Narrow Therapeutic Margin Research Articles

Chemotherapy ordering process: Safety and efficiency considerations

6110 Background: Antineoplastic therapy is generally considered high-risk treatment due to the narrow therapeutic margin. Recently, safety-related consequences of medication errors involving antineoplastic agents have become the major focus of quality improvement in health care settings in the United States. Methods: In 1995 a group, consisting of medical oncologists from TCI, oncology nurses and pharmacists from FH met to review the safety and efficiency of the chemotherapy ordering process. Because errors can result from illegibility due to individually handwritten chemotherapy orders, computerized preprinted orders (CPO) were developed. A standard chemotherapy ordering process for both inpatient and outpatient settings was formulated. CPOs were piloted for inpatients receiving chemotherapy. These orders include premedication, antiemetics, drug dosage, dilution, infusion rate, and proper administration sequence. Chemotherapy regimens were categorized by tumor types. Because the practice of oncology is a dynamic process, new chemotherapy regimens are included regularly in the CPO process. Over 145 chemotherapy and supportive care regimens are available as of December 2003. This process was extended to the outpatient setting at FH in February 2003 and at all affiliated outpatient clinics. CPOs were placed on a common computer drive for accessibility at multiple locations and were write-protected. Additionally, CPOs were transferred to a removable external drive for portability, enabling use by physicians at their offices. Results: Since this process was initiated no major error related to chemotherapy has been reported. There have been 79 inpatient and about 2200 outpatient chemotherapy treatments since this process was initiated. Conclusions: To improve safety of the chemotherapy process, we developed standardized CPO. We believe its implementation has decreased the potential for errors related to chemotherapy administration. To increase accessibility, we plan to transfer this process to the use of portable handheld devices and to incorporate it onto our secure website so it can be accessed via the Internet from any of our sites in the future. No significant financial relationships to disclose.

Small molecule inhibitors of Herpes simplex virus type 1 immediate early gene expression

The only therapeutic agents that are currently available for the treatment of herpes simplex virus type 1 (HSV-1) infections are a small number of nucleoside analogues, each of which acts by inhibiting the replication of the DNA genome of this pathogen. The observations that these drugs fail to modulate the frequency of latent virus reactivation and that their effectiveness can be significantly weakened through the acquisition of viral resistance mutations argue that efforts to identify additional classes of HSV-1 inhibitors should continue. One stage in the viral life cycle that would seem to be an excellent target for the development of novel therapeutic agents is the expression of HSV-1 immediate early genes, as this represents a key regulatory checkpoint utilized not only during lytic infections but also reactivation from latent infections. Full activation of HSV-1 immediate early gene promoters requires two viral-encoded polypeptides, VP16 and ICP0, each of which stimulates transcription by effecting multiple interactions with host cell proteins. Although to date no small molecule inhibitors of the VP16 and ICP0 proteins themselves have been discovered, a number of compounds that interfere with host cell functions critical for immediate early gene expression have been described. Several of the latter molecules target previously identified proteins that are known to be critical for cell viability, such as the proteasome, cyclin-dependent kinases and nuclear transcription factors. Unfortunately, these compounds typically reveal narrow therapeutic margins and poor selectivity when their antiviral and cytotoxic properties are compared. However, a number of other small molecule inhibitors have recently been described that exhibit remarkable levels of selective inhibition of HSV-1 immediate early gene expression. Although the development of each of these compound series has been discontinued because of pharmacokinetic or toxicological concerns, further studies with these promising leads could lead to the identification of one or more novel cellular targets against which a new generation of antiherpesviral drugs may be discovered. (c) 2002 Prous Science. All rights reserved.

Perioperative monitoring of potentially toxic drugs.

A list of drugs considered to have a narrow therapeutic margin are discussed. These potentially toxic drugs will be reviewed, including recommended therapeutic ranges, when therapeutic levels should be obtained, and additional laboratory studies that may be required for patients on these medications who are preparing to undergo surgery.

