Joseph F. Gallelli

Development of a Questionnaire for Detecting Potential Adverse Drug Reactions

OBJECTIVE: To develop a comprehensive list of symptoms categorized by body system as part of a questionnaire for detecting potential adverse drug reactions. DATA SOURCES: A preliminary list of symptoms in lay terminology was extracted from the “Side Effects” section of all drug monographs contained in the United States Pharmacopeia Dispensing Information (USP DI) computerized database (Volume II, Advice for the Patient) using natural language processing software. The list was sorted alphabetically and duplicate terms were eliminated. Symptoms were then categorized by body system or anatomic region. A preferred term for each symptom was selected when multiple synonyms and related words were listed. Finally, all of the symptom terms were incorporated into a thesaurus from which the questionnaire was derived. RESULTS: The questionnaire will be used as part of a computer-assisted interview, developed to solicit information from patients regarding their medication regimens and to systematically query them regarding the presence of salient symptoms or complaints. The computer system will eventually interface with the USP DI database to identify drugs from a patients regimen that may be associated with adverse symptoms. The symptom thesaurus will provide the link to the USP DI database. Preliminary experience with the questionnaire in a limited number of patients has been encouraging. CONCLUSIONS: The questionnaire can assist clinicians in identifying drug-related symptoms including unreported adverse clinical effects of newly marketed or investigational therapeutic agents. When the questionnaire is computerized and linked to a comprehensive database, it can be more widely used to alert healthcare providers of potential adverse drug reactions that may otherwise go undetected.

Thermal stability of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH)

The stability of solutions of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH [LHRHa] after heating to 60C for 5 days, after repeated freezing and thawing, and after refrigeration at 4C for 8 days has been examined. None of the treatments caused a detectable alteration in the HPLC profile, and none caused a significant change in biological activity in vivo. It is concluded that D-trp6-pro9-NEt-LHRH can withstand mild heating, repeated freezing and thawing, and short-term refrigeration without apparent change in HPLC profile or biological activity. It is also concluded that the results obtained with the HPLC method correlate well with the results from the in vivo bioassay.

Development of carbamazepine:phospholipid solid dispersion formulations

Abstract This study is concerned with the development of a carbamazepine (CBZ):phospholipid (PL) solid dispersion formulation with improved dissolution characteristics. CBZ powders were blended with PL to produce CBZ:PL physical mixtures or made into solid dispersions with PL by the solvent method. CBZ exhibited significantly improved dissolution rates in PL coprecipitate (coppt) as compared to the physical mixtures or CBZ alone. Dissolution studies suggested that less than 10:1 ratio of CBZ to PL (9.1% PL) was required to disperse amorphous CBZ completely in the carrier. The coppt yielded a 3.6-fold greater initial dissolution rate (computed over the 5 min of dissolution) than the pure CBZ. Also, the total amount dissolved after 60 min was 2.1-fold greater at a CBZ:dimyristoylphosphatidylglycerol (DMPG) of 10:1 ratio (9.1% DMPG) than for the corresponding pure drug. Increasing the DMPG concentration to 4:1 (20% DMPG) compositions resulted in only a further 10% increase in the initial dissolution rate and 8.5% increase in the limiting concentration. Thus, a small amount of PL improved the dissolution of CBZ to a significant level. Some effect was also observed by changing the composition of the PLs. The coppts were formulated into tablets in order to compare the dissolution profile with that of TegretolR, a commercially available tablet of CBZ. It was found that the total amount dissolved after 60 min was two-fold higher in our tablet formulation than the commercial product, TegretolR. Powder X-ray diffraction spectra showed no changes in the diffraction patterns of CBZ in the coppt. It is concluded that CBZ:PL solid dispersions may have clinical advantages of quick in-vivo release to yield better bioavailability than existing commercial formulations.

Quantitation of flupirtine and its active acetylated metabolite by reversed-phase high-performance liquid chromatography using fluorometric detection.

