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At least 253 records · Page 14Linked to original sources
PubMed2004

Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis.

We describe a drug-drug interaction between coformulated lopinavir/ritonavir and itraconazole in a patient infected with human immunodeficiency virus type 1 who had disseminated histoplasmosis. Coadministration of these agents led to a strong increase in itraconazole concentrations and a decrease in concentrations of its metabolite, hydroxyitraconazole, which is equally active pharmacologically. The dosage of itraconazole was reduced when it was used in combination with lopinavir/ritonavir.

AIDS-Related Opportunistic Infections↗
PubMed2006

Optimizing classification of drug-drug interaction potential for CYP450 isoenzyme inhibition assays in early drug discovery.

In drug discovery, the potential of cytochrome P450 inhibition of new chemical entities is frequently quantified in terms of IC50 values. In early drug discovery, a risk classification into low, medium, or high potential inhibitors is often sufficient for ranking and prioritizing of compounds. Although often 6 or more inhibitor concentrations are used to determine the IC50 value, the question arises whether it is possible to predict the risk class based on fewer inhibitor concentrations with comparable reliability. In this article, the authors propose a new integrated 2-point method with inhibitor concentrations chosen in accordance with the risk classification. They analyze its predictive power and the feasibility of not only classifying the compounds into different risk classes but also ranking those compounds that have been binned into the middle risk class. The proposed integrated 2-point method is thus highly suitable for automation. Altogether, it maintains the quality of the prediction while considerably reducing time and cost. The proposed method is applicable to other IC50 assays and risk classifications.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1995

The application of in vitro models of drug metabolism and toxicity in drug discovery and drug development.

In vitro models are being used increasingly during all phases of the drug development process in concert with the more traditional in vivo toxicological and pharmacokinetic evaluations. These in vitro models may be classified empirically as either validated in vitro screens, value-added screens or 'ad-hoc' mechanistic screens. The application of these screens is discussed with respect to their level of validation, standardization, uses of human tissue, level of iteration with in vivo studies, regulatory position and utility in the drug discovery and development process. The predictability and reproducibility of these screens is discussed, as well as future trends in regard to emerging technology and its application.

Animals↗
PubMed1990

Drug use in pregnancy: a preliminary report of the International co-operative Drug Utilization Study. Collaborative Group on Drug Use in Pregnancy.

In a field, such as drug use in pregnancy, where knowledge is often based on scanty information, and systematic permanent surveillance is needed, so as to avoid reliance on data obtained in widely differing contexts, an international co-operative network was set up, using a cheap and standardized interview technique. The study, originally European, can now be considered 'intercontinental', as the twenty-five countries where data is already being collected represent four of the five continents. Thirteen participating countries have already returned about ten thousand completed forms. Fifteen per cent of the 9714 enrolled women took no drugs at any state of pregnancy, while each taker received an average of 2.6 (range 1-13) prescriptions. Intracountry and intercountry differences were found in prescribing habits and in other characteristics of the population. Although the large amount of data collected is still being processed, preliminary findings indicate that this study seems to have been warranted.

Drug Utilization↗
PubMed2006

Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug.

Sulfamethoxazole (SMZ), a sulfonamide with well-known anti-bacterial properties, is not freely soluble in water and causes problems in its clinical applications. In the present study we investigated the potential of ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimers as drug carriers of SMZ by aqueous solubility, in vitro release as well as anti-bacterial activity studies. Results showed that the aqueous solubility of SMZ was approximately proportional to dendrimer concentration (a 40-fold increase in solubility in 10mg/ml G3 PAMAM dendrimer solutions compared with that in double-distilled water at 37 degrees C). The in vitro release of SMZ in the presence of PAMAM dendrimers was significantly slower compared to pure SMZ dissolved in ethanol. Microbiology studies showed that PAMAM dendrimers could increase the anti-bacterial activity of SMZ (a 4- or 8-fold increase in the anti-bacterial activity of SMZ in dendrimer solution compared to pure SMZ dissolved in dimethylsulfoxide (DMSO) or 0.01 M NaOH solution). The in vitro release behavior and anti-bacterial activity studies indicated that PAMAM dendrimers might be considered as potential drug carriers of sulfonamides with a sustained release behavior under suitable conditions.

Anti-Bacterial Agents↗
PubMed1999

Food and Drug Administration Modernization Act of 1997; list of documents issued by the Food and Drug Administration that apply to medical devices regulated by the Center for Biologics Evaluation and Research. Food and Drug Administration, HHS. Notice.

