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PubMed2000

[Potential drug interactions and number of prescription drugs with special instructions at hospital discharge].

OBJECTIVE: Up to 6% of all hospitalizations are due to adverse drug reactions and 20% of these are caused by drug-drug interactions. There is only little information on the prescription frequency of drug-combinations with the potential to induce dangerous drug-drug interactions and drugs with the need for special patient instruction (e.g. inhalers). The aim of our study was to investigate the frequency of such drug prescriptions at hospital discharge. PATIENTS AND METHODS: In a retrospective, descriptive study drug prescriptions of 100 patients discharged consecutively from the department of internal medicine of a 300 bed-hospital were analysed. Possible drug-drug interactions were detected using a special computer program. Furthermore, the number of prescriptions warranting patient instruction such as anticoagulants, antidiabetics, hormones, immunosuppressive drugs, chemotherapeutics, antituberculotic and antiepileptic drugs as well as inhalatives and injections was recorded. RESULTS: The mean age of the 100 patients (61 men, 39 women) was 61.7 years, the mean duration of the hospital stay was 9.2 days. At discharge, patients took an average of 3.5 different drugs. Half of the patients were given drug-combinations with the potential for drug-drug interactions, whereby 5% were at risk for the development of interactions of severe and 42% of intermediate degree. All drug-combinations with potentially severe interactions were prescribed deliberately. 31% of all patients took medications with the need for special education, with inhalatives being the most frequent. The prescription of drugs with potential interactions and the necessity for special patient instruction was more frequent in the elderly. CONCLUSIONS: Drug-combinations with the potential of harmful interactions and drugs with the requirement for special patient instruction are frequently prescribed at hospital discharge. The frequency of prescribing these drugs increases with age. Detection of potentially dangerous drug-drug interactions is simplified by special computer programs. Careful patient instruction about the use of certain drugs is a key issue to improve patient compliance and to guarantee an optimal treatment effect.

Aged↗
PubMed1998

Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole.

OBJECTIVE: To study, in three separate investigations, the potential interaction between omeprazole and three different non-steroidal anti-inflammatory drugs (NSAIDs; diclofenac, naproxen and piroxicam) in healthy male and female subjects. METHODS: Each investigation was an open, randomized, three-way cross-over study, in which the subjects were given omeprazole 20 mg once daily for 1 week, the NSAID in therapeutic daily doses (diclofenac 50 mg bid, naproxen 250 mg bid, or piroxicam 10 mg om), or a combination of omeprazole and each NSAID. The plasma concentrations of the NSAID as well as of omeprazole were determined on the last day of each investigation period. RESULTS: None of the NSAIDs studied had any effect on the plasma concentration versus time curve (AUC) of omeprazole. It was also demonstrated that omeprazole 20 mg daily had no significant influence on the pharmacokinetics of the NSAIDs. The AUC ratio, (NSAID +omeprazole):NSAID alone, was 1.11, 0.99, and 0.99 for diclofenac, naproxen, and piroxicam, respectively. CONCLUSION: Diclofenac, naproxen, and piroxicam can be administered together with omeprazole 20 mg daily without need for dosage alteration. There was no significant change in the bioavailability of theses NSAIDs during omeprazole therapy in this study.

Adult↗
PubMedDate not supplied

Drug utilization review of sedative/hypnotic agents in Texas Medicaid patients. Texas Medicaid Vendor Drug Program Drug Utilization Review Board.

OBJECTIVE: To assess use of sedative/hypnotic agents in Texas Medicaid patients and evaluate practitioner receptiveness to intervention letters concerning sedative/hypnotic prescribing generated by the Texas Medicaid Drug Utilization Review (DUR) Board. DESIGN: Retrospective DUR. SETTING: Texas Medicaid retrospective DUR program. PATIENTS OR OTHER PARTICIPANTS: 244 Texas Medicaid patients and 291 Texas physicians. INTERVENTION: Patient profiles for Texas Medicaid patients were reviewed retrospectively to quantify sedative/hypnotic prescribing practices. Intervention letters were prepared and sent to physicians directly involved in the care of patients receiving excessive sedative/hypnotic therapy. Physician responses were categorized based on information presented in the intervention letter and circumstances surrounding the identified patient. Prescribing practices were assessed approximately 1 year after the intervention to determine the impact of intervention letters on prescribing. MAIN OUTCOME MEASURE: Physician response to intervention letter. RESULTS: Responses were received from 208 of 291 physicians (71.5%). Approximately 40% of physicians agreed in principle with the suggestions offered by the Texas Medicaid DUR Board to minimize chronic sedative/hypnotic use. Almost one-half of these physicians had discontinued sedative/hypnotic therapy for the identified patients 1 year after the intervention. Approximately 9% justified continued sedative/hypnotic use based on patient diagnosis or refractory response to treatment, and 55 physicians (26.4%) were unwilling to alter therapy because of patient-specific factors. CONCLUSION: Through the use of retrospective DUR, Texas Medicaid patients receiving excessive amounts of sedative/hypnotic agents were identified and improvements in sedative/hypnotic therapy were initiated. DUR can be useful not only in identifying problem areas, but also in encouraging physicians to modify prescribing practices through educational means.