Pharmacokinetic Optimisation of Asthma Treatment

Asthma is generally managed with bronchodilator therapy and/or anti-inflammatory drugs. Guidelines now advocate selection of drugs and pharmaceutical formulations (long-acting vs short-acting, inhaled vs systemic) on the basis of disease severity. Theophylline has a narrow therapeutic margin. Clearance is highly variable and plasma concentrations should be monitored to avoid the occurrence of plasma concentration-related adverse effects. The rate of absorption of theophylline differs depending on the sustained release formulation administered. Some products do not provide sufficient plasma drug concentrations for therapeutic efficacy over a 12-hour period, particularly in patients with high clearance rates (e.g. children and patients who smoke). Administration of drugs via inhalation offers several advantages over systemic routes of administration (e.g. adverse effects are decreased). Inhalation is now advocated as first-line therapy. Aerosol medications available for the treatment of asthma are beta 2-agonist (including the newer long-acting agents such as salmeterol), corticosteroids, anticholinergic drugs, sodium cromoglycate (cromolyn sodium) and nedocromil. To reach the airways, aerosolised particles should be 1 to 5 microns in diameter. Particles of this size can be produced by nebuliser for continuous administration or by metered-dose inhaler and drug powder inhaler for unit dose medication. For efficient use of the metered-dose inhaler, slow inhalation and actuation must be coordinated. However, efficacy and convenience can be improved when spacer devices are used. Furthermore, spacer devices lessen the oropharyngeal adverse effects of inhaled corticosteroids. Dry powder inhalers are more easily used by children and elderly patients than metered-dose inhalers. Regardless of the device used, a maximum of 10% of the inhaled dose reaches the airways. The rest of the dose is swallowed and absorbed through the gastrointestinal tract. Most inhaled drugs have low oral bioavailability, either because of a high first-pass metabolism (beta 2-agonists and glucocorticoids) or because of lack of absorption (sodium cromoglycate). Sulphation of beta 2-agonists occurs in the wall of the gastrointestinal tract and extensive metabolism of inhaled corticosteroids occurs in the liver. Low bioavailability of the swallowed fraction contributes to reduced adverse effects. The pharmacokinetic properties of an inhaled drug are of interest. The fraction of the dose absorbed through the lung has the same disposition characteristics as an intravenous dose, and the swallowed fraction has the same disposition as an orally administered dose. However, for many drugs, pharmacokinetic data after inhalation are limited and cannot be used as a criteria for selection of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Changing Trends in the Treatment of Asthma in a Tertiary Canadian Pediatric Hospital

During the last few years there has been a major change in the perception of childhood asthma management, with more focus on the anti-inflammatory aspects of therapy, the use of inhaled ipratroprium bromide, and decreased home usage of theophylline. Our clinical impression that the management of asthma at our institution has altered in response to these trends prompted us to review our experience with childhood asthma. A random sample of approximately 70 cases was reviewed from admissions to The Hospital for Sick Children during the first 6 months of 1987 and 1990. There was a major reduction in theophylline usage in 1990 accompanied by increased use of ipratroprium and oral corticosteroids. Significantly fewer cases of potentially toxic theophylline serum levels were observed in 1990, suggesting increased awareness of the this drug's narrow therapeutic margin of safety. In 1990, patients tended to be pyrexial and were treated with antibiotics more often. They were also younger, which may explain the higher pulse and respiratory rates observed. Despite these trends toward younger, sicker patients being admitted to the hospital, the length of stay did not increase, and similar numbers needed intensive care. This suggests that the shift in therapeutic modality did not affect hospitalized asthmatic children adversely.

Clinical relevance of cimetidine drug interactions.

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

Aspirin Prodrugs: Synthesis and Hydrolysis of 2-Benzyloxy-2-methyl-4H-1,3-benzodioxin-4-ones.

