Biomedical subjects

A Markham

Publications and source records attributed to A Markham.

At least 37 records · Page 2Linked to original sources

PubMed1997

Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation.

Ibutilide is the first 'pure' class III antiarrhythmic drug to become available. Its predominant action is prolongation of the myocardial action potential duration. This appears to be achieved by a unique ionic mechanism of action that involves activation of a late inward sodium current and possibly blockade of the rapidly activating component of the cardiac delayed rectifier potassium current. Intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2 mg successfully converted atrial flutter or fibrillation to sinus rhythm in 33 to 49% of patients in 2 placebo-controlled trials involving 439 patients with sustained arrhythmia. In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2 mg successfully converted the arrhythmia in 57% of patients. The mean times to conversion were < or = 30 minutes in these trials. In 3 comparative trials, ibutilide was significantly more effective than racemic sotalol or procainamide in terminating atrial flutter or fibrillation. The pretreatment duration of the arrhythmia is an important predictor of the success of ibutilide treatment; the greatest conversion rates are achieved when the arrhythmia is of recent onset (i.e. < or = 30 days' duration). Ibutilide is more effective in terminating atrial flutter than atrial fibrillation. Adverse events associated with ibutilide are predominantly cardiovascular. Sustained polymorphic ventricular tachycardia developed in 1.7%, and non-sustained polymorphic ventricular tachycardia in 2.7%, of 586 patients treated with ibutilide in clinical trials. However, no proarrhythmia-related deaths have been reported with the use of ibutilide. The drug has minimal haemodynamic effects and is associated with few noncardiovascular adverse events. Thus, ibutilide is a useful agent for the pharmacological cardioversion of recent-onset atrial fibrillation or flutter, provided that adequate steps are taken to monitor for proarrhythmic events. The drug causes few noncardiovascular adverse events and has minimal haemodynamic effects. Furthermore, it appears to be more effective than procainamide (especially in patients with atrial flutter) and racemic sotalol.

Anti-Arrhythmia Agents↗

PubMed1997

Fenoldopam: a review of its pharmacodynamic and pharmacokinetic properties and intravenous clinical potential in the management of hypertensive urgencies and emergencies.

Fenoldopam is a dopamine agonist that causes peripheral vasodilation via stimulation of dopamine 1 (D1) receptors. The efficacy of an intravenous infusion of fenoldopam in decreasing blood pressure in patients with a hypertensive urgency, including patients who developed hypertension after coronary artery bypass graft surgery, and in a small number of patients with hypertensive emergency, is similar to that of sodium nitroprusside. However, unlike sodium nitroprusside, fenoldopam also increases renal blood flow and causes diuresis and natriuresis. There is no evidence of rebound hypertension after stopping the infusion. As the tolerability profile of fenoldopam is generally similar to that of sodium nitroprusside, fenoldopam appears to be an effective alternative to sodium nitroprusside in the immediate treatment of patients who develop severe hypertension and in whom oral treatment is not practical. Fenoldopam may be particularly useful in patients who develop hypertension after coronary artery bypass graft surgery, but further studies are required to confirm its role in hypertensive emergency.

Antihypertensive Agents↗

PubMed1997

Clopidogrel.

Clopidogrel is a thienopyridine that irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface. In animal models, clopidogrel reduced the formation of both arterial and venous thrombi. After oral administration, clopidogrel is rapidly absorbed and undergoes metabolic activation in the liver. The principal circulating metabolite is SR 26334, an inactive carboxylic acid derivative. The active metabolite is not yet known. Findings of a large, well controlled study of clopidogrel versus aspirin in patients with atherosclerotic vascular disease (CAPRIE study) indicate that clopidogrel has superior efficacy in terms of prevention of ischaemic stroke, myocardial infarction and vascular death. Clopidogrel-treated patients experienced less frequent gastrointestinal upset, abnormal liver function and gastrointestinal haemorrhage than patients who received aspirin, but more frequent rash and diarrhoea. Neutropenia and thrombocytopenia occurred rarely and at similar rates in both groups.

Animals↗

PubMed1997

Mibefradil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris.

