of pneumonia. Fifty-eight patients were randomized to receive rifampin (600 mg orally every 8 h for the first 72 h and then every 12 h for a total of 10 days) plus a beta-lactam agent plus an aminoglycoside. Sixty-three received the standard therapy of a beta-lactam plus an aminoglycoside agent (control). Bacteriologic cure occurred significantly more frequently in patients randomized to the rifampin+ regimen. Breakthrough or relapsing bacteremias occurred in 2% of the three-drug (rifampin+) group, compared with 14% for the two-drug (standard therapy) group. Despite this favorable trend in bacteriological response, no significant differences in survival were seen for the two treatment groups. Rifamycin derivatives warrant further clinical study as antipseudomonal agents. The Zelen protocol appears well suited for comparative trials of antimicrobial agents.
Aged↗
Role and functions of the Nordic Pharmacopoeia.
It was proposed as early as in 1860 that a common pharmacopoeia should be worked out in the Nordic countries but it took more than a hundred years before such a pharmacopoeia was published and put into force. Ever since that early date the Nordic countries have, however, been striving for common regulations in the drug field with more or less intensity. The accomplishment of the common pharmacopoeia is therefore to be regarded only as a milestone on the long way to complete conformity of the different national drug regulations. The Nordic Pharmacopoeia has definitely broken through the borderlines of the earlier national pharmacopoeias, which were designed for the activities of the pharmacies, and has obtained recognition as a work on drug standards possible to apply in the manufacture and control of drugs no matter where they are produced or controlled. The Nordic Pharmacopoeia thus has wider functions and a greater responsibility than the earlier pharmacopoeias. This depends partly on the pharmacopoeia itself, partly on the development in the field of drug control. On the other hand the Nordic Pharmacopoeia has left some of the tasks of the earlier pharmacopoeias to different national formularies, manuals and other sources of information. This applies especially to galenical preparations. As expected the Nordic Pharmacopoeia has facilitated drug trade in the Nordic countries to a certain extent and it is no doubt of greatest value in the different control activities of the national health authorities. It is also a guide-book and a reference work for manufacturers and control laboratories of different kinds. But this is what it should be, what it is intended to serve as. In addition to that the Nordic Pharmacopoeia has played an essential role in many other respects; not least as initiator of different progressive work and drawer of guide-lines for future development in the drug field.
Pharmacopoeias as Topic↗
Role and function of the "Compendium Medicamentorum".
The increase of the co-operation among countries of Council for Mutual Economic Aid (CMEA = COMECON) in the area of drug production has forced these countries to elaborate a collection of unified quality specifications and test procedures for pharmaceutical preparations: the Compendium Medicamentorum (CM). The CM is in hands of the Expert Panel on Drug Standardization, the president of which is prof. J. Richter, head of the Institute for Drugs and Drug Control of the GDR, Berlin. It is issued in Akademie-Verlag Berlin in russian and german. The aim of the CM is to enable the multilateral contact among CMEA countries, above all on the basis of the specialization of drug production.
Drug Information Services↗
Relations between sales authorisation and pharmacopoeia.
At a time when the production and distribution of drugs and drug products is no longer confined within the national boundaries of particular countries, many thoughtful people are concerning themselves with the idea of standardisation of quality control procedures and specifications. For medicines currently marketed in different countries, a multitude of standards and specifications for both the raw materials and finished products exists. Plans for the regionalisation of drug standards have been put into operation but realistic estimates of progress agree that it will be measured and dignified. In one area there is the possibility for earlier action in reaching agreement on adequate specifications. The process of registration of a new drug substance for the first time presents an opportunity to make known to drug regulation authorities, academic and industrial pharmaceutical specialists, and other interested parties, the qualities and characteristics of the newly proposed agent and its dosage forms. A wide range of information will be needed on the chemical, physical, biological and physicochemical properties of the dosage forms as well as the raw materials of the active and inactive ingredients. Many of these requirements have already been described (3). There may be apprehension that the disclosure of some of this information could imperil the confidentiality of certain manufacturing processes or trade secrets, and adequate steps would be demanded to prevent this happening. The promulgation of a standard, at or shortly after the time of registration, should have been preceded by experimental tests, in the laboratories of the Authority, to verify the robustness of the analytical methodology. In some cases more extensive confirmation by collaborative study may be warranted. The elaboration of these concepts will be presented and examples brought forward of problems that have occurred in the past, and means to prevent them in the future.