The Food and Drug Administration (FDA) is publishing a list of documents issued in response to the Food and Drug Administration Modernization Act of 1997 (FDAMA), and clarifying their applicability to medical devices regulated by the Center for Biologics Evaluation and Research (CBER). This notice is intended to inform the public of the availability of these documents, clarify their scope of applicability, and to provide instructions on ways to access them.

Equipment and Supplies↗
PubMed1984

[Antisecretory and mucosa-protecting drugs in the acute care of peptic ulcer. Review of action principles, healing rates and side effects of approved ulcer drugs and drugs under clinical trial].

Peptic ulcers can be treated successfully with antisecretory drugs and drugs which have a protective effect. Thanks to their good tolerance and a form of administration acceptable to patients, the H2-receptor antagonists have won a leading position amongst the other ulcer therapeutics. It remains to be seen whether the substituted benzimidazoles will develop into a serious competitor. Until now the clinical experiences with the prostaglandins in the treatment of ulcers are not very encouraging.

Acute Disease↗
PubMed1998

Drugs for pediatric emergencies. Committee on Drugs, Committee on Drugs, 1996 to 1997, Liaison Representatives, and AAP Section Liaisons.

This statement provides current recommendations about the use of emergency drugs for acute pediatric problems that require pharmacologic intervention. At each clinical setting, physicians and other providers should evaluate drug, equipment, and training needs. The information provided here is not all-inclusive and is not intended to be appropriate to every health care setting. When possible, dosage recommendations are consistent with those in standard references, such as the Advanced Pediatric Life Support (APLS) and Pediatric Advanced Life Support (PALS) textbooks. Additional guidance is available in the manual Emergency Medical Services for Children: The Role of the Primary Care Provider, published by the American Academy of Pediatrics, as well as in the PALS and APLS textbooks.

Drug Therapy↗
PubMed2004

[1, 2-Bis(2, 6-difluoro-3-hydroxyphenyl)ethylene-diamine]platinum(II) complexes, compounds for the endocrine therapy of breast cancer - mode of action II: contribution of drug inactivation, cellular drug uptake and sterical factors in the drug-target interaction to the antitumor activity.

The marked activity of [meso-1, 2-bis(2, 6-difluoro-3-hydroxyphenyl)ethylenediamine]platinum(II) (meso-3-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) on the hormone-sensitive MXT-M-3, 2 breast cancer implanted in mice is most probably due to a mechanism based on the reduction of the endogenous estrogen level. Cytotoxic effects which are poorly pronounced in experiments on several breast cancer cell lines (e.g. MCF-7), do not significantly contribute to the anti-breast cancer activity of this compound. In contrast to this, the standard cisplatin and the structurally related comparison compound [meso-1, 2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (meso-4-PtLL', L, L' = Cl(2) or L = OH(2), L' = OSO(3)) are strongly active in vivo as well as in vitro. Both effects entail programmed cell death, which is responsible for the inhibition of the tumor growth. The minor cytotoxicity of meso-3-PtLL' in breast cancer cell cultures is caused neither by an inappropriate rate of reaction with bionucleophiles (e.g. by a too fast inactivation by plasma proteins) nor solely by the observed poor absorption by the tumor cells resulting in an insufficient drug concentration at the DNA. Additionally, an impeded reaction with biologically important, guanine-rich sequences of DNA (owing to the 2, 6-standing F atoms which hinder the drug-target inter action) must be assumed as cause of its marginal cytotoxicity.

Absorption↗
PubMed2001

Screening of drug candidates for their drug--drug interaction potential.

Within the past year, additional papers have been published that focus on higher-throughput drug-interaction screening. Some papers have described enzyme assays that can be used to evaluate inhibition or induction of the human cytochrome P450s. At the same time, numerous investigators have developed computational (in silico) methods to predict interactions and have validated the approach using in vitro (assay-derived) data. These so called 'in silico--in vitro' correlations have great potential and may complement existing 'in vitro--in vivo' correlations.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed2006

Clinical risk management in Dutch community pharmacies: the case of drug-drug interactions.