Mibefradil belongs to a new class of calcium antagonists, the tetralol derivatives. It selectively blocks T-type calcium channels in contrast to other calcium antagonists which block only L-type channels. Mibefradil relaxes coronary arteries without suppressing myocardial contractility and causes a dose-related decrease in heart rate. When given orally once daily to patients with hypertension mibefradil produces a dose-related decrease in blood pressure which is sustained for 24 hours and improves exercise performance in patients with stable angina pectoris. In patients with generally mild to moderate hypertension oral mibefradil was superior to nifedipine SR and diltiazem CD, tended to be more effective than nifedipine GITS and had similar efficacy to amlodipine. Mibefradil 50 to 100mg once daily also has antianginal and anti-ischaemic effects. The drug improves the duration of symptom-limited exercise and the time to onset of ischaemia, and reduces the frequency of anginal attacks and consumption of nitroglycerin. Its efficacy is similar to that of diltiazem and tends to be greater than that of amlodipine in patients with stable angina. Mibefradil is generally well tolerated and is associated with a lower incidence of leg oedema than amlodipine and nifedipine. Thus, mibefradil is a calcium antagonist with a predictable cardiovascular profile, which, on the basis of available clinical data, is an effective alternative to other drugs widely used in the treatment of hypertension and stable angina pectoris.

Angina Pectoris↗

PubMed1997

Irbesartan. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in the management of hypertension.

Irbesartan inhibits the activity of angiotensin II (AII) via specific, selective noncompetitive antagonism of the AII receptor subtype 1 (AT1) which mediates most of the known physiological activities of AII. In patients with mild to moderate hypertension, once daily administration of irbesartan 150 or 300 mg, with or without adjunctive antihypertensive agents, provides effective 24-hour BP control. Irbesartan reduced BP to a similar extent to enalapril and atenolol and to a significantly greater extent than losartan. The combination of irbesartan and hydrochlorothiazide resulted in additive antihypertensive effects. The drug is effective in the elderly and dosage adjustment is not required in these patients or in those with renal or hepatic failure. Preliminary studies evaluating the efficacy of irbesartan in patients with heart failure have produced encouraging results. Irbesartan is very well tolerated and neither the frequency nor the pattern of adverse events differed from those seen in placebo recipients, although headache was significantly more frequent with the latter. Similarly, the incidence of adverse events did not differ significantly between irbesartan and enalapril in patients who received either drug as monotherapy. Headache, upper-respiratory tract infection and musculoskeletal pain were the most common complaints. Thus, irbesartan is an effective therapy for patients with mild to moderate hypertension and had an adverse event profile similar to that of placebo in clinical trials. On this basis it would appear to be an effective therapeutic option in this indication.

Angiotensin II↗

PubMed1997

Danaparoid. A review of its pharmacology and clinical use in the management of heparin-induced thrombocytopenia.

Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has low cross-reactivity with HIT-associated antibodies. Further comparative trials are needed to confirm these promising findings.

Blood Coagulation↗

PubMed1996

Selenium homeostasis in the central nervous system of the rat.

These experiments have investigated selenium movement between blood and CNS in anaesthetised rats. Each animal was surgically anaesthetised and the left femoral blood vessels cannulated for blood withdrawal and solute infusion. Each rat received 75-selenium as sodium selenite infused in normal saline and experiments lasted between 5 minutes and 5 hours during which blood samples were periodically taken. At termination, the CNS was removed, regionally dissected and analysed with the plasma samples for 75-Se radioactivity by gamma-counting. Data were analysed by graphical analysis. Results showed unidirectional uptake of 75-Se into the CNS and regional differences were not found except for the hypothalamus. On average the CNS influx rate constant (Kin) was about 7 +/- 1 x 10(-5) ml/min/g. Data suggest that the 75-Se most likely entered the CNS as a free ionic form.

Animals↗

PubMed1996

Clarithromycin and omeprazole as helicobacter pylori eradication therapy in patients with H. pylori-associated gastric disorders.