Adolescent↗
PubMed1997

Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users.

Many clinicians are confronted by the use of illicit drugs on a daily basis. The unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and nicotine is a major cause of morbidity and mortality. Multiple factors have inhibited the scientific study of these agents including prohibition, public denial and lack of commercial interests. In dealing with problems related to these drugs, clinicians need a scientific understanding of their pharmacology, quantifiable effects and potential adverse effects. Illicit drug users select drugs with particular pharmacokinetic parameters and pharmacodynamic properties. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution and high free drug clearance are pharmacokinetic characteristics which predict a high potential for harmful use because these factors increase positive reinforcement. Drug users adapt the method and route of drug administration to optimise the delivery of the drug to the brain while attempting to maximise the bioavailability of the drug. Inhalation and smoking are the routes of administration which allow the most rapid delivery of drug to the brain, while intravenous injection maximises the bioavailability of an administered drug. Each route of administration results in attendant complications related to mucosal damage, carcinogenesis and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long half-life, low free drug clearance and sufficient drug exposure to allow development of tolerance. The preventive or reductive pharmacotherapeutics of illicit drug use makes use of several subsets of agents: those which act on the same receptor or system as the illicit drug (such as methadone), those which produce an adverse reaction on consumption of the illicit drug (such as disulfiram) and those which symptomatically attenuate illicit drug withdrawal symptoms (such as clonidine). Many new agents are being trialled as potential preventive or reductive agents. It is important to consider pharmacotherapy as only one potential part of the treatment of illicit drug users. The complications of illicit drug use present many therapeutic challenges. As with all patients consuming multiple drugs, illicit drug users are prone to developing drug interactions. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the additive effects of different drugs on the central nervous system. However, alcohol, cocaine, disulfiram, methadone and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme stimulating drugs in diminishing the efficacy of methadone are the most commonly encountered.

Drug Interactions↗
PubMed1998

Drug interactions at the renal level. Implications for drug development.

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vivo animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development. It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism. The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (> 30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.

Animals↗
PubMed2006

Drug-herb interactions: eliminating toxicity with hard drug design.

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called "hard drugs" that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Illicit drug initiation among institutionalized drug users in China.

AIMS: To examine the circumstances and correlates associated with initiation of illicit drug use among institutionalized drug users in China. DESIGN: Cross-sectional, retrospective study. SETTINGS: Six compulsory drug cessation programs in Yunnan Province and Gunagxi Zhuang Autonomous Region of China. PARTICIPANTS: A gender-stratified random sample of 833 drug users (88% males and 12% females) enrolled in compulsory drug cessation programs in November 1996. MEASUREMENTS: Circumstances of illicit drug initiation (age, type of drugs, routes of drug administration, social setting, source of drugs, reasons for drug use), the risk behaviors and risk perceptions prior to drug initiation. FINDINGS: The majority of participants initiated drug use with heroin (90%). Initial drugs were frequently administered through sniffing/snorting (55%) and smoking cigarettes mixed with a drug (38%). First drug use occurred most commonly at a friend's home (65%) and in the company of other drug users (83%). Drugs were generally provided free for first-time use by other drug users (72%). Reasons for first drug use included experimentation (90%), being lured into drugs by other people (44%) and relaxation (42%). Most drug users had a history of regular cigarette smoking (89%), alcohol consumption (49%) and deviant behaviors (51%) prior to their drug initiation. The majority perceived that their friends (90%) and neighbors (88%) used illicit drugs. CONCLUSIONS: The findings are similar to studies in western countries with respect to the pattern and correlates of illicit drug initiation, and underscore the need for drug prevention efforts in China.

Adolescent↗
PubMed2004

Knowledge and perceptions of drug quality among drug sellers and consumers in Lao PDR.