Aspirin is widely used for its analgesic, antiinflammatory and antipyretic properties. Among its disadvantages are the relatively narrow therapeutic margin, its irritancy towards the gastric mucosa, and occasionally patient hypersensitivity towards aspirin. As part of our effort to develop prodrugs without these liabilities eleven new title compounds have been isolated and characterized. These 'superaspirin' candidates were subjected to non-enzymatic hydrolysis for a first rapid screening in vitro. Only 2-(2,6-dimethoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4c) was observed to act as an exclusive aspirin prodrug, while 2-(2-methoxybenzyloxy)-2-methyl-4H-1,3-benzodioxin-4-one (4b) and 2-(2-ethoxybenzyloxy)-2-methyl-4H-1,3- benzodioxin-4-one (4d) were shown to release both aspirin 6 and salicylic acid 7. Subsequently, these three candidates were further characterized by investigation of the pH profile of their hydrolysis rates.

Hypolipidemic 2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-activity relationships of a novel series of high-density lipoprotein elevators.

The preparation and plasma lipid altering characteristics of a series of 4H-3,1-benzoxazin-4-ones are described. Hypocholesterolemic, hypotriglyceridemic, and high-density-lipoprotein elevating properties are found for derivatives bearing a 4-(1,1-dimethylethyl)phenyl group at the 2-position, and this activity is displayed in both hypercholesterolemic and in normolipidemic rats when the ring system is substituted at position 6 with hydrogen, methyl, chloro, or iodo groups, and is optimal when the 6-position is substituted by a bromine atom. Evidence is presented suggesting that a metabolite or degradation product is responsible for the changes in lipoprotein concentration observed with active molecules of this type. Synthesis of anticipated degradation products of the active molecules gave products displaying the expected in vivo activity, but no improvement in the narrow therapeutic margin of the best compound, 6-bromo-2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one, was obtained.

Evolution of therapy for cytomegalovirus infection.

The first antiherpes agents discovered in the early 1960s were 2'-deoxy-5-iodouridine (idoxuridine; IUDR), beta-D-arabinofuranosylcytosine (cytarabine; ara-C), and 9-beta-D-arabinofuranosyladenine (vidarabine; ara-A), 2'-deoxy-5-fluorouridine (floxuridine; FUDR), and 2'-deoxy-5-trifluoromethyluridine (trifluridine; TFT). All of these drugs showed potency against herpes simplex virus (HSV) and cytomegalovirus (CMV) in vitro but had a narrow therapeutic margin. Although ribavirin, a nucleoside analogue synthesized in 1972, was much less toxic than earlier drugs, it proved ineffective against CMV. Phosphonoformic acid (PFA), a pyrophosphate analogue, has recently shown encouraging results for CMV infections in bone marrow and renal transplant recipients. Several interferons, alone or in combination with other antiviral agents, have proved clinically ineffective against CMV infections. Antiviral nucleoside analogues synthesized in the late 1970s generated much hope and enthusiasm, and acyclovir (9-[(2-hydroxyethoxy)methyl]guanine; ACV) has emerged as a safe and efficacious anti-HSV agent and has shown some promise in the treatment of CMV infection in transplant recipients. The most recent anti-CMV agent, ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine; DHPG), is an analogue of 2'-deoxyguanosine. It was reported independently in 1982 by four laboratories. DHPG is a potent agent against all five human herpesviruses. Its toxicity, unfortunately, limits its clinical use at present to life- and sight-threatening CMV infections.

Role of extracorporeal drug removal in acute theophylline poisoning. A review.

