Drug Interaction

Vitamin B 12 deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is considered normal, 10 -15% of the elderly are deficient. Today, however, a threshold of 220 -258 pmol/L (300 -350 pg/mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20 -50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B 12 . An already moderately reduced vitamin B 12 level is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B 12 status is assumed to be involved in the development and progression of dementia (e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of elderly persons (z60 years) should be regularly controlled and a general supplementation with vitamin B 12 (>50 Ag/day) should be considered.

Photobinding of drugs to biomolecules constitutes an important early event in the onset of photoallergy. In the present work, UV irradiation of human serum albumin in the presence of either suprofen (SUP) or its major photoproduct, decarboxylated suprofen (DSUP), has been studied as a model system for drug-photosensitised protein binding. Both dark binding and binding in the presence of light were investigated since this will affect the mode, site and mechanism of drug interaction with the protein. In order to determine the binding features of SUP to albumin, competitive binding experiments were carried out using fluorescent probes specific for site I and II. Suprofen was found to selectively dark bind to site II on HSA. Photobinding of DSUP to HSA was more efficient than SUP. Parallel to this, the intrinsic tryptophan fluorescence of HSA decreased when the protein was previously irradiated in the presence of the photoactive compounds, again being DSUP more efficient compared with SUP. As fluorescence quenching involves electron transfer from the excited Trp to the ground state DSUP, it follows that the photoactive compound binding to HSA must be on (or in close proximity to) site I Trp 214 residue. It appears that photobinding of SUP is largely preceded by its photodecomposition to DSUP which, in turn, associates and photobinds to HSA.

Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H 1 receptors. H 1 receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H 1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H 1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated.

Alzheimer's disease (AD) is often associated with multiple comorbidities and subsequent polypharmacy. Treatment of AD with acetylcholinesterase (AChE) inhibitors can carry a risk of drug interaction with multiple medications often prescribed for other co-existing illnesses. Rivastigmine is an AChE inhibitor that is enzymatically cleaved by AChE, minimally metabolized by cytochrome P450 enzymes, has low protein binding, has a short plasma halflife, and a relatively short duration of action. Such properties make it ideal for use in this patient population. A pharmacodynamic analysis of rivastigmine administered concomitantly with other medications (22 dierent therapeutic classes) did not reveal any signi®cant pattern of increase in adverse events that would indicate a drug interaction. In summary, rivastigmine was well tolerated and safely administered to a population receiving multiple medications for`real-world' comorbidities.

Naltrexone (NTX) and fluoxetine (FLU) are useful for treating alcoholism and depression, respectively. Furthermore, these afflictions covary. Given the possibility that people might be prescribed NTX and FLU concurrently, we assessed the effects of these two agents on rats' pmpensityto drink an alcoholic beverage. Rats were given 65 days of access to a sweetened alcoholic beverage and water for 2 hr daily. At fitst, they took l i i ethanol, but after20 days, they took on average 20 to 2 5 g/kg of ethanol, daily during the 2-hr session. They also took sufficientw~tomaintaintheirhea~.After30days,theywemdivided into four groups to receive, 30 min before the drinking session, 1 of 4 different kinds of injections. For the next 20 days, one group received pbcebo daily. Another group received 5 mgkg of NTXdaily and another 5mgkg of FLU daily.Thefourth group received both 5 mgkg o f m and 5 mgkg of FLU daily. After #)days, the doses of NTXand FLU wem doubled acrossan additional10 days. Both NTXand FLU reduced rats' intake of alcoholic beverage. The combinatiorw of NTX and FLU, however,werenomOreeftechve ' in reducing rats' intake of alcoholic bev--than either alone. Also, the small dose of NTX seemed to lose its tbmedthecondusknthatsmalldOsesofNTXlose~effectiveness in suppressing intake of alcoholic bmmrage cross repeated adminisIrations. In summary, data provide 110 support forthe idea that FLU and NTX would act synergistically to reduce pmpemty to take alcohdic beverages.