Helicobacter pylori is susceptible to many antibacterial drugs in vitro but has proved difficult to eradicate in vivo. The macrolide clarithromycin has good activity against H. pylori in vitro and has demonstrated the highest eradication rate for any antibacterial monotherapy in vivo. However, it is clear that antibacterial monotherapy is not a sufficiently effective treatment for patients with H. pylori infection. The suggestion that high intragastric acidity impairs the action of antibacterial drugs led to the evaluation of combination H. pylori eradication regimens including H+,K+-ATPase inhibitors and antibacterial drug(s) with or without bismuth compounds. Noncomparative studies evaluating the efficacy of dual therapy with clarithromycin plus omeprazole in patients with H. pylori infection have reported eradication rates of between 58 and 83% > or = 4-weeks after therapy. In comparative studies, clarithromycin plus omeprazole was at least as effective as amoxicillin plus omeprazole. However, direct comparisons have shown that eradication rates achieved by dual therapy are not as high as those achieved by triple therapy. Indeed, triple therapy with clarithromycin plus omeprazole in combination with amoxicillin or a nitroimidazole has achieved eradication rates of up to 100%. Although 14-day triple drug regimes were initially considered necessary for effective eradication, it now seems clear that 7-day regimes are equally effective. Factors known to influence response to H. pylori eradication therapy include bacterial resistance and patient compliance. A review of 4 studies evaluating the efficacy of dual eradication therapy with clarithromycin plus omeprazole reported an overall incidence of adverse events (patient or investigator reported, whether related to treatment or not) of 45%. The most common adverse event was taste disturbance (an adverse event commonly reported during the development of clarithromycin); nausea, headache, diarrhoea, vomiting and abdominal pain occurred less frequently. Although dual therapy might be expected to cause fewer adverse events than triple therapy this has not been the case in direct comparisons conducted to date. Thus, although clarithromycin plus omeprazole is associated with an H. pylori eradication rate of approximately 70%, 1 week of triple therapy with these 2 drugs together with amoxicillin or a nitroimidazole, which eradicates the organism in approximately 90% of cases, may represent optimal H. pylori eradication therapy.

Anti-Bacterial Agents↗

PubMed1996

Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation.

Mycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an important enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or mycophenolic acid inhibit the proliferation of lymphocytes and the production of antibodies induced by a variety of mitogens and antigens. Mycophenolate mofetil is also active in several animal models of transplantation and has produced effects in animals that indicate that it may inhibit the chronic rejection process. Mycophenolate mofetil has been compared with azathioprine or placebo in 3 large, randomised, double-blind, multicentre trials as part of combination immunosuppression therapy with cyclosporin and corticosteroids. Compared with either placebo or azathioprine (1 to 2 mg/kg/day or 100 to 150 mg/day), mycophenolate mofetil 2 or 3 g/day was associated with a significantly lower proportion of patients experiencing acute rejection or treatment failure during the first 6 months after transplantation. Mycophenolate mofetil also tended to be associated with a lower proportion of patients who required a full course of antirejection therapy. However, the proportion of patients who died or who had graft loss was similar between all of the treatment groups. There are currently no data regarding the effects of mycophenolate mofetil on long term patient or graft survival, which are important clinical outcomes in assessing its place in the management of renal transplantation. Clinical trials are also needed to evaluate mycophenolate mofetil in specific patient populations (e.g. repeat renal transplant patients or highly sensitised patients), to determine its efficacy in alternative immunosuppressive protocols and to investigate its use in the transplantation of other solid organs. In summary, mycophenolate mofetil appears to be an attractive new agent in the prevention of graft rejection in renal transplant recipients that has shown superior efficacy to azathioprine. Although long term clinical outcome data are required, mycophenolate is a potentially important advance in transplant immunosuppression.

Animals↗

PubMed1996

Epoetin beta. A review of its pharmacological properties and clinical use in the management of anaemia associated with chronic renal failure.

Epoetin beta is a recombinant form of erythropoietin, the hormone responsible for the maintenance of erythropoiesis. The drug binds to and activates receptors on erythroid progenitor cells which then develop into mature erythrocytes. Epoetin beta increases reticulocyte counts, haemoglobin levels and haematocrit in a dose-proportional manner. These changes are accompanied by beneficial cardiovascular effects, including decreased cardiac output, resting heart rate and left ventricular hypertrophy in patients with chronic renal failure (CRF). Increases of 15 to 54% in haemoglobin levels and 17 to 60% in haematocrit were reported after subcutaneous or intravenous epoetin beta therapy in studies of 8 weeks' to 12 months' duration. Two multicentre clinical trials demonstrated clearly the superior efficacy of epoetin beta over placebo in 229 patients with CRF undergoing haemodialysis. Reduction or elimination of transfusion requirements was reported in studies where this parameter was measured. Comparative data indicate that dosage reductions of approximately 30% compared with intravenous therapy are possible when subcutaneous administration of epoetin beta is used. Haematocrit increased more rapidly in 5 multicentre studies in patients who received epoetin beta subcutaneously than in those who received the same dosage intravenously. Correction of anaemia with epoetin beta is associated with significant improvements in quality of life in patients with CRF. Available data indicate greatest cost-effectiveness in patients who are severely incapacitated by anaemia before treatment. The cost of administration of the drug may also be reduced by the use of the subcutaneous route. Hypertension may occur in patients who receive epoetin beta but may be minimised by avoiding rapid increases in haematocrit (> 0.5%/week), and is managed in most cases with control of fluid status and antihypertensive medication. Although clotting of the vascular access has not been conclusively linked to epoetin beta, caution is recommended in patients undergoing haemodialysis. Increased heparinisation is recommended to prevent clotting in dialysis equipment. Epoetin beta is more effective and/or better tolerated than alternative treatments (e.g. androgenic steroids) for anaemia associated with CRF. It also causes significant improvements in quality of life, exercise capacity and overall well-being. Results of clinical studies indicate that subcutaneous administration is desirable where possible in the majority of patients. Thus, epoetin beta has become established as an effective treatment for anaemia associated with CRF.