Theophylline, with its narrow therapeutic margin, is a common cause of iatrogenic and deliberate overdose. Most cases of self-poisoning are with sustained release preparations, with peak concentrations occurring up to 12 or more hours after overdose. Toxic symptoms are often seen at concentrations above 15 mg/L. Theophylline is metabolised within the cytochrome P-450 system, with an average total body clearance of 50 to 60 ml/min. Clearance is, however, affected by many factors such as other drugs or disease, and in overdose zero order kinetics may result in prolonged half-lives. Toxicity is characterised by agitation, tremor, nausea, vomiting, abdominal pains, seizures, and tachyarrhythmias. Hypokalaemia and metabolic acidosis are more profound in acute toxicity, and hypercalcaemia is usually present. Seizures occur at lower concentrations after chronic over-medication than after acute overdose. Gastric lavage should be performed in all patients presenting early, and an oral multiple dose charcoal regimen started with 50 to 100g charcoal, repeating with 50g doses and checking theophylline concentrations at 2- to 4-hour intervals. Multiple dose charcoal can be expected to double the clearance of theophylline, being as effective as a haemodialysis. Of the invasive techniques available, charcoal haemoperfusion is the most effective, increasing clearance 4- to 6-fold. Supportive care is particularly important. The aggressive supplementation of potassium, treatment of emesis with droperidol and ranitidine, and treatment of tachyarrhythmias and hypotension (possibly with propranolol), together with oral multiple dose charcoal may obviate the need for haemoperfusion. Seizures suggest increased morbidity and mortality. Charcoal haemoperfusion should be considered if plasma concentrations are greater than 100 mg/L in an acute intoxication or greater than 60 mg/L in a chronic intoxication. The decision to haemoperfuse should not be based on plasma concentrations alone, but an overall evaluation of the patient's laboratory and clinical status.

Outcome from severe head injury in children and adolescents.

A consecutive series of 37 children (17 years old and under) with severe head injury is presented. The data confirm that morbidity and mortality are lower in children than in adults: 51% of these young patients had a good recovery or moderate disability at 6 months. The mortality rate in this series (33%) is higher than in some reports, but probably more closely approximates the death rate from these injuries in an unselected pediatric population than do statistics from tertiary care hospitals. There was no significant relationship between age and outcome in this age group, but mass lesions and uncontrolled intracranial hypertension adversely affected outcome. Diffuse cerebral swelling was commonly seen on computerized tomography scans, and generally was associated with a satisfactory outcome (75%). Two of 13 deaths were considered preventable, emphasizing the narrow therapeutic safety margin and extreme care required in treating these patients.

Influence of food intake on presystemic clearance of drugs.

Many drugs have a low degree of oral bioavailability even though their gastrointestinal absorption is complete. This is because they undergo extensive presystemic metabolic transformation during the first passage of the drug through the gastrointestinal mucosa and the liver. In addition to effects on the absorption of some drugs, food intake has been found to influence the bioavailability of drugs with extensive presystemic metabolic clearance. Extensive presystemic clearance occurs commonly with compounds that are lipophilic bases, e.g. propranolol and amitriptyline, but rarely if ever with lipophilic acids, e.g. salicylic acid and penicillin, except for esters of such acids, e.g. acetylsalicylic acid (aspirin) and pivampicillin. While presystemic clearance of (esterified) acidic drugs is unaffected by food, concurrent food intake markedly reduces presystemic clearance, and thus enhances bioavailability, of several lipophilic bases. Among these are propranolol, metoprolol, labetalol, dixyrazine and hydralazine, which are presystemically metabolised by hydroxylation, glucuronidation and acetylation enzymes systems. In contrast, the bioavailability of lipophilic bases which undergo presystemic dealkylation (amitriptyline, codeine, dextropropoxyphene, prazosin, zimelidine) is unaffected by concurrent food intake. Food intake reduces presystemic clearance of hydralazine and propranolol when these drugs are administered in conventional rapid-release tablets but not when they are given in slow-release formulations. Likewise, coadministration of hydralazine reduces presystemic clearance of rapid-release but not slow-release propranolol. These and other observations favour the view that food may reduce presystemic clearance of (certain) lipophilic basic drugs via transient, complex effects on splanchnic-hepatic blood flow and/or shunt processes, and that the extent of this effect is influenced by the rate of drug delivery to the liver. In addition, these findings refute the notion that the reduced presystemic clearance results from (long-lasting) hepatic enzyme inhibition by some nutrient. On the other hand, repeated intake of specific nutrients (protein) and food contaminants (benzpyrene) can enhance presystemic drug clearance by enzyme induction. Thus, food may exert a dual effect on presystemic drug clearance. A complete evaluation of the influence of food on presystemic drug clearance necessitates bioavailability studies carried out following both single and repeated meals, including different kinds of food prepared by various cooking methods. The influence of food on the presystemic clearance of drugs is most likely to be clinically relevant with drugs having narrow therapeutic margins and/or steep dose-response curves.