Induction of cytochrome P450 (CYP) by drugs is one of major concerns for drug-drug interactions. Thus, the assessment of CYP induction by novel compounds is a vital component in the drug discovery and development processes. Primary human hepatocytes are the preferred in vitro model for predicting CYP induction in vivo. Howevel, their use is hampered by the erratic supply of human tissue and donor-to-donor variability. Although cryopreserved hepatoeytes have been recommended for short-term applications in suspension, their use in studies on induction of enzyme activity has been limited because of poor attachment and response to enzyme inducers. In this study, we report culture conditions that allowed the attachment of cryopreserved human hepatocytes and responsiveness to CYP inducers. We evaluated the inducibility of CYP1A1/2 and CYP3A4 enzymes in cryopreserved hepatoeytes from three human donors. Cryopreserved human hepatocytes were cultured in serum-free medium for 4 d. They exhibited normal morphology and measurable viability as evaluated by the reduction of tetrazolium salts (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) by cellular dehydrogenases. Treatment with [3-naphthoflavone (10 gM) for 3 d increased ethoxyresorufin-O-deethylase activity (CYP1A1/2) by 6-to l 1-fold over untreated cultures and increased CYP1A2 messenger ribonucteic acid (mRNA) expression by three-to eightfold. Similarly, treatment of cryopreserved human hepatocytes with rifampicin (25 IxM) for 3 d increased testosterone 6[3-hydroxylase activity (CYP3A4) by five-to eightfold over untreated cultures and increased CYP3A4 mRNA expression by four-to eightfold. The results suggest that cryopreserved human hepatocytes can be a suitable in vitro model for evaluating xenobiotics as inducers of CYP1A1/2 and CYP3A4 enzymes.

The purpose of this study was the classification and identification of drug binding sites on albumins from several species in order to understand species differences of both drug binding properties and drug interaction on protein binding. Binding properties and types of drug-drug interaction on the different albumins were examined using typical site I binding drugs, warfarin (WF) and phenylbutazone (PBZ), and site II binding drugs, ibuprofen (IP) and diazepam (DZ) on human albumin. Equilibrium dialysis was carried out for two drugs and the free concentrations of drugs were then treated using the methods of Kragh-Hansen (Mol. Pharmacol. 34. 160-171, (1988)). Binding affinities of site I drugs to bovine, rabbit and rat albumins were reasonably similar to human albumin. However, interestingly, those to dog albumin were considerably smaller than human albumin. On the other hand, binding parameters of DZ to bovine, rabbit and rat albumins were apparently different from those of human alb...

Objectives: To determine the prevalence of inappropriate medication prescribing in Middle Eastern community-dwelling elderly persons, and to determine factors associated with inappropriate prescribing. Methods: Prescriptions from 3,000 elderly-patient visits (≥65 years) to physicians in Isfahan, Iran were collected between September and December 2002; only the first patient visit was considered in the study. Inappropriate prescriptions were defined according to Beers' explicit criteria (1997). The presence of at least one drug-drug interaction (DDI) and at least one drugclass duplication within each patient visit was also determined. Multivariate analyses were performed to determine factors associated with receiving at least one inappropriate medication. These factors included age, gender, number of prescribed medications per visit, DDIs, duplications, and physician's number of years of experience. Similar analyses were performed to determine whether these factors were associated with a composite index (defined as having at least one of the following: receiving at least one inappropriate prescription, DDI, or duplication). Results: The mean age of our cohort was 72.6 (±5.7) years, and 1,735 (57.8%) were females. A total of 829 (27.6%) patients received at least one inappropriate prescription, 285 (9.5%) had at least one DDI during the visit, and 746 (24.9%) had at least one duplication during the visit. The three most inappropriately prescribed medication classes were antihistamines (29%), non-steroidal anti-inflammatory agents (23%) and benzodiazepines (16%). In multivariate analyses, the number of prescribed medications per visit was the only factor significantly associated with receiving at least one inappropriate prescription (OR 1.24; 95%CI: 1.16-1.32); analyses using the composite index as outcome gave similar results (OR: 1.70; 95%CI: 1.60-1.80). Conclusion: Our findings indicate a high prevalence of inappropriate prescribing in elderly patients. Given the potential severity of this problem, further steps need to be implemented to prevent this occurrence.

