Reduction Of Adverse Effects Research Articles

Optimisation of treatment by applying programmable rate-controlled drug delivery technology.

A number of programmable rate-controlled drug delivery technologies have been developed during the last two decades with the aim of regulating the rate of drug delivery, sustaining the duration of therapeutic action and/or targeting the delivery of drug to a specific tissue. As a result, several therapeutically beneficial outcomes can be achieved, such as: (i) controlled delivery of a therapeutic dose at a desirable rate of delivery; (ii) maintenance of drug concentrations within an optimal therapeutic range for prolonged duration of treatment; (iii) maximisation of efficacy-dose relationship; (iv) reduction of adverse effects; (v) minimisation of the need for frequent dose intake; and (vi) enhancement of patient compliance. The treatment of illness can thus be optimised. To gain a better understanding of how to optimise the treatment of illnesses by applying programmable rate-controlled drug delivery technologies, this article reviews the scientific concepts and technical principles behind the development of various programmable rate-controlled drug delivery systems that have been marketed or are under active development. Finally, the roles of these technologies in optimising therapeutic outcomes in nine therapeutic areas are discussed.

Improvements to snow and ice control on European highways

The need for innovative snow and ice control techniques and processes has continued to grow as national and European road networks have developed substantially over recent decades. The demand for improvement, including the sophistication of the techniques and technology used, continues to be driven by the increasing need for safe and efficient national and international road freight and passenger transport and by the environmental and other policies affecting highways (roads and bridges). The European Commission project ‘COST Action 344: Improvements to snow and ice control on European roads and bridges’ started in April 1999 as a three-year project, with participation from 18 European countries–Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Iceland, Ireland, Norway, Poland, Romania, Slovenia, Spain, Sweden, Switzerland and United Kingdom. The project's aims are to: 1) review existing international practices, 2) define snow and ice control requirements in different European climatic regions, 3) specify ‘Best Practice’ in different European climatic regions, 4) develop guidelines for the integration of specified snow and ice control methods into network level road management and maintenance systems, 5) recommend improvements to driver information and traffic management systems, and 6) recommend future research projects. This COST Action will promote the exploitation of technological advances in the application and distribution of snow and ice control measures, with a view to providing significant environmental and safety benefits and lower operational costs. Millions of ECUs could be saved through lower operational costs and a reduction in adverse effects on the highway infrastructure and the environment. For road users, more effective management of winter operations could lead to a reduction in traffic delays and accidents. For practitioners, implementation of ‘Best Practice’ should enhance standards and lead to ‘best value’ being achieved. The implementation of best value could provide the means to measure the performance of the winter maintenance service within various road administrations. For widespread dissemination of knowledge, interim results of the COST Action are being made available to European and national policy-makers, regional planners, engineers, road and vehicle operators, industry and academia. The internet, a CD-ROM, email, handbooks and events such as workshops, conferences and seminars are also being used to target a wider audience of practitioners and researchers. Copyright © 2001 Royal Meteorological Society

Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management.

Mycophenolate mofetil (MMF) is a relatively new immunosuppressive drug. It inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis, and thus causes lymphocyte-selective immunosuppression. Large clinical trials have revealed the efficacy of MMF in the prevention of allograft rejection when administered together with cyclosporin or tacrolimus and corticosteroids. Although the adverse effect profile of MMF is comparatively benign, gastrointestinal adverse effects are a major concern. These effects are partially explained by the increased immune suppression, by the mode of action and by interactions, particularly with other immunosuppressants. The aetiology of the rarest gastrointestinal adverse effects is still not completely clear. Therapy depends upon the clinical gravity of the adverse effects and is therefore a case of waiting and ob- serving. An adjustment of dosage of immunosuppressants according to the clinical situation and, particularly in the case of MMF, spreading the total dosage over more than 2 daily doses are often sufficient. Should adverse effects persist for a longer period of time and be of a more serious nature, a comprehensive invasive diagnostic process is necessary, including endoscopy and biopsy and the search for opportunistic infections. In this case, dosage reduction or the complete withdrawal of MMF seems to be unavoidable. Severe gastrointestinal complications with MMF are rare, but when they do occur they may require extensive diagnosis and treatment. In the future, therapeutic drug monitoring and, where necessary, pharmacological modifications of MMF could lead to a further reduction of adverse effects with an equal or even increased efficacy.

Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis is now a treatable disease and several immunomodulating therapies exist, but their clinical efficacy is moderate and treatment failure during the course of the disease is an increasing problem. As agents with different targets are available, the question was raised whether combination of these therapies would: be safe;result in reduction of adverse effects; andprovide synergistic benefit by additive or complementary modes of action. The areas under clinical investigation are general immunosuppression as well as more targeted approaches that interfere with antigen presentation, immune cell transmigration, release of myelinotoxic factors or even axonal damage. Combination of these immunomodulatory drugs seems to be rational and promising. Nevertheless, combination therapies need to be studied in carefully designed clinical trials in selected patient populations in order to demonstrate additive or synergistic effects. This article will summarise current drug combination strategies in relapsing-remitting multiple sclerosis and provide an overview of the initial clinical trials.

The addition of ketamine to patient controlled morphine analgesia does not improve quality of analgesia after total abdominal hysterectomy

Abstract We undertook a prospective, randomised, double-blind clinical trial of 50 ASA I and II patients undergoing total abdominal hysterectomy to compare the effect of intraoperative ketamine (0.3 mg kg −1 i.v.) and ketamine 1 mg ml −1 plus morphine 1 mg ml −1 patient controlled analgesia (PCA) (group MK) — with morphine 1 mg ml −1 PCA (group M) for postoperative analgesia. There was no significant difference in pain scores at rest or after compulsory cough at 24 hours. The mean total dose of morphine used at 24 hours was 33 mg in the control group v s 34.5 mg in the ketamine group (ns). Patient reporting of adverse effects was similar in both groups, although the ketamine group reported significantly less sleepiness. No patients reported hallucinations, confirming that low-dose ketamine is well tolerated. Overall satisfaction with the quality of analgesia was significantly better in the control group. Our results have not confirmed that the addition of low-dose ketamine to a standard anaesthetic/postoperative regimen in total abdominal hysterectomy patients provides any improvement in analgesia, morphine sparing effect or a reduction in adverse effects (except sedation).

Genetic factors in osteoporosis. What are the implications for prevention and treatment?

Osteoporosis is a common disease that affects 1 in 3 women. Family and twin studies have demonstrated that there is a strong genetic component to this condition. Potential candidate genes examined for their regulatory effect on bone mass include those for collagen type I, estrogen and vitamin D receptors, and various cytokines and growth factors. To date, most work has focused on the vitamin D receptor (VDR) gene, and experience with this locus will probably act as a model for many future studies. There is increasing evidence, from population studies that have examined the relationship between VDR genotype and bone mineral density, of genetic heterogeneity and gene-environment interactions. Response to therapeutic agents may also be affected by an individual's underlying genotype, partly explaining the range of responses that are commonly observed in clinical practice. Knowledge of a person's genotype could, therefore, allow current therapies to be targeted to those most likely to benefit, with a possible reduction in adverse effects. Largescale genomic studies of osteoporosis may also identify novel genes, and this may lead to both a better understanding of disease pathophysiology and to the discovery of potential targets for drug development.

Reduction in adverse effects of mechanical ventilation in rabbits with acute respiratory failure by treatment with extracorporeal CO2 removal and a large fluid volume of diluted surfactant.

The long-term outcome of infants with severe respiratory distress syndrome can be improved by optimizing surfactant therapy and minimizing the risk for pulmonary barovolutrauma and oxygen toxicity. The authors hypothesized that this may be achieved with low frequency ventilation and extracorporeal CO2 removal (LFV-ECCO2R), in combination with intratracheal instillation of a large fluid volume with diluted surfactant. Lung lavaged rabbits were initially ventilated with continuous positive pressure ventilation. The rabbits were randomized to treatment with LFV-ECCO2R and surfactant (experimental group), or surfactant only (control group). In the experimental group, the rabbits were treated with a large volume (16 ml/kg) of diluted surfactant (6.25 mg/ml) at a dose of 100 mg/kg body weight. After surfactant therapy, the FiO2 100% was gradually decreased. During 4 hours, the extracorporeal bloodflow was adjusted to maintain the PaCO2 between 4.0-6.0 kPa. Thereafter, the rabbits were allowed to breathe spontaneously with 2.5 cm H2O continuous positive airway pressure ventilation (CPAP) and 40% oxygen. In the control group, the rabbits received the same surfactant therapy. During the study period, the rabbits remained ventilated with an inspiratory oxygen concentration (FiO2) of 100% for 4 hours. The ventilator flow was adjusted to maintain the PaCO2 between 4.0 and 6.0 kPa. Thereafter, positive-end expiratory pressure was decreased to 2.5 cm H2O and FiO2 was gradually decreased to 40%. In the experimental group, FiO2 was decreased to 40% in a stepwise fashion whereby the PaO2 could be maintained easily within the normal range. Extracorporeal flow rates during perfusion ranged from 20-35 ml/kg/min and were sufficient to keep the PaCO2 and pH within normal limits. After 4 hours, the rabbits could breathe spontaneously with CPAP and 40% oxygen, while normal blood gas values were maintained. All rabbits survived the experiment. In the control group, all rabbits experienced severe hypoxemia, despite FiO2 of 100% oxygen and, during the course of weaning, all rabbits died because of hypoxia. In conclusion, the present study demonstrated that barovolutrauma due to mechanical ventilation, and oxygen toxicity due to high FiO2, can be minimized in an animal model of acute respiratory failure by the combination of LFV-ECCO2R and surfactant therapy.