Anemia↗

PubMed1996

Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability.

Ciprofloxacin is a broad spectrum fluoroquinolone antibacterial agent. Since its introduction in the 1980s, most Gram-negative bacteria have remained highly susceptible to this agent in vitro; Gram-positive bacteria are generally susceptible or moderately susceptible. Ciprofloxacin attains therapeutic concentrations in most tissues and body fluids. The results of clinical trials with ciprofloxacin have confirmed its clinical efficacy and low potential for adverse effects. Ciprofloxacin is effective in the treatment of a wide variety of infections, particularly those caused by Gram-negative pathogens. These include complicated urinary tract infections, sexually transmitted diseases (gonorrhoea and chancroid), skin and bone infections, gastrointestinal infections caused by multiresistant organisms, lower respiratory tract infections (including those in patients with cystic fibrosis), febrile neutropenia (combined with an agent which possesses good activity against Gram-positive bacteria), intra-abdominal infections (combined with an antianaerobic agent) and malignant external otitis. Ciprofloxacin should not be considered a first-line empirical therapy for respiratory tract infections if penicillin-susceptible Streptococcus pneumoniae is the primary pathogen; however, it is an appropriate treatment option in patients with mixed infections (where S. pneumoniae may or may not be present) or in patients with predisposing factors for Gram-negative infections. Clinically important drug interactions involving ciprofloxacin are well documented and avoidable with conscientious prescribing. Recommended dosage adjustments in patients with impaired renal function vary between countries; major adjustments are not required until the estimated creatinine clearance is < 30 ml/min/1.73m2 (or when the serum creatinine level is > or = 2 mg/dl). Ciprofloxacin is one of the few broad spectrum antibacterials available in both intravenous and oral formulations. In this respect, it offers the potential for cost savings with sequential intravenous and oral therapy in appropriately selected patients and may allow early discharge from hospital in some instances. In conclusion, ciprofloxacin has retained its excellent activity against most Gram-negative bacteria, and fulfilled its potential as an important antibacterial drug in the treatment of a wide range of infections. Rational prescribing will help to ensure the continued clinical usefulness of this valuable antimicrobial drug.

Anti-Infective Agents↗

PubMed1996

Ropivacaine. A review of its pharmacology and therapeutic use in regional anaesthesia.

The enantiomerically pure (S-enantiomer) amide local anaesthetic drug ropivacaine blocked nerve fibres responsible for transmission of pain (A delta and C fibres) more completely than those that control motor function (A beta fibres) in in vitro studies. The drug shares the biphasic vascular effects common to the amide local anaesthetic drug class. In vitro studies indicate that ropivacaine is less cardiotoxic than equimolar concentrations of bupivacaine. Apart from one trial in women undergoing hysterectomy, clinical studies that compared the efficacy of different doses of epidurally administered ropivacaine in patients undergoing various surgical procedures did not reveal any consistent dose-related differences with respect to sensory blockade. However, motor blockade did become more intense as the dose of ropivacaine increased. Overall, direct comparisons show that epidural ropivacaine is less potent than epidural bupivacaine when the 2 drugs are administered at the same concentration. However, this difference is less marked in terms of sensory blockade than motor blockade. The greater degree of separation between motor and sensory blockade seen with ropivacaine relative to bupivacaine is more apparent at the lower end of the dosage scale. Nevertheless, higher doses of ropivacaine than bupivacaine are generally required to elicit equivalent anaesthetic effects. Ropivacaine has been shown to induce successful brachial plexus anaesthesia when given at a concentration of 5 mg/ml, but not 2.5 mg/ml, and was as effective as bupivacaine in comparative studies in this indication. Limited data indicate that continuous epidural infusion of ropivacaine postoperatively reduces postsurgical pain in a dose-related manner. Morphine consumption was also reduced. Higher doses of ropivacaine were significantly more effective than placebo. Similarly, ropivacaine controlled postsurgical pain when infiltrated directly into surgical wound sites (i.e. would infiltration) and was as effective as bupivacaine, and more effective than placebo, in this regard. Adverse events associated with epidurally administered ropivacaine include hypotension, nausea, bradycardia, transient paraesthesia, back pain, urinary retention and fever. The drug appears to have an adverse event profile similar to that of bupivacaine. In animal studies, overdoses of ropivacaine were better tolerated than overdoses of bupivacaine but not lidocaine (lignocaine). Human volunteers tolerated a higher intravenous dosage of ropivacaine than bupivacaine before developing initial signs of toxicity. Thus, ropivacaine, according to animal data, is less cardiotoxic than bupivacaine. Based on available clinical data, ropivacaine appears to be as effective and well tolerated as bupivacaine when equianalgesic doses are compared. The greater degree of separation between motor and sensory blockade seen withropivacaine relative to bupivacaine at lower concentrations (approximately 5 mg/ml) will be advantageous in certain applications.