Allicin, the main biologically active component of garlic clove extracts, has been evaluated for its′ efficacy in preventing deltamethrin-induced oxidative damage in Nile tilapia; Oreochromis niloticus. Fish were fed on 2 different doses of 0.5 g and 1 g of allicin/ kg diet for 28 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), cholesterol, urea, uric acid, creatinine, total protein, albumin and globulin were estimated. Moreover, the level of malonaldehyde (MDA) was analyzed as a lipid peroxidation marker. In addition, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were analyzed as antioxidant biomarkers in liver, kidney and gills. Results show that deltamethrin subacute intoxication (1.46 mg/L for 28 days) increased serum AST, ALT, ALP, cholesterol, urea, uric acid, creatinine and tissue MDA. At the same time, serum total protein and albumin as well as tissue level of GSH, GSH-Px, SOD and CAT were reduced. Allicin supplemented diets enhanced all the altered serum biochemical parameters as well as tissues′ lipid peroxidation and antioxidant biomarkers in a dose-dependent manner. The results suggest that feeding allicin can ameliorate deltamethrin-induced oxidative stress and might have some therapeutic properties to protect Nile tilapia on subacute deltamethrin toxicity.

Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced ≥ grade 3 treatmentrelated toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased ≥ grade 3 treatment-related toxicities in multivariate analysis.

Busulphan and cyclophosphamide (Bu/CP) are widely used in preparative regimens for bone marrow transplantation. Many studies have shown a wide variation in busulphan pharmacokinetics. Moreover, higher rates of liver toxicity were reported in Bu/CP protocols than in a total body irradiation (TBI)-containing regimen. In the present paper we investigated the effect of the time interval between the last dose of busulphan and the first dose of cyclophosphamide on the pharmacokinetics of CP and its cytotoxic metabolite 4-hydroperoxycyclophosphamide (4-OHCP). Thirty-six patients undergoing bone marrow transplantation (BMT) were included in the study. We also investigated the occurrence of venoocclusive disease, mucositis and graft-versus-host disease. Ten patients conditioned with CP followed by TBI served as a control group (TBI). Twenty-six patients were conditioned with Bu/CP. The patients received Bu (1 mg/kg ؋ 4 for 4 days), followed by CP (60 mg/kg for 2 days) administered as a 1-h infusion. Patients received their CP therapy either 7-15 h (group A, n ‫؍‬ 12) or 24-50 h (group B, n ‫؍‬ 14) after the last dose of Bu. None of the patients were given phenytoin or any other drug known to enhance CP metabolism. The administration of CP less than 24 h after the last dose of Bu resulted in: (1) a significantly (P ‫؍‬ 0.003) lower clearance for cyclophosphamide was observed in group A (0.036 l/h/kg) compared to 0.055 and 0.055 l/h/kg, in the B and TBI groups, respectively; (2) significantly (P ‫؍‬ 0.002) longer elimination half-life in group A (10.93 h) than in groups B and TBI (6.87 and 7.52 h, respectively); (3) significantly (P Ͻ 0.001) lower exposure to the cytotoxic metabolite (4-OHCP), expressed as the ratio AUC 4-OHCP /AUC CP , in group A (0.0053) than that obtained in group B (0.013) and group TBI (0.012); (4) the patients in group A had a significantly (P Ͻ 0.05) higher incidence of VOD (seven of 12) than the other groups, B and TBI (2/14 and 1/10, respectively); and (5) mucositis was significantly higher in group A patients (8/12), being seen in only one patient in group B and none in the TBI group. The present study has shown that the interval between busulphan and cyclophosphamide administration can negatively affect the pharmacokinetics of cyclophosphamide and its cytotoxic metabolite. We conclude that the timing of CP administration must be considered in order to improve drug efficacy and reduce conditioning-related toxicity. Bone Marrow Transplantation 25, 915-924. Effect of busulphan on cyclophosphamide pharmacokinetics M Hassan et al Effect of busulphan on cyclophosphamide pharmacokinetics M Hassan et al