Pharmacotherapy of epilepsy: state of the art and developments

A discussion of modern day practice and new developments in antiepileptic drug treatment. Important principles of antiepileptic therapy are addressed--starting with antiepileptic drug therapy, pharmacokinetics and pharmacodynamics, therapeutic drug monitoring, drug-induced adverse effects and the withdrawal of antiepileptic drugs. Furthermore, the pathophysiology of focal and generalized epilepsies and the mechanism of action of several antiepileptic drugs are briefly reviewed. Modern treatment algorithms for different types of epileptic seizures are presented. A significant development is the introduction of new antiepileptic drugs and particularly of those drugs that have been developed according to the latest insights into pathophysiology. Also of interest is the increased focus on adverse effects and on quality of life. Partly due to these developments, combining antiepileptic drugs has received renewed attention in an attempt to maintain effective seizure control but with a reduction of adverse effects.

Néoral® en transplantation hépatique

Intestinal absorption of the microemulsion formulation of cyclosporin, Neoral®, unlike that of the conventional formulation, Sandimmun®, is relatively independent of factors such as the presence of bile acids, pancreatic enzymes and food. The consequent improvement in pharmacokinetic parameters, bioavailability and interindividual variability has particular advantages in liver transplantation. The first situation in which Neoral® may have a significant advantage over Sandimmun® is immediately after liver transplantation, when oral administration (which is not possible with Sandimmun®) is desirable because i) intravenous administration of cyclosporin may lead to increased toxicity and ii) the switch from intravenous to oral administration may cause a fall in blood cyclosporin concentration, with the consequent risk of rejection. In 4 of the 5 series comparing Neoral® and Sandimmun® de novo after liver transplantation, a significant reduction of the rejection rate in favour of Neoral® was observed, without significant differences in nephrotoxicity or neurotoxicity. The second situation in which Neoral® may have a particular advantage is in patients with impaired intestinal absorption, e.g. those with cystic fibrosis, in whom oral administration of Neoral® twice daily is usually successful. This finding may extend to other patients with limited cyclosporin absorption, such as young children and patients with cholestasis and gastroparesis. The third situation to consider is conversion from Sandimmun® to Neoral® some time after transplantation, where the improved pharmacokinetics of Neoral® may lead to reduced rates of acute and chronic rejection and possibly to a reduction in adverse effects. In patients converted to Neoral® more than 6 months after transplantation, the improved bioavailability necessitated a dosage reduction of 15 to 20%, particularly in those patients who were receiving relatively high dosages of Sandimmun®, and the incidence of adverse effects was not increased. Finally, there is the issue regarding discontinuation of corticosteroids in patients receiving Neoral® after liver transplantation. A pilot study has shown that this can be achieved more rapidly with Neoral® than with Sandimmun®.

Practice Guidelines for Cancer Pain Management

Practice Guidelines for Cancer Pain Management

2161 Reduction of adverse effects of combined modality therapy with subtotal nodal irradiation in stage IIIA Hodgkin's disease

2161 Reduction of adverse effects of combined modality therapy with subtotal nodal irradiation in stage IIIA Hodgkin's disease

Intra-operative epidural morphine, fentanyl, and droperidol for control of pain after spinal surgery A prospective, randomized, placebo-controlled, and double-blind trial

The present study was conducted to investigate the analgesic effects of intra-operatively administered epidural morphine in patients undergoing surgery for lumbar disc disease. Three treatment groups were constituted: one with 5.0 mg morphine and 2.5 mg dehydrobenzperidol (DHB) in 10 ml physiological saline, one with 5.0 mg morphine and 0.1 mg fentanyl in the same amount of saline, and one placebo group with saline only. The test solution was injected epidurally via catheter after haemostasis and before closure of the wound. Sixty eight patients were randomly assigned to each of the three groups and subjected to a double-blind evaluation. In the morphine/fentanyl and morphine/droperidol groups, significantly better analgesia was found as compared to the placebo group. No significant difference was found between the morphine/fentanyl and morphine/droperidol groups considering side effects of therapy, as well as duration and quality of analgesia. The side effects in the treatment groups were only slight and not significantly different from the placebo group. It was shown that additional epidural fentanyl offers no significant improvement of postoperative analgesia. No significant reduction of adverse effects could be found in the morphine/droperidol group compared to the morphine/fentanyl group. In conclusion, the intra-operative epidural application of morphine is a safe, effective and simple method for achieving sufficient analgesia in the first 24 hours after lumbar spinal surgery for disc disease.