Amides↗

PubMed1996

Irinotecan. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer.

Irinotecan (CPT-II) is a semisynthetic derivative of camptothecin. It and other camptothecin analogues/derivatives appear to exert their antitumour activity by binding to topoisomerase I. The active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), has demonstrated potent growth inhibition of human colorectal cancer cells in vitro, with superior activity to fluorouracil. In phase II clinical studies in patients with advanced colorectal cancer, objective response rates after irinotecan therapy ranged between 20.5 and 32%. These studies used a range of irinotecan regimens including 350 mg/m2 once every 3 weeks (Europe), 125 to 150 mg/m2 once a week for 4 weeks followed by a 2-week drug-free interval (US) and 100 mg/m2/week or 150 mg/m2 every 2 weeks (Japan). The median duration of response ranged between 5.6 and 10.6 months. Disease stabilisation occurred in 30 to 71.2% of patients. Objective response rates to irinotecan therapy in patients who had received no prior chemotherapy were similar to those in patients pretreated with fluorouracil. Importantly, irinotecan also induced responses in some patients with tumours refractory to fluorouracil. Severe (grade 3 or 4) neutropenia and diarrhoea, which occurred in up to 40% of patients receiving irinotecan therapy in phase II studies, require careful monitoring and appropriate management. Thus, irinotecan is a valuable agent for the second-line treatment of patients with advanced colorectal cancer who fail to respond to or relapse after fluorouracil therapy.

Antineoplastic Agents, Phytogenic↗

PubMed1996

Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications.

The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications. Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e.g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e.g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinson's disease treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinson's disease. Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.

Animals↗

PubMed1995

Uptake of 75-Selenium into the central nervous system of the rat.

These experiments have investigated selenium movement between blood and the CNS in anaesthetized rats. Each animal was anaesthetized and the left femoral blood vessels cannulated for blood withdrawal and solute infusion. Each rat received 75-Se as sodium selenite infused in normal saline and experiments lasted between 5 minutes and 5 hours during which blood samples were periodically taken. At termination, the CNS was removed, dissected and analysed with the plasma samples for 75-Se radioactivity by gamma-counting. Data were analyzed by multiple-time uptake analysis. Results showed unidirectional uptake of 75-Se into the CNS and some regional differences were found. On average the CNS influx rate constant (Kin) was about 7 +/- 1 x 10(-5) ml/min/g. This indicates that the 75-Se most likely entered the CNS in a protein-bound form.

Animals↗

PubMed1995

Epoetin alfa. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in nonrenal applications.