Drug-drug interactions (DDIs) are preventable medical errors, yet exposure to DDIs continues despite systems that are designed to prevent such exposures. The purpose of this study was to examine pharmacy characteristics that may be associated with dispensed potential DDIs. This study combined survey data from community pharmacies in 18 metropolitan statistical areas with pharmacy claims submitted to 4 pharmacy benefit managers (PBMs) over a 3-month period from January 1, 2003 to March 31, 2003. Pharmacy characteristics of interest included prescription volume, the number of full-time equivalent pharmacists and pharmacy staff, computer software programs, and the ability to modify those programs with respect to DDI alerts, the use of technologies to assist in receiving, filling and dispensing medication orders, and prescription volume. The dependent variable in this study was the rate of dispensed medications that may interact. A total of 672 pharmacies were included in the analysis. ...

There is growing concern that serious interactions are occurring between prescribed/over the counter and herbal medicines and that there is a lack of disclosure of herbal use by patients to doctors. This study explores women's perspectives about the safety of herbal remedies, herb-drug interactions and communication with doctors about herbal medicines. Qualitative, cross-sectional study, with purposive sampling which took place in Cheshire, UK. Eighteen in depth semi-structured interviews were conducted with female herbal medicine users aged 18 years and above. The large majority did not inform their GPs of their use of herbal medicines. This was due to lack of physician enquiry, perception of importance and fear of a negative response. Several women were not aware that herbal remedies could interact with prescribed or over the counter medicines. Of the women who had experienced adverse effects none had reported them, believing them of low importance. The women had little knowle...

P-glycoprotein (P-gp) belongs to superfamily of ABC (ATP-binding cassette) drug transporters. It is expressed in intestines, brain, kidneys, testes, liver, adrenal gland, lungs heart and eyes. This protein functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. P-gp could modulate pharmacokinetics of antibacterial drugs through limitation of their oral absorption and penetration into target organs. Drug-drug interactions with antibacterials could be mediated by inhibition or induction of P-gp. Among the antibiotics recognized as substrates and modulators of P-gp are structurally unrelated compounds as fluoroquinolones, macrolides, ansamycines, tetracyclines and antracyclines. These findings provide a basis for the understanding of the pharmacokinetics, pharmacodynamics and toxicodynamics of the antibiotics in healthy and diseased individuals.

Nitazoxanide is a new thiazolide antiparasitic agent that shows excellent in vitro activity against a wide variety of protozoa and helminths. It is given by the oral route with good bioavailability and is well tolerated, with primarily mild gastrointestinal side effects. At present, there are no documented drug-drug interactions. Nitazoxanide has been licensed for the treatment of Giardia intestinalis-induced diarrhea in patients у1 year of age and Cryptosporidum-induced diarrhea in children aged 1-11 years. At present, it is pending licensure for treatment of infection due to Cryptosporidium species in adults and for use in treating immunocompromised hosts. It represents an important addition to the antiparasitic arsenal.

The antifungal armamentarium has expanded greatly over the past two decades. This expansion, along with the pharmacologically complex therapeutic regimens used in treating many patients with systemic fungal disease, enhances the risk of clinically significant drug-drug interactions. This review examines the drug-drug interaction potential of antifungal agents by pharmacologic class and attempts to provide perspective on the time course and clinical significance of these events.