Novel Oral Drug Formulations

The rationale for specialised oral formulations of drugs include prolongation of effect for increased patient convenience and reduction of adverse effects through lowered peak plasma concentrations. Local and systemic adverse effects due to high concentrations of drug can be minimised by the use of controlled release delivery systems. Local effects in the gastrointestinal (GI) tract from the release of irritant drug molecules can also be reduced, but the gastric damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is only partially relieved by formulation approaches because of the involvement of systemic factors in the aetiology of GI adverse events. The advantages for each drug class must be examined. Newer dosage forms include: (i) osmotic pumps and zero order kinetics systems to control the release rate of the drug; (ii) bioadhesive systems and gastric retention devices to control GI transit; (iii) bioerodible hydrogels; (iv) molecular carrier systems (e.g. cyclodextrin-encapsulated drugs) to modulate local toxicity in the GI tract; (v) externally activated systems; and (vi) colloidal systems such as liposomes and microspheres. There is evidence for improved tolerability for a variety of drugs administered in novel delivery systems. However, the evidence for improved tolerability is complicated by the potential bias in adverse reaction reporting systems, and a lack of studies directly comparing conventional and modified release preparations. The technology now available to produce delivery systems which not only release drugs in a controlled and predetermined fashion, but which can also target to regions of the GI tract such as the colon, should allow greater control of therapy and potentially might minimise patient variables. However, the problem of variable GI transit times still eludes solution. Systems which rely on time to release drug might be more vulnerable to patient-to-patient variability than those which respond to local environments. The effect of food intake is more apparent on single-unit, nondisintegrating dosage forms, although of course none so far are immune from influence. The risk of new adverse effects resulting from such positional therapy with novel delivery devices must be considered. Understanding the mechanisms of induction of individual adverse effects can lead to advances in modes of delivery to decrease the potential for adverse reactions and events while maintaining therapeutic efficacy. Increased compliance can led to increased therapeutic control and hence safety. Each system has to be considered on its merits. No generalisations can be made, although invariably the modulation of high peak plasma concentrations diminishes adverse effects due to rapid absorption.

Radiation-induced increase in hyaluronan and fibronectin in bronchoalveolar lavage fluid from breast cancer patients is suppressed by smoking

Bronchoalveolar lavage (BAL) fluid was analysed from 21 patients with breast cancer, stage T1N0M0, who had undergone tumour resection and post-operative local irradiation (accumulated dose 56 Gy). The lavage was performed two months after radiotherapy, in the anterior part of the lingula (left side) or of the right middle lobe (right side), depending on which side had been exposed to radiation. The patients had significantly increased concentrations of fibronectin (FN) (p less than 0.001), hyaluronan (HA) (p less than 0.01) and albumin (p less than 0.05) in BAL fluid compared with the healthy controls (n = 19). However, when the patients were separated, according to smoking history, it was obvious that the inflammatory reaction occurred entirely in the nonsmoking patient group (n = 10), whilst no difference could be found between the smoking patients (n = 11) and the controls. In the nonsmoking patient group, there was a sevenfold increase in BAL concentrations of FN and a threefold increase in HA. Moreover, four patients had detectable levels of procollagen III peptide in BAL, all were nonsmokers. The smoking habits of the controls had no influence on the BAL measurements. These findings indicate that smoking interferes with the radiation-induced early inflammatory connective tissue reaction of the lung. Finally, the results justify further investigation of interaction of smoking with cancer treatment, both from the view of therapy effectiveness and reduction of adverse effects.

P-519 - Clinical application of cisplatin-phosphatidylcholine-lipiodol suspension for hepatocellular carcinoma. (2) Reduction of adverse effects by DDS preparations

P-519 - Clinical application of cisplatin-phosphatidylcholine-lipiodol suspension for hepatocellular carcinoma. (2) Reduction of adverse effects by DDS preparations

New antihypertensive agents: benefit of treatment.