In most developing countries, including the Lao People's Democratic Republic (PDR), high prevalence of low quality drugs has been reported. The aim of this study was to explore knowledge and perceptions regarding drug quality among drug sellers and consumers, in Savannakhet province, Lao PDR. Quantitative and qualitative methods were used. Fifty-nine drug sellers and 278 exit customers were interviewed. Eight focus group discussions with drug sellers and community members were conducted. There was inadequate scientific drug knowledge among drug sellers. Only a few customers were aware of the existence of low quality drugs. Only one drug seller knew what constitutes a good quality drug according to the given criteria, and only two drug sellers knew the correct temperature for drug storage. Forty-four per cent had correct knowledge on drug labelling and 73% could read the expiry date. Fifty-eight per cent stated that they bought some drugs from unauthorized sources. Both drug sellers and consumers also elaborated on a local definition of drug quality. They determined drug quality by its perceived efficacy in the sense that a drug is good if it takes the disease away. They also trusted the responsible authorities not to provide them with low quality drugs. A majority of the consumers (73%) did not worry about the quality of the drugs, their greatest problem being financial constraints. People living in urban districts had significantly more knowledge on aspects of drug quality than those living in rural and remote areas. The limitations in scientific knowledge among drug sellers and the low awareness among consumers may contribute to the continued existence of low quality drugs. Government interventions through training of drug sellers and drug information for lay people are suggested.

Adolescent↗
PubMed1998

Drug trafficking and drug use among urban African-American adolescents: a causal analysis.

OBJECTIVE: To test the hypothesis that involvement in drug trafficking leads to illicit drug use among urban African-American adolescents. METHODS: Self-reports of substance use, illicit drug use, and drug trafficking were obtained at baseline and every 6 months for 24 months from 383 African-American early adolescents. Transitions between involvement in drug trafficking and illicit drug use over time were examined. Path analysis was conducted to examine the causal relation between drug trafficking and drug use. RESULTS: Among the 35 youth who were initially involved only in drug trafficking, 22 (67%) subsequently used illicit drugs. Of the 53 youth who were initially involved only in illicit drug use, only 19 (42%) continued using drugs at later waves (p < 0.05). Path analysis revealed that baseline drug trafficking had a strong effect on subsequent drug trafficking and drug use, whereas baseline drug use did not have an effect on subsequent drug use or drug trafficking. CONCLUSIONS: Initiation of drug trafficking by adolescents appears to lead to sustained involvement in drug-related activities, including continued drug trafficking and drug use. By contrast, initiation of drug use does not necessarily lead to continued involvement in drug-related behaviors.

Adolescent↗
PubMed1993

[Role of drug metabolism studies in the development of new drugs].

The efficacy and toxicity of drugs are closely related to the kinetics and metabolism of drugs. The metabolism of drugs is variable depending on individual, age, sex and species differences. Therefore, in this paper, the following strategies of drug metabolism studies on each phase of development of new drugs is discussed: 1. Early selection of drug candidates for the development of new drugs by a preliminary drug metabolism study. 2. Selection of a drug candidate for the repeated administration of drug toxicity study. 3. Drug metabolism studies on sex- and species-related differences in experimental animals. 4. Drug toxicity and metabolic activation of drug candidates. 5. In vitro and in vivo drug metabolism studies in humans. 6. Arrangement of drug metabolism and pharmacokinetic profile of drug candidate for the phase I study. 7. Role of pharmacokinetics and drug metabolism studies in the phase I study. 8. Pharmacokinetic and metabolic studies for the development of chiral drugs. 9. Approach to drug design from the viewpoint of drug metabolism studies. In conclusion, performance of drug metabolism studies starting from the early stage of drug development is a powerful and useful tool to increase the efficiency and to minimize the period and cost for the development of new drugs.

Animals↗
PubMed2000

[Development and evaluation of an individuals-oriented information-provision system for outpatients--utility of "drug Usage sheets" and "Drug Information Cards" for patient consultation].