Background: Critically ill-patients frequently receive multidrug regimens (polypharmacy) with the goal of providing the superlative
pharmacotherapeutic support. Drug-drug interaction (DDI) is a specific type of adverse event, which develops due to multiple regimen therapy, and
that may lead to significant hospitalization and death.
Methods: A retrospective study was conducted for a period of 3 months to assess the prevalence potential DDIs in medical Intensive Care Unit (MICU)
patients of a north Indian tertiary care hospital using Lexi Comp drug interact android mobile application.
Results: A total of 72 patients were identified for this study. 65.27% (47) were males, and 34.72% (25) were females. The average age of the study
population was 52 years, and average length of stay in hospital was found to be 7 days. An average of 17.09 drugs per patient was administered to the
patients during the study period. 90.02% (65) of patients experienced at least one potential DDI. A total of 222 interactions observed during the study
period with an occurrence rate of 3.08 DDI per patient. There were 106 types drug pairs was found to get interacted at least 1 time. Corticosteroids,
anticonvulsants, central nervous system depressants, sympathomimetics and quinolone antibiotics are the main class of drugs mostly interacted in
MICU.
Conclusion: The study shows that, concomitant administration rate of potentially interacting drugs are very high in MICU. We suggest that, special
safety measures must be followed by physicians, pharmacists, and nurses to prevent and monitor DDIs in all departments of the hospital especially in
intensive care departments. Health providers must be able to identify and classify drug interactions (DIs), and know how to manage them clinically,
that is, how to minimize or more over prevent them. Practice of a computer assisted DI checker before prescribing/administering of the drugs can
avoid DDIs. In settings with multiple drug use like in ICUs, attendance of a pharmacist or clinical pharmacist, taking the responsibility for monitoring
DIs and notifying the physician about potential problems could decrease the harm inpatient and ensure the patient safety.

Se denomina interacción farmacológica a la modificación cuantitativa o cualitativa del efecto de un fármaco por la administración simultánea o sucesiva de otro. Los pacientes con hipertensión arterial, sobre todo los ancianos, presentan con frecuencia enfermedades concomitantes que requieren la administración conjunta de varios medicamentos, lo que facilita la aparición de interacciones. La falta de eficacia del tratamiento antihipertensivo es un hecho relativamente frecuente que, en ocasiones, se debe a interacciones de los fármacos antihipertensivos con otros tratamientos concomitantes. La incidencia de las interacciones es difícil de determinar, pero se relaciona con el número de fármacos administrados conjuntamente. Entre el 37 y el 60% de los pacientes que ingresan en un hospital están tratados con asociaciones de medicamentos potencialmente peligrosas y hasta un 6% de acontecimientos mortales son debidos a esta circunstancia. Entre los fármacos antihipertensivos, los diuréticos y los inhibidores de la enzima conversiva de la angiotensina (IECA) son los menos afectados por las interacciones. Los bloqueadores beta adrenérgicos liposolubles pueden presentar algunas con interés clínico, mientras que el grupo de los antagonistas del calcio, en especial los no dihidropiridínicos, es el más implicado en interacciones farmacocinéticas que pueden tener importancia clínica. Los antagonistas del receptor de la angiotensina II (ARA II) presentan diferencias entre ellos que deberían ser tenidas en cuenta al administrarlos a pacientes que reciben otros medicamentos. Aunque para el médico práctico es imposible recordar todas las interacciones de interés clínico, tenerlas presentes y considerar los posibles mecanismos de producción puede ayudar a identificarlas y contribuir a su prevención. Las interacciones que con mayor frecuencia causan problemas son las de tipo farmacocinético, sobre todo las relacionadas con el metabolismo a través del sistema del citocromo P450 o el aclaramiento presistémico por medio de la P-glucoproteína. El hecho de que algunas isoformas del citocromo puedan presentar polimorfismos explican las diferencias interindividuales en la respuesta a algunos fármacos o en la presentación de interacciones. Palabras clave: Interacciones farmacológicas. Antihipertensivos. Reacciones adversas a medicamentos. Hipertensión. Antihypertensive drug-drug interactions A drug interaction is the quantitative or qualitative modification of the effect of a drug by the simultaneous or successive administration of a different one. Hypertensive patients, mainly the more elderly ones, frequently present concomitant diseases that require the administration of several medicines which facilitates the appearance of interactions. The lack of effectiveness of the antihypertensive treatment is a relatively frequent fact that sometimes is due to interactions of antihypertensive drugs with other treatments. It is difficult to determine the incidence of interactions, but it is related to the number of drugs administered simultaneously. Between 37 and 60% of hospital-admissions are treated with potentially dangerous drug associations and up to a 6% of fatal events are due to this circumstance. Among antihypertensive drugs, diuretics and angiotensin converting enzyme inhibitors are less affected by drug-interactions. Lipophilic beta-blockers agents may present some clinical relevant interactions, whereas calcium channel blockers, especially the non-dihydropiridinic ones, are implied in clinically relevant pharmacokinetic interactions. Among the angiotensin receptor blockers there are differences that would have to be considered when they are used in patients who receive other drugs. Although it is impossible for the doctor to remember all the clinical relevant interactions, it is important to bear in mind their existence and the possible mechanisms of production which can help to identify them and to contribute to their prevention. The most frequent interactions related with clinical problems are the pharmacokinetic ones, mainly those related to the metabolism through the cytochrome P450 system or the presystemic clearance by means of the P-glycoprotein. Enzymes of the cytochrome P450 system may present polymorphisms that can explain the individual differences in the response to drugs or the appearance of drug-interactions.