Large-scale end-point trials have demonstrated that antihypertensive treatment reverses the risk of stroke attributable to high blood pressure and probably reduces the incidence of myocardial infarction. Despite this major achievement in therapeutics, substantial goals still need to be achieved. Thus, there is a need for improvement in existing antihypertensive agents in terms of greater blood pressure-lowering efficacy and improved impact on coronary heart disease in younger subjects. There is also a pressing need for a reduction in adverse effects. The incidence of these far exceeds the potential benefit of treatment. Last, the costs of therapy are assuming growing importance in the face of tight financial constraints on health care systems throughout the world.

The loading dose for continuous infusion epidural analgesia. A technique to reduce the incidence of hypotension.

The effects of 0.08% and 0.5% bupivacaine, given in equal volumes as the loading dose prior to continuous infusion epidural analgesia, were compared. The incidence of hypotension, as well as the height of sensory blockade, was markedly lowered by reducing the loading dose of bupivacaine. However, the efficacy of the epidural analgesia was maintained by using the same volume for the loading dose. The mean onset of analgesia was delayed from 9.1 to 13.6 minutes. There were fewer calls for intervention consequent upon the reduction in adverse effects. The use of 8 ml 0.08% bupivacaine for the loading dose or for subsequent top-ups is recommended. The concept of a liquid sleeve of local anaesthetic in the epidural space is further supported.

Combination Analgesics

Six rationales for using combination analgesics are identified, but most combinations are formulated with two rationales in mind: enhancement of analgesia and reduction of adverse effects by combining two analgesics with different mechanisms of action. Acetaminophen and aspirin are the mainstays of oral analgesic combinations. There is substantial evidence that combining an optimal dose of acetaminophen or aspirin with an oral opioid such as codeine, hydrocodone, or oxycodone produces an additive analgesic effect greater than that obtained by doubling the dose of either constituent administered alone. There is also some evidence that the adverse effects produced by such combinations are less than would be produced by an equi-analgesic dose of a single constituent. The physician need not be confined to existing fixed-ratio combinations; he or she may extemporize to the patient's advantage by co-administering acetaminophen, aspirin, or other nonsteroidal anti-inflammatory drugs with available oral opioids and, in select situations, co-administering oral or injectable analgesics with psychoactive drugs.

Rethinking Community Medicine: towards a renaissance in public health

<h3>Background and importance</h3> A non-comparative study, a randomised pilot clinical trial and a cohort suggest that the change is virologically safe. There are still no results from two large randomised clinical trials in development. In naive patients, this pattern has shown no inferiority of dolutegravir and lamivudine compared with triple treatment with dolutegravir plus tenofovir/emtricitabine. <h3>Aim and objectives</h3> To evaluate the efficacy, economic impact and reduction in adverse effects in HIV patients undergoing bi-therapy treatment with dolutegravir and lamivudine. <h3>Material and methods</h3> A retrospective observational study was conducted in a second level hospital. Patients who started antiretroviral treatment or switched to dual therapy based on lamivudine and dolutegravir between June 2018 and September 2019 were included. Study variables were age, sex, date and reason for the change, duration of treatment, viral load (CV, copies/mL), CD4 and CD8 cells (cells/µL) before and after the change and on the date of the last available analysis, previous therapy, glomerular filtration rate (GFR) (mL/min), and levels of cholesterol (mg/dL), low density lipoprotein (LDL, mg/dL) and triglycerides (mg/dL). <h3>Results</h3> Nine patients (66.66% men) with a mean age of 49 years (30–58), 3 of whom were naive patients (33.33%) were analysed. Effectiveness was 100% of patients who achieved CV &lt;50 copies at 4–6 weeks, maintaining the virological response for an average of 26 weeks. CD4 and CD8 counts increased significantly from 690 to 805 and 910 to 943, respectively. The lipid profile showed differences in LDL from 170 to 120. A significant decrease in GFR was observed from 102 to 87. The annual cost saw a decrease of 1690€/patient/year. <h3>Conclusion and relevance</h3> Simplification to dual therapy was a safe and effective option that allowed optimisation of the resources against triple therapy. <h3>References and/or acknowledgements</h3> 1. Taiwo BO, Marconi VC, Berzins B, et al. Dolutegravir plus lamivudine maintains human immunodeficiency virus-1 suppression through week 48 in a pilot randomised trial. <i>Clin Infect Dis</i> 2018;66:1794–1797. 2. Cahn P, Sierra Madero J, Arribas J, <i>et al</i>. Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in antiretroviral treatment-naïve adults with HIV-1 infection: 48-week results from the GEMINI studies. 22nd International AIDS Conference, 23–27 July 2018, Amsterdam. Abstract TUAB0106LB. No conflict of interest.