A simple, selective and sensitive procedure is described for the quantitation of flupirtine maleate (FLU) and its active acetylated metabolite (Met. 1) in plasma and urine. Using a 0.5-ml sample, a sensitivity of 10 ng/ml is easily achieved with a reversed-phase octadecylsilane (C18) column, and a high-performance liquid chromatographic system with fluorescence detection. Quantitation from plasma involves addition of an internal standard, protein precipitation with acetonitrile and a sample concentrating step, while for urinalysis the samples are taken through a single extraction with methylene chloride. Analytical recoveries of FLU and Met. 1 from plasma averaged greater than or equal to 95%, while from urine only 60 and 50%, respectively, could be recovered. The overall, inter- and intra-day variability for both FLU and Met. 1 averaged 6, 5 and 3%, in plasma, respectively. Standard calibration plots in plasma were linear (r greater than or equal to 0.99) for FLU (range: 0.01-10.0 micrograms/ml) and Met. 1 (range: 0.5-25 micrograms/ml) over the extended range. A slightly modified elution system was employed for quantitation of FLU and Met. 1 in urine.

Quantitation of testolactone and 4,5-dihydrotestolactone in plasma and urine using high-performance liquid chromatography

A rapid, sensitive, and selective assay is described for the quantitation of both testolactone and its recently identified metabolite, 4,5-dihydrotestolactone, in plasma and urine using high-performance liquid chromatography. The procedure includes a methylene chloride extraction prior to chromatography and quantitation using peak height ratios (ultraviolet absorbance detection, 242 nm) of testolactone and 4,5-dihydrotestolactone to the internal standard, testosterone. A sensitivity of 20 ng/ml for both testolactone and 4,5-dihydrotestolactone is easily achieved using only 0.5 ml of sample. Mean recoveries for testolactone and its metabolite are 95.0% and 81.8%, respectively, and the mean coefficient of variation of the procedure is 3.5% for the drug and 7.1% for the metabolite. This method is currently being used to study the pharmacokinetics of testolactone and 4,5-dihydrotestolactone in male patients. A steady-state plasma concentration versus time profile from a representative patient is included.

Investigational Drug Information

The drug information appearing in this column is for investigational drugs studied in clinical research protocols being pursued in the Clinical Center at the National Institutes of Health. This same information, in the form of an “Investigational Drug Fact Sheet,” is distributed, prior to its use, to the dispensing pharmacist and the appropriate nursing units involved in the administration of the drugAs with all investigational drugs, the drugs reported in this column have a Notice of Claimed Investigational Exemption for o New Drug (IND) assigned to them by the Food and Drug Administration (F.D.A.).

EVALUATION OF ANTINEOPLASTIC DRUG PACKAGE INSERTS FROM DIFFERENT COUNTRIES

1. Gillum JG, Israel DS, Polk RE. Phannacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 1993;25:450-82. 2. Lindstrom TO, Hanssen BR, Wrighton SA. Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers. Antimicrob Agents Chemother 1993;37:265-9. 3. Grau E, Fontcuberta J, Felez J. Erythromycin-oral anticoagulants interaction (letter). Arch Intern Med 1986;146:1639. 4. Gascon MP, Dayer P. Comparative effects of macrolide antibiotics on liver monooxygenases (letter). Clin Phannacol Ther 1991;49:158.

An Aerosol Laboratory in a Hospital Pharmacy

An aerosol laboratory was established in the hospital pharmacy at The Clinical Center of the National Institutes of Health in late 1965. The need for such a laboratory was prompted by the requests of nurses and clinical investigators for pharmaceuticals in an aerosol dosage form. Specifically, physicians in the Dermatology Branch of the National Cancer Institute had requested the formulation of dermatological preparations in the form of aerosols for the possible treatment of patients with mycosis fungoides. It was hoped that aerosol therapy would be effective and lead to better patient care because of its ease of application, elimination of contamination or deterioration of product by contact, oxidation, moisture or light, and elimination of physical contact with a consequent reduction of pain and infection. Evaluation of the potential usefulness of an aerosol unit in a hospital pharmacy, and the advantages and disadvantages of such a unit, are reported. Selection of the basic equipment needed for the aerosol filling or packaging, principles of operation and control and evaluation procedures are discussed.

Environment for Sterile Dosage Formulation & Control

The need for removal of particulates, either biological or inert, in clean rooms of hospitals involved in preparation and control of sterile dosage formulations and intravenous additive solutions, prompted an investigation of the methods used to aid in controlling contamination. This was accomplished in large part by the use of laminar flow hoods in clean rooms. Evaluation of laminar flow hoods and clean room ultraviolet hoods, along with advantages and disadvantages of each, is reported. Selection of equipment for specific operations is discussed.