Although children's responses to drugs have much in common with the responses in adults and indeed in other mammals, they are not just small adults. Often, it is assumed that drug effects differ in children but in reality this perception often arises because the drugs have not been adequately studied in pediatric populations of different ages and with different diseases. Many factors affect the bioavailability, half-life and drug clearance of immunosuppres-Filler G. Value of therapeutic drug monitoring of MMF therapy in pediatric transplantation.

This review promotes the value of isolated hepatocytes in modern Drug Discovery programmes and outlines how increased understanding, particularly in the area of in vitro-in vivo extrapolation (IVIVE), has led to more widespread use. The importance of in vitro metabolic intrinsic clearance data for predicting in vivo clearance has been acknowledged for several years and the greater utility of hepatocytes, compared with hepatic microsomes and liver slices, for this application is discussed. The application of hepatocytes in predicting drug-drug interactions (DDIs) resulting from reversible and irreversible (time-dependent) inhibition is relatively novel but affords the potential to study both phase I and phase II processes together with any impact of drug efflux and/or uptake (cellular accumulation). Progress in this area is reviewed along with current opinions on the comparative use of primary hepatocytes and higher throughput reporter gene-based systems for studying cytochrome P450 (CYP) induction. The appreciation of the role of transporter proteins in drug disposition continues to evolve. The study of hepatic uptake using isolated hepatocytes and the interplay between drug transport and metabolism with respect to both clearance and DDIs and subsequent IVIVE is also considered.

The treatment of war wounds is an ancient art, constantly refined to reflect improvements in weapons technology, transportation, antiseptic practices, and surgical techniques. Throughout most of the history of warfare, more soldiers died from disease than combat wounds, and misconceptions regarding the best timing and mode of treatment for injuries often resulted in more harm than good. Since the 19th century, mortality from war wounds steadily decreased as surgeons on all sides of conflicts developed systems for rapidly moving the wounded from the battlefield to frontline hospitals where surgical care is delivered. We review the most important trends in US and Western military trauma management over two centuries, including the shift from primary to delayed closure in wound management, refinement of amputation techniques, advances in evacuation philosophy and technology, the development of antiseptic practices, and the use of antibiotics. We also discuss how the lessons of history are reflected in contemporary US practices in Iraq and Afghanistan.

Purpose: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide–thioTEPA–carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. Methods: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1000 or 1500 mg/m2 per day), thioTEPA (80 or 120 mg/m2 per day) and carboplatin (265 or 400 mg/m2 per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. Results: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased Cmax (−62%) and AUC (−26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC50 of 23 μM. No inhibition of the formation of TEPA by cyclophosphamide was observed. Conclusions: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance.