BACKGROUND: The prevention of drug-drug interactions requires a systematic approach for which the concept of clinical risk management can be used. The objective of our study was to measure the frequency, nature and management of drug-drug interaction alerts as these occur in daily practice of Dutch community pharmacies. METHODS: In total, 63 Dutch pharmacies collected all drug-drug interaction alerts during 153 research days (on average 2.4 days/pharmacy), as well as variables related to these alerts, such as involved medicines, first time or recurrent drug-drug interaction, same or different prescribers, patient data (age, sex) and information about the management of drug-drug interactions by the pharmacy. The latter was discriminated into internal procedures only and external action, such as communication with the patient, the prescriber or the anticoagulation clinic and prescription modification. All drug-drug interactions were classified into categories of clinical relevance (A-F) and available evidence (0-4). RESULTS: A total of 43,129 prescription-only medicines were dispensed during the study period. On average, 16.8 interaction alerts per day per pharmacy were collected. Approximately 6% of all prescriptions generated a drug-drug interaction alert. Of all alerts (n = 2572), 31.1% occurred for the first time and with 21% two different prescribers were involved. The 20 most frequently occurring drug-drug interaction alerts accounted for approximately 76% of all alerts. Cardiovascular drugs, NSAIDs, oral contraceptives and antibacterials were most frequently involved. External action was taken in response to 27.3% of the alerts, meaning either a modification of one of the concerned prescriptions (n = 65; 9.3%), communication with the prescriber or anticoagulation clinic (n = 90; 12.8%) or communication with the patient or a relative (n = 547; 77.9%). Where there was no external action (n = 1860; 72.3%), pharmacists concluded in about two-thirds of cases that the drug-drug interaction had been managed in the past. Other reasons not to intervene externally were for instance: incorrect alert; acceptable drug-drug interaction; or outcome of the interaction considered irrelevant. Adjusted for several variables, a first alert was found to be a main determinant for external action. After stratifying for first alerts no other significant determinants were found. CONCLUSIONS: A high frequency of drug-drug interaction alerts was found. Most concerned recurrent alerts, which were the main reason not to act externally. Concerning the assessment phase in the risk-management process, drug-drug interactions with no or low evidence/relevance should be reconsidered. Concerning the management of drug-drug interactions in pharmacies, the opportunity to actively suppress alerts for a certain period of time should be studied in more detail. There are indicators that the management of patient-orientated advice could be improved and a greater degree of consistency developed for the management of first and recurrent interaction alerts.

Adolescent↗
PubMed2006

Role of follow-on drugs and indications on the WHO Essential Drug List.

INTRODUCTION: The World Health Organization's Essential Drug List (EDL) contains first-in-class drugs and subsequent class entrants (follow-on drugs) deemed necessary to combat diseases prevalent throughout the world, with a special emphasis on developing nations. The EDL also includes originally approved and follow-on indications. There are opposing views regarding the value of follow-on drugs and indications. Critics suggest many follow-on drugs and indications offer little or no benefit to patients. Advocates counter that follow-on drugs offer advantages in terms of improved effectiveness, compliance and patient satisfaction. OBJECTIVE: In order to inform this debate on the value of follow-on drugs and indications we examined the numbers of follow-on drugs on the EDL and the extent to which follow-on indications are recommended. METHODS: We identified all 312 drugs on the 14th edition of the EDL, omitting 72 non-pharmaceutical entities. For the 240 pharmaceutical entities we ascertained whether the Food and Drug Administration (FDA) had approved them, and, if so, when each was approved. We chose a validated therapeutic classification system - the United States Pharmacopeia's Model Guidelines for Medicare formulary management - in order to distinguish first-in-class and follow-on drugs on the EDL. Specifically, we selected the formulary key drug type as our benchmark therapeutic class. We assigned each EDL drug to a formulary key drug type. We defined first-in-class drugs as the first in each formulary key drug type, and follow-on drugs as all other drugs in each formulary key drug type. We identified follow-on indications by comparing WHO-listed indications with the original approved indication(s) by the FDA. Finally, we examined the therapeutic rating (priority vs. standard) given by the FDA to follow-on drugs on the EDL. RESULTS: Sixty-three per cent of the EDL drugs were follow-ons; 15% of the indications were follow-on indications. Fourteen drugs were listed in multiple WHO (sub) groupings; and 49% of follow-on drugs were given a priority rating by the FDA. CONCLUSIONS: In light of the fact that the EDL only includes drugs and indications deemed essential, the large number of follow-on drugs, follow-on indications, and priority-rated follow-on drugs on the EDL suggest their importance. From a public policy perspective, it may prove counterproductive to erect hurdles that impede follow-on research and development.

Developing Countries↗