Epoetin alfa is a recombinant form of the principal hormone responsible for erythrogenesis, erythropoietin. Already an established treatment for anaemia associated with renal failure, epoetin alfa may also be used to correct anaemia in other patient groups. The drug increases the capacity for autologous blood donation in patients scheduled to undergo surgery and attenuates the decrease in haematocrit often seen in untreated autologous donors. However, transfusion requirements did not significantly decrease in many trials. Epoetin alfa also accelerates red blood cell recovery after allogeneic--but not autologous--bone marrow transplant. Limited data in patients with adult rheumatoid arthritis suggest that while epoetin alfa increases haematocrit/haemoglobin levels, overall clinical rheumatological status may not improve. However, the drug did improve quality of life in a small cohort of children with juvenile rheumatoid arthritis in addition to correcting anaemia. Response rates to treatment with epoetin alfa in patients with anaemia associated with cancer range between 32 and 85%. Anaemia associated with cancer chemotherapy also responds well to treatment with the drug as does anaemia associated with zidovudine therapy in patients with acquired immune deficiency syndrome (AIDS). Studies evaluating the use of epoetin alfa as treatment for anaemia of prematurity have used different methodologies and dosages, making overall analysis difficult. Nevertheless, it appears that high dosages are necessary for response. Results from 1 study suggest that treatment with epoetin alfa appears to be more costly than transfusional support in this application; the relevance of this finding is questionable, however, given that the aim of treatment with epoetin alfa is elimination of transfusion requirements. The incidence of many adverse events associated with epoetin alfa treatment in patients with renal failure (hypertension, seizures and thromboembolic events) has been minimal in patients without renal failure. Adverse events occurred at a similar rate in placebo and epoetin alfa recipients in placebo-controlled trials evaluating the use of the drug as treatment for anaemia in patients with cancer receiving chemotherapy or patients with AIDS receiving zidovudine. In summary, epoetin alfa is an effective alternative to blood transfusion, reducing anaemia and producing consequent improvements in quality of life in many nonrenal applications. It was more effective than placebo in a number of double-blind trials and may be particularly useful as treatment for anaemia associated with other drugs such as cisplatin and zidovudine.

Absorption↗

PubMed1995

Cefixime. A review of its therapeutic efficacy in lower respiratory tract infections.

Cefixime is an orally active third generation cephalosporin with in vitro antibacterial activity against most important lower respiratory pathogens. The drug is active against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae but not Staphylococcus aureus. Cefixime has a long elimination half-life (3 hours compared with 0.5 hours for cefaclor and 1.5 hours for cefalexin), which allows once daily administration. Several trials have established the clinical efficacy of the drug in patients with lower respiratory tract infection (LRTI). In comparative studies cefixime had similar efficacy to amoxicillin +/- clavulanic acid, cefaclor, cefalexin, cefuroxime axetil and clarithromycin. Trials evaluating the efficacy of cefixime as the oral component of intravenous to oral switch therapy have produced promising preliminary results although further carefully designed trials are needed in this area. As with certain other drugs of its class, gastrointestinal disturbances are the most frequently reported adverse events in patients taking cefixime and cases of pseudomembranous colitis have been reported. Thus, cefixime is an effective treatment for mild to moderate LRTI and may have a role as the oral component of intravenous to oral switch therapy although further well designed studies are needed to confirm initial favourable results in this important emerging area of antibacterial therapy.

Anti-Bacterial Agents↗

PubMed1995

Deflazacort. A review of its pharmacological properties and therapeutic efficacy.

Deflazacort is an oxazoline derivative of prednisolone with anti-inflammatory and immunosuppressive activity. Both short (4 to 6 weeks) and longer term (13 to 52 weeks) studies have shown deflazacort to be as effective as prednisone or methylprednisolone in patients with rheumatoid arthritis. The drug was at least as effective as prednisone in children with juvenile chronic arthritis. Insufficient data are available to draw firm conclusions regarding the efficacy of deflazacort as treatment for patients with severe asthma, but the drug has demonstrated some efficacy as treatment for nephrotic syndrome and other applications such as Duchenne dystrophy, systemic lupus erythematosus, uveitis and transplantation. The overall incidence of adverse events in deflazacort recipients (16.5%) is lower than that recorded in patients treated with prednisone (20.5%) or methylprednisolone (32.7%) and similar to that in betamethasone recipients (15.3%). Gastrointestinal symptoms are the most frequently reported adverse events in deflazacort recipients; other adverse events associated with the drug include metabolic and nutritional disorders, central and peripheral nervous system disturbances and psychiatric disorders. In general, deflazacort appears to have less effect than prednisone on parameters which may be associated with the development of corticosteroid-induced osteoporosis. Further, the drug appears have less negative impact on growth rate in children with diseases requiring corticosteroid therapy. In a study of 2 months' duration in patients with conditions requiring corticosteroid treatment, moderate dosages of deflazacort produced no clinically relevant diabetogenic effects. Thus, deflazacort may be associated with less serious metabolic sequelae than prednisone but further well designed long term trials are required to confirm this. In the meantime, in adults, deflazacort should be reserved for use in those pre-disposed to, or who develop, intolerable metabolic sequelae during treatment with corticosteroids. In children, however, even though available efficacy data are minimal, deflazacort should be considered as an initial option in those requiring corticosteroid therapy since the adverse effects caused by this drug class are particularly debilitating in this patient group.

Anti-Inflammatory Agents↗