Significant pharmacokinetic/pharmacodynamic interactions between various herbal products and warfarin have recently been reported. The aim of this study was to determine whether concomitant treatment of rats with Kan Jang (a standardized fixed combination of extracts from Andrographis paniculata and Eleutherococcus senticosus) and warfarin would lead to an alteration in the pharmacological effects of warfarin. Each day for 5 days a group of animals was treated orally with an aqueous solution of Kan Jang at a dose of 17 mg/kg of the active principle andrographolide (a daily dose some 17-fold higher than that recommended for humans): the control group received similar treatment with appropriate volumes of water only. Sixty minutes after the final daily administration of Kan Jang or water, an aqueous solution of warfarin (0.2 mg/ml) was given to each animal at a dose of 2 mg/kg. From each group, 6 animals were sacrificed at 0, 2, 4, 6, 8, 12, 24, 30 and 48 h after warfarin administration and blood samples taken. The concentration of warfarin in blood plasma was measured by capillary electrophoresis using 50 mM borate buffer (pH 9.3) as mobile phase with simultaneous detection of warfarin at 208.1 and 307.5 nm. Prothrombin time in blood plasma was measured using thromboplastin reagent. The concomitant application of Kan Jang and warfarin did not produce significant effects on the pharmacokinetics of warfarin, and practically no effect on its pharmacodynamics.

Herbal remedies (phytomedicines) possess significant pharmacological activity and consequently potential adverse effects and drug interactions. The explosion in sales of herbal therapies has brought products to the marketplace that do not conform to the standards of safety and efficacy that physicians and patients expect. Relatively few physicians inquire about herbal medicine use, and up to 70% of patients do not reveal their use of herbal medicines to their physicians and pharmacists. All physicians should question patients regarding the use of herbal remedies and document their responses in the medical record. They should caution patients that lack of standardization, quality control, and regulation may result in variability in herbal content, efficacy, and potential contamination. Physicians should be aware of potential adverse reactions stemming from herbal medicine use, especially with regard to perioperative bleeding, cardiovascular instability, and interactions with commonly prescribed sedative-hypnotic agents.

The interaction of phenylbutazone and diazepam with smectite were studied in in-vivo and invitro. The kinetics of both drugs were investigated in healthy subjects after oral administration as monotherapy or in association with smectite. Smectite did not substantially alter the kinetics of phenylbutazone, whereas the peak plasma concentration of diazepam was reduced to 91%, and the time of peak concentration was prolonged by 153% of the control values. The in-vitro investigations were conducted at pH 5.5 and 8 and showed that there was no interaction between phenylbutazone and smectite, but that it adsorbed diazepam. The findings suggest that smectite delays the absorption of basic drugs and does not alter the absorption kinetics of acidic drugs.

Although thousands of articles on drug interactions have been published and numerous computerized screening systems have been developed, patients continue to suffer from adverse drug interactions. Possible methods for reducing the risk of drug interactions include improving the knowledge of health care providers, improving computerized screening systems, providing information on patient risk factors, increased use of pharmacogenetic information, more attention to drug administration risk factors, and improving patient education on drug interactions.

Using radioligand binding assays and postmortem normal human brain tissue, we obtained equilibrium dissociation constants (KdS) for 17 antidepressants and two of their metabolites at histamine H~, muscarinic, ~-adrenergic, ~2-adrenergic, dopamine D2, serotonin 5-HTIA, and serotonin 5-HT 2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but ~2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at u2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H~ receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant.

The drug transporter P-glycoprotein (P-gp) influences drug distribution across the blood-brain barrier (BBB) by actively extruding drugs into the neural capillaries. Several psychotropic drugs, including nortriptyline (NT) and risperidone (Risp), are substrates of P-gp. Here we compared the in vitro P-gp interactions of Risp and its major metabolite, 9-OH-Risperidone (OH-Risp), with their distribution over the BBB in P-gp knock-out mice and in rats where P-gp was inhibited. K m and V max were determined by an in vitro ATPase assay, and V max /K m ratios of 2.7 and 0.5 were recorded for Risp and OH-Risp, respectively, suggesting that Risp is a better substrate for P-gp than OH-Risp. In Mdr1a (À / À) knock-out mice, the brain-serum ratios of both Risp and OH-Risp were more than ten times those of control mice (14 and 11, respectively). When P-gp was inhibited with cyclosporine A (CsA) in Wistar rats, the effect was an order of magnitude less than that observed for the knock-out mice experiments (1-1.5 times the controls), and co-administration of NT had no effect.