Reliability of antiarrhythmic drug plasma concentration monitoring.

Measurement of drug levels is becoming increasingly popular to optimise the dosage of various drugs. In the case of antiarrhythmic drugs, the narrow therapeutic margin of most of these agents and a direct relationship between their pharmacological effects and plasma concentrations would justify more widespread use of monitoring. Optimum plasma concentration ranges have been described for lignocaine (lidocaine), procainamide, quinidine and, more recently, also for disopyramide, mexiletine, tocainide and other new antiarrhythmics. A critical analysis of the original data shows, however, that therapeutic and toxic levels are not so well defined as often assumed: small numbers of patients, marked interindividual variability, sometimes inadequate documentation of arrhythmias and lack of standardised blood sampling characterise many of these studies. Uncertainty about the reliability of concentration-effect relationships also arises when active drug metabolites are identified or there are marked concentration-dependent changes of drug protein-binding. In addition, abolition of various types of arrhythmias might require different drug concentrations. Nevertheless, therapeutic monitoring can be of practical value in patients with life-threatening ventricular arrhythmias and can also greatly facilitate dosage adjustment in cases with renal hepatic or severe cardiac failure. For a correct interpretation of drug levels, the time of blood sampling, dosage regimen, duration of treatment, pharmacokinetic principles, and the clinical condition of the patient must be taken into account. Further studies are needed to define the optimum therapeutic range for several drugs and to evaluate the usefulness of plasma concentration measurements in routine antiarrhythmic treatment.

Detection of repeated gonorrhea by a modified follow-up method

The rate of reinfection after treatment was studied in four groups of patients. The first group of 100 patients were evaluated retrospectively after treatment with 1.0 g ampicillin twice followed by two re-examinations over a 2-week period during which time intercourse was prohibited. The second and third prospectively groups consisted of 100 and 200 patients respectively, treated with 1 g ampicillin twice and 1.4 g pivampicillin + probenecid respectively, with re-examinations at intervals of 1 week and 4 weeks after treatment. In these two groups sexual intercourse was allowed during the last 10 days of the follow-up period. The fourth study group consisted of all patients infected with gonococci having MIC greater than or equal to 0.3 micrograms/ml for ampicillin and/or benzylpenicillin, who were treated with 1 g ampicillin twice during the period of 1973-76. In the first group no positive cultures were obtained at re-examination. In groups two and three, 35 out of 300 (12%) were found to have positive cultures at re-examination. Some of these were probably treatment failures. The failure rate in group four was found to be 20%, indicating that the treatment regimen used left a narrow therapeutic margin. However, the risk of re-infection, in this urban clinic, seems to be higher than the risk of treatment failure which would have remained undetected had sexual intercourse been forbidden.

Intravenous administration of aminophylline in asthmatic children taking theophylline orally

INTRAVENOUS AMINOPHYLLINE is commonly recommended for the treatment of children with acute exacerbations of asthma. 1:~ However, enthusiasm for this agent is tempered by concern for its relatively narrow therapeutic margin? In spite of advances in understanding the pharmacokinetics of theophylline, serious toxic effects continue to occur? ~ Some authors explicitly caution that the usual dose must be adjusted downward if the patient has received a recent oral dose of theophylline? :~ particularly if given within six hours. It was the purpose of this study to assess the safety of intravenous administration of aminophylline in the child who recently has received theophylline orally. METHODS Forty children with asthma were studied in the emergency room at The Children's Hospital of Buffalo. The patients ranged in age from 0.5 to 20.9 years (mean 6.6 years). Each patient received beta adrenergic bronchodilators in the emergency room and continued to have signs of bronchoconstriction and respiratory distress, necessitating intravenous use of aminophylline. Each child had received a theophylline preparation orally at home and had taken a dose within six hours of coming to the hospital. Nine children were taking sustained release preparations. Oral doses ranged from 2.7 to 9.6 mg/kg of anhydrous theophylline equivalent (mean -- 5.4 mg/kg). Prior to the intravenous administration of aminophylline, blood was drawn for determination of serum theophylline level (time zero level). An aminophylline dose of 6.0 mg/kg of the patient's total body weight (equivalent to 5.1

Therapeutic drug monitoring of aminoglycoside antibiotics.