We have implemented an information-provision system for outpatients at the department of pharmacy, University of Tokyo Hospital, in order to comply with the revised Pharmacists' Law by which pharmacists have been obliged to provide patients with information necessary for rational usage of medicine at the time they receive dispensed drugs. This system is linked on-line with the order entry system to print "Drug Usage Sheets" containing important drug information such as therapeutic effects and adverse reactions, as well as photographic color views of drugs. We prepared the sheets by extracting and classifying the original information, and by converting medical terms into lay expressions. Moreover, we developed "Drug Information Cards" to inform each patient of severe side effects and drug interactions, which should affect drug compliance, and implemented an individuals-oriented information system using both the "Drug Usage Sheets" and "Drug Information Cards." In this study, we evaluated the usefulness of this system from the viewpoint of patients' recognition and understanding on necessary drug information. It was indicated from questionnaires to patients that the "Drug Usage Sheets" help most patients understand the names, usage, effects, and general cautions including slight adverse reactions (i.e. grade 1), and that the use of colored letters for important parts and pictograms is a useful method to attract more attention from patients as compared with a conventional method using only letters. Most patients answered that the "Drug Usage Sheets" can be utilized in many ways and valuable in taking drugs with assurance. We formulated the "Drug Information Cards" by information processing: separation of early symptoms of adverse effects into subjective and objective ones and their classification into related organs. Moreover, the brand names of drugs which may cause drug interactions have been listed on the cards so that worsening of adverse reactions and drug interactions can be avoided. Although 14% of the patients answered that they became unsecured when informed on side effects, the percentage of such patients was significantly higher with those who received caution-required drugs for the first time or who have experienced drug side effects before, suggesting the need for combining oral explanation based on each patient's background and understanding on drug adverse effects. In conclusion, an efficient provision of drug information became possible through our integration of necessary drug information in this study, and the individuals-oriented system of drug information was established, which was demonstrated to contribute to the rational usage of medicine.

Drug Information Services↗
PubMed2003

Potentially significant drug interactions of class III antiarrhythmic drugs.

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin. Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug. Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions. Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism. Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide. It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism. Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically. If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.

Amiodarone↗
PubMed2002

The drug lag: new drug introductions in India in comparison to United States.

CONTEXT: Important drugs become available late in India, some much later, than in the United States. The prevailing trends in new drug introduction in India as compared to USA have been looked into this study. OBJECTIVES: To determine the trends in new drug introduction, both qualitative and quantitative, during the period, 1988 to 1999, in India. DESIGN: Data search, compilation and analysis. SOURCE: Various issues (1982-1997) of "Journal of the American Pharmaceutical Association" and "Indian Drug Manufacturers Association" Bulletin (1988-2000). MAIN OUTCOME MEASURES: Average drug lag, trends in drug lag over years (1988-1999), drug lag by therapeutic categories, drug lag by FDA classification of drugs. RESULTS: Average drug lag in India during the years 1988 to 1999 was 4.02 +/- 2.77 years. It has shown a decreasing trend over the years. Gastrointestinal drugs have the least drug lag (1.2 +/- 2 years). Cardiovascular drugs suffer the highest drug lag among therapeutic categories (5.21 +/- 2.2 years). 1AA drugs and 1P drugs (FDA classification) are priority drugs in India also. 1A drugs, which are important new therapeutics agents have been unfortunately neglected by drug developers and regulatory authorities in India. CONCLUSION: Important new drugs become available in India with a drug lag. This 'drug lag' has declined over the years. Qualitative analysis show that 1A class drugs, supposedly the most important category, has been the worst affected.

Drug Approval↗
PubMed2002

Drug abuse's smallest victims: in utero drug exposure.

The social and economic impact of drug use on our global population continues to increase leaving no geographical, social or cultural group untouched. The National Institute on Drug Abuse (NIDA), in one of the few large surveys of maternal abuse, found that 5.5% of mothers reported taking an illicit substance during gestation. These figures certainly are underestimates due to the stigma of drug use during pregnancy and the accompanying legal, ethical and economic issues. Although drugs of choice and routes of administration vary by country, exposure of our most valuable resource, our children, to the developmental effects of drugs is an enormous problem. In utero drug exposure can have a severe impact not only on the development of the fetus, but also on the child during later stages of life. More than 75% of infants exposed to drugs have major medical problems as compared to 27% of unexposed infants. The cost of treating drug-affected infants was twice the cost of non-affected infants. Obstetrical complications including placental insufficiency, miscarriage, intrauterine death, and increased incidence of infectious and sexually-transmitted diseases are higher in the drug-abusing mother. Treatment for pregnant addicts should be a high priority for our governments. Increased awareness and improvement in our understanding of drug abuse in the medical, legal and social realms will enable us to reduce the barriers to treatment for this important population.Accurate identification of in utero drug exposure has important implications for the care of the mother and child, but can raise difficult legal issues. Society discourages prenatal care with the infliction of harsh criminal penalties. Maternal drug use during pregnancy can be monitored with urine, sweat, oral fluid and/or hair testing. Detection of in utero drug exposure has traditionally been accomplished through urine testing; however, the window of detection is short, reflecting drug use for only a few days before delivery. Monitoring exposure through testing of alternative matrices, such as neonatal meconium and hair, offers advantages including non-invasive collection and detection earlier in gestation. There are many unresolved issues in monitoring in utero drug exposure that urgently require research. These can be divided into research to definitively differentiate drug exposed and non-drug-exposed fetuses, determine the most efficient methods to routinely monitor women's drug use, and determine how these drug test results relate to neonatal and maternal outcomes. Research in this area is difficult and expensive to perform, but necessary to assess accurately drug effects on the fetus. By increasing our understanding of the physiological, biochemical and behavioral effects of gestational drug exposure, we may ultimately provide solutions for better drug prevention, treatment and a reduction in the number of drug-exposed children.