Legislation, Pharmacy↗
The effect of aprotinin (trasylol) on postoperative bleeding in cyanotic congenital heart disease.
Despite the widespread clinical success in open-heart surgery, bleeding after cardiopulmonary by-pass (CPB) has been a common problem especially in cyanotic congenital heart disease. Recently, there have been reports demonstrating that treatment with high doses of aprotinin reduces postoperative bleeding. We studied the effect of aprotinin on postoperative bleeding in patients with tetralogy of Fallot who had undergone total correction in the Department of Thoracic and Cardiovascular Surgery of the Hacettepe University Faculty of Medicine, and compared our results with those in the literature. Ten patients out of 20 in the study were given high doses of aprotinin and were compared with the remaining 10 patients who had not received the drug. Standard anesthesia, perfusion and surgical techniques were used in all operations. The total amount of bleeding in the aprotinin-treated group was found to be 1530 ml, while in the other group it was 4185 ml (p < 0.05). The total quantity of blood transfused in the aprotinin-treated patients was 3250 ml while it was 5865 ml in the control group (p < 0.05). No significant effect of aprotinin was found on Hb, Hct, PT, aPTT and thrombocyte counts (p > 0.05). However, the effect of the drug on bleeding and coagulation time was found to be statistically significant (p < 0.05).
Aprotinin↗
Simultaneous liquid-chromatographic determination of 12 common sedatives and hypnotics in serum.
We present a method for simultaneously determining 12 hypnotics and sedatives (primidone, methyprylon, phenobarbital, butabarbital, butalbital, ethchlorvynol, pentobarbital, amobarbital, phenytoin, glutethimide, secobarbital and methaqualone) in 200 microliter of serum. Serum proteins are precipitated with an acetonitrile solution containing 5-(4-methylphenyl)-5-phenylhydantoin, the internal standard. The drugs are eluted from a reversed-phase column with a mobile phase consisting of an acetonitrile/phosphate buffer, at a flow rate of 3.0 ml/min. The eluted drugs are detected by their absorption at 195 nm; their quantities are estimated from their peak heights. Each analysis requires no longer than 30 min at the optimum column temperature of 50 degrees C. The lower limit of detection for all of these drugs is less than 10 ng/sample for drug standard. A sensitivity of 1.0 mg/liter of serum is attained routinely for each of the drugs. Analytical recoveries for the 12 drugs varied from 94 to 112%, with good day-to-day precision (CV between 3.8 and 10.4%). Of more than 35 drugs tested for possible interference, only ethotoin interferes with the analysis of phenobarbital.
Chromatography, Liquid↗
Clinical bioavaiability of nitrofurantoin--a case of bioinequivalence.
In a crossover study of the bioavailability of marketed nitrofurantoin tablets, there were significant differences in the urinary excretion of nitrofurantoin suggestive of bioavailability problems with this drug. Standard in vitro assessments of dissolution rate and disintegration time were not correlated with bioavailability and failed to detect 3 to 18 fold differences in the amount of nitrofurantoin absorbed. In fact, four lots, made by the same manufacturer had almost identical in vitro measurements (dissolution rate; distinegration time), yet two of these lots were only 6.6 and 26% as available as the reference nitrofurantoin product, and two others were comparatively available. The need for the development of an in vitro - in vivo correlation for control of lot to lot uniformity has clearly been demonstrated for nitrofurantoin. Such correlations must include tests other than those presently required.
Adult↗