Aminoglycosides are widely used antibacterial agents, particularly for serious infections. They have a narrow therapeutic margin of efficacy over toxicity relative to many other agents, a disadvantage which can be obviated to some extent by precise dosing regulated by blood concentration monitoring. The relationships of efficacy and toxicity to concentrations are discussed, as are the practical aspects of clinical indications for monitoring and specimen collection. Dosing by predictive methods is useful but not always of sufficient precision. A large number of methods for assay are now available. With care, microbilogical plate assays can give results of adequate accuracy and selectivity, and with sufficient speed. Immunoassays give more accurate, specific and rapid answers; EMIT, in particular, seems the best method available at the present time. Whichever method is used, control of its accuracy is essential.

The effect of assay methods on plasma levels and pharmacokinetics of theophylline: HPLC and EIA.

1 The effects of two assay methods, HPLC and EIA, on theophylline plasma levels (n = 254) and pharmacokinetics (n = 6) were examined on blood samples obtained from asthmatic patients and normal adult male volunteers. 2 The standard curves obtained and the plasma level values during plasma level monitoring of theophylline measured with two methods are well correlated each other within concentration range of 2.5 to 20.0 microgram/ml (P less than 0.001). EIA, however in general, appears to give a lower value than HPLC. 3 The values of plasma theophylline half-life and clearance analyzed using a two-compartment open system model were found different between the two assay methods and dissimilar to those previously reported by using ultraviolet method. 4 The sampling end-point and/or assay sensitivity particularly to measure a lower level of theophylline (less than 2.5 microgram/ml) can influence the pharmacokinetics for a potent bronchodilator with a narrow therapeutic margin, theophylline.

Correlation of Predicted Versus Measured Creatinine Clearance Values in Burn Patients

Four methods for predicting creatinine clearance (Ccr) from serum creatinine concentration (Scr) were evaluated in 19 male burn patients with burn wound sepsis. Measured Ccr values were calculated from 24-hour urinary catheter collections. Steady state Scr values were obtained during the same collection interval. Predicted Ccr values were derived from Scr using the methods of Cockcroft and Gault (Method II), Siersbaek-Nielsen, Kampmann and others (Method III) and Jeliffe (Methods I and IV). Wide differences between measured and predicted values were observed but were statistically significant (p less than 0.05) for Method I only. The smallest mean difference (+/-0.02 ml/min/1.73 m2) occurred with Method II measured-predicted data pairs. Method III predicted Ccr values which correlated best with measured values (r=0.770) and showed the least variability (+/-7.6 ml/min/1.73 m2). All methods appeared to overestimate when measured Ccr was less than 60 ml/min/1.73 m2. Use of estimated lean body weights did not improve correlations between predicted and measured Ccr values. While Methods II and III may provide useful initial approximations of Ccr in burn patients, reliance upon predicted Ccr values for dosage modification in burn patients may result in an insufficient reduction in dosage. Whenever possible, dosage regimens for drugs with narrow therapeutic margins should be developed or adjusted using pharmacokinetic values determined in the individual patient.

Determination of Serum Gentamicin Sulfate Levels

Determination of serum gentamicin levels (SGLs) is helpful in monitoring therapy in patients receiving this drug because there is a narrow therapeutic margin and serum levels may vary greatly between patients receiving similar doses. During a ten-month period, definite indications for obtaining SGL determinations were present for 189 of 212 serum samples (89.2%) submitted to the laboratory. However, 110 samples (51.9%) were improperly drawn and results of 85 samples (40.1%) were ignored. Only 26 of the 62 correctly drawn and not ignored samples (41.9%) were appropriately acted on. At most, 42 of the 212 samples (19.8%) were appropriately used in making patient-care decisions. Thus, in this study, an inordinatley large number of SGLs were incorrectly drawn, apparently ignored, or inappropriately used in making patient-care decisions.