Female↗
PubMed1990

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful for optimum scheduling of subsequent bolus injections in a multiple bolus dosing regimen. There are no reported applications of the FFT method to solve repeated input functions in either the chemical engineering or pharmaceutical science literature. Thus, the application of FFT method to solve multiple bolus injections is a unique one. Use of this FFT based analysis as a predictor tool can limit the number of costly experiments which are being done now to achieve this purpose. Even though the model in its present form is simplified, the analysis thereof has nevertheless led to a better understanding of the various factors that must be taken into account for rational design of drug therapy.

Drug Administration Routes↗
PubMed2000

Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?

The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. It appears that most idiosyncratic drug reactions are due to reactive metabolites; however, many drugs that form reactive metabolites are associated with a very low incidence of idiosyncratic drug reactions. Therefore. screening drug for their ability to generate reactive metabolites is likely to cause the rejection of many good drug candidates. There is evidence to suggest that an idiosyncratic drug reaction is more likely if there is some "danger signal'. Thus drugs that cause some degree of cell stress or damage may be more likely to lead to a high incidence of idiosyncratic drug reactions. The exact nature of the putative danger signals is unknown. However, a screen of the effects of drugs known to be associated with a high incidence of idiosyncatic reactions using expression genomics and proteomics may reveal a pattern or patterns of mRNA and protein expression that predict which drugs will cause a high incidence of idiosyncratic drug reactions. Although idiosyncratic drug reactions are not usually detected in animal tests because they are just as idiosyncratic in animals as they are in humans, it is likely that drug reactive metabolites would also cause similar cell stress in animals. It is more likely that in most cases it is differences in the immune response to the reactive metabolites that determine which individuals will develop an idiosyncratic reaction. If the expression of certain proteins in animals treated with a drug candidate could be used as a screening method to predict a drug's potential to cause a high incidence of idiosyncratic drug reactions, it would greatly facilitate the development of safer drugs.

Animals↗
PubMed1996

Strategic proposals for avoiding toxic interactions with drugs for clinical use during development and after marketing of a new drug--proposals for designing non-clinical and clinical studies--is the non-clinical study useful?

Since sorivudine incident has happened in Japan in 1993, an adverse drug-drug interaction has been of special meanings at each step of new drug development including the discovery step, NDA process, and on market. While it is known that several mechanisms are involved in the drug-drug interactions, the mechanisms related to drug metabolism are 1) inhibition of drug metabolizing enzymes, 2) induction of the enzymes, 3) drug absorption, 4) renal excretion, 5) hepatic transport, and 6) protein binding (displacement) interaction. In this report, proposals to avoid serious/lethal drug-drug interactions are presented with the examples. The proposals are: 1) To estimate the drug-drug interactions in consideration of the mechanisms reported so far, 2) To be especially careful for drugs with a small therapeutic index and severe/lethal toxicity, 3) To estimate the drug-drug interactions in consideration of physiological factors of patients, who receive drugs in combination, 4) Not to leave the mechanism unclear, when some data, which do not deny the critical drug-drug interactions, were obtained, and 5) To conduct the drug-drug interaction studies in humans in careful consideration of the safety.

Animals↗
PubMed2000

In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987 to 1997.

Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studies. In period I (used as a comparator), 32 applications contained drug-drug interaction studies for a total of 117 studies. In period II, 106 applications reported drug-drug interaction studies, and the number of studies per new molecular entity ranged from 0 to 15. Most studies (77%) were performed in healthy subjects, with 44% using crossover designs, 7% using parallel designs, and the remaining using fixed sequence designs. The most common dosing scheme for new molecular entities/interacting drug was multiple dose (47%), whereas single dose/multiple dose was used in 31% of studies, and single dose/single dose was used in 18% of studies. Of the 540 drug-drug interaction studies submitted in period II, 80 (15%) resulted in clinically significant labeling statements. Submissions for new molecular entities to the Center for Drug Evaluation and Research divisions most likely to include drug-drug interaction studies were neuropharmacology, cardiorenal, antiviral, and antiinfective drugs. Some drug classes such as oncology drug products and radioimaging products were least likely to include drug-drug interaction studies in their submissions. We conclude that the use of drug-drug interaction studies in the drug development process has increased between the two periods.

Biopharmaceutics↗