We conducted a literature search using PubMed, EMBASE and recent abstracts from thrombosis meetings to identify publications related to food, drug and dietary supplement interaction studies with the new oral anticoagulants, dabigatran etexilate, rivaroxaban and apixaban. In the absence of peer-reviewed publications, some information was extracted from the product monographs, which do not contain detailed information about clinical trial design and assay procedures.

Cyclosporine is highly effective in the treatment of a multitude of dermatoses. Concern over its side effect profile has limited its use in dermatology. Adverse effects are, for the most part, dose dependent and related to duration of therapy. Using the recommended monitoring protocols results in a significant decrease in the incidence of cyclosporine-related toxicities. This article provides a comprehensive review of the pharmacokinetics of cyclosporine, potential drug interactions, adverse effects, and recommendations for monitoring in patients treated with cyclosporine. The use of cyclosporine in pregnancy and in the pediatric population is also addressed. ( J Am Acad Dermatol 2010;63:949-72.)

Drug therapy is essential when caring for elderly patients, but clearly it is a double-edged sword. Elderly patients are at high risk of having drug interactions, but the prevalence of these interactions is not well documented. Several types of interactions exist: drug-drug, drug-disease, drug-food, drug-alcohol, drug-herbal products, and drug-nutritional status. Factors such as age-related changes in pharmacokinetics and pharmacodynamics, frailty, interindividual variability, reduced homoeostatic mechanisms, and psychosocial issues need to be considered when drug interactions are assessed. Software can help clinicians to detect drug interactions, but many programmes have not been updated with the evolving knowledge of these interactions, and do not take into consideration important factors needed to optimise drug treatment in elderly patients. Any generated recommendations have to be tempered by a holistic, geriatric, multiprofessional approach that is team-based. This second paper in a series of two on prescribing in elderly people proposes an approach to categorise drug interactions, along with strategies to assist in their detection, management, and prevention.

This study was performed to asses and establishes the prevalence of Polypharmacy in geriatric population in the Medicine ward of Rajah Muthaiya Medical College and Hospital, Annamalai University, during one year from January 2013 to January 2014. Demographic analyses of this prospective study revealed that out of 520 patients, 342 (65.76%) were males and 178 (34.23%) were females. All the collected prescriptions were scrutinized for Polypharmacy and were categorized as minor Polypharmacy -concurrent use of ≤ 5 drugs; and major Polypharmacy -concurrent use of > 5 drugs. Out of 502 Prescriptions 61(11.73%) prescriptions were minor Polypharmacy and 457(88.26%) prescriptions were major Polypharmacy. The maximum patients were in the age group of 60-64 (38.84%) range lead to a significant increase in the number of medications. The most common diseases associated systems were Cardiovascular system 147 (28.26 %) patients, and followed by Respiratory system 103(19.80%). Our results show that there is a higher prevalence of Polypharmacy among the males than females. The length of hospital stay of geriatric patients is increase in major Polypharmacy compare with minor Polypharmacy. The prevalence of cardiovascular drugs and respiratory drugs were often involved in Polypharmacy among geriatric patients. Polypharmacy is very common among geriatric patient and health care professional’s interventions to improve the optimal use of medication in geriatric could lead to reduction in the drug related problems associated with Polypharmacy.

Background: Warfarin is a highly efficacious oral anticoagulant, but its use is limited by a well-founded fear of bleeding. Drug and food interactions are frequently cited as causes of adverse events with warfarin. We provide an updated systematic overview of the quality, clinical effect, and importance of these reported interactions. Data Sources: MEDLINE, TOXLINE, IPA, and EMBASE databases from October 1993 to March 2004. Database searches combined the keyword warfarin with drug interactions, herbal medicines, Chinese herbal drugs, and fooddrug interactions.