Search

Library-based digital humanities “skunkworks” are semi-independent research-and-development labs staffed with librarians who act as scholar-practitioners. Their creation is an uncommon, yet uncommonly potent, organizational response to opportunities opened up by digital scholarship. This article describes the Scholars’ Lab at the University of Virginia Library and asserts a critical role for library-embedded digital centers in forging new paths for knowledge work in the humanities. [ABSTRACT FROM PUBLISHER]

Compares the penetration of moxifloxacin and sparfloxacin into the lung and peritoneum of infected mice with or without neutropenia. Materials and methods; Results; Discussion.

Rapacuronium bromide (rapacuronium) is an aminosteroid, nondepolarising neuromuscular blocking agent (NMBA). At the recommended dose for endotracheal intubation (1.5 mg/kg), an intravenous bolus of rapacuronium has a rapid onset (≈1.2 to 1.8 minutes) and short duration of action (10.2 to 16.5 minutes) in adults undergoing elective surgery. Rapacuronium 1.5 mg/kg produced clinically acceptable intubating conditions in 68 to 89% of these patients at about 1 minute after administration. The onset, extent and duration of action and clinical efficacy of an intubating dose of rapacuronium appeared to be similar in the general adult population, adult patients with renal or hepatic dysfunction, patients undergoing Caesarean section, and elderly, paediatric or obese adult patients. Onset time with rapacuronium 1.3 to 2.5 mg/kg (0.9 to 1.8 minutes) was similar to or slower than that with a 1 mg/kg dose of the depolarising NMBA suxamethonium chloride (0.8 to 1.2 minutes). Intubating conditions were clinically acceptable about 1 minute after administration in 86 to 100% of patients with rapacuronium 1.3 to 2.5 mg/kg compared with in 88 to 97% of patients with suxamethonium chloride 1 or 1.5 mg/kg. Spontaneous recovery was slower with rapacuronium than with suxamethonium chloride, but neostigmine 0.04 or 0.05 mg/kg administered 2 or 5 minutes after rapacuronium 1.3 or 1.5 mg/kg accelerated recovery. In the few available comparative clinical trials, rapacuronium 1.5 mg/kg appeared to have a more rapid onset of action than the nondepolarising NMBAs mivacurium chloride 0.25 mg/kg, rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg, and a shorter duration of action than rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg. Additional boluses (≤3) of rapacuronium 0.5 or 0.55 mg/kg after an intubating bolus of 1.5 mg/kg provided continued skeletal muscle relaxation during short surgical procedures in adult patients. However, these patients may recover more slowly than those who receive a single bolus of the drug. Bronchospasm was the most common treatment-related adverse event with rapacuronium 0.3 to 3 mg/kg (3.4% of adult patients). Tachycardia, injection site reaction and hypotension were also reported in small proportions of patients (1.6, 1.1 and 0.9%). The overall incidence of drug-related adverse events was similar with rapacuronium 1.5 or 2.5 mg/kg or suxamethonium chloride 1 mg/kg (8 vs 6%) but bronchospasm, tachycardia and injection site reaction tended to occur more often with rapacuronium. Conclusions: At the recommended dose of 1.5 mg/kg, the nondepolarising NMBA rapacuronium has a rapid onset and short duration of action. It may provide a nondepolarising alternative to suxamethonium chloride for endotracheal intubation. Rapacuronium may be preferred over rocuronium bromide, vecuronium bromide or mivacurium chloride in this indication. [ABSTRACT FROM AUTHOR]

▴ Gatifloxacin is a novel extended-spectrum fluoroquinolone with improved Gram-positive and anaerobe coverage compared with older agents such as ciprofloxacin. It has good activity (but is slightly less active than ciprofloxacin) against Enterobacteriaceae. ▴ Gatifloxacin is generally 2- to 4-fold more active than ciprofloxacin against staphylococci, streptococci and enterococci and 4- to 16-fold more active than ciprofloxacin against anaerobes, including Clostridium and Bacteroides spp. ▴ In comparative clinical trials that included patients with lower respiratory tract, urinary tract, skin and soft tissue or gonococcal infections, clinical cure rates of ≥89% were achieved with oral gatifloxacin 400 mg/day for 7 to 14 days. ▴ Data from a subset of North American patients included in a multinational trial showed that oral gatifloxacin 400 mg/day produced a significantly higher clinical cure rate than cefuroxime axetil 250mg twice daily (89 vs 77%; p = 0.01) in patients with acute exacerbations of chronic bronchitis. The clinical efficacy of gatifloxacin was similar to that of clarithromycin or levofloxacin or ceftriaxone (with or without erythromycin) in the treatment of patients with community-acquired pneumonia. ▴ Oral gatifloxacin 400 mg/day showed clinical and bacteriological efficacy similar to that of levofloxacin in patients with skin and soft tissue infections. In patients with urinary tract infections, clinical cure and bacterial eradication rates achieved with a single 400mg oral dose of gatifloxacin were similar to those produced with ciprofloxacin. ▴ In a pooled analysis of tolerability data from trials that included 3021 patients treated with oral gatifloxacin 400 mg/day, the most commonly reported adverse events were nausea (8%), diarrhoea (4%), headache (4%) and dizziness (3%). The drug was reported to be well tolerated. Gatifloxacin does not appear to cause phototoxic effects. [ABSTRACT FROM AUTHOR]

Acute coronary syndromes and percutaneous coronary interventions share a common pathophysiological mechanism of intimal disruption and platelet aggregation. Glycoprotein (GP) IIb/IIIa receptor antagonists, which interrupt the final common pathway of platelet activation and aggregation, have been shown to have clear clinical benefit as acute therapy. Treatment of 1000 patients with parenteral formulations prevents at least 1 death, 20 deaths or myocardial infarctions (MIs), and 30 deaths, MIs or revascularisation procedures over a 30-day period. These benefits are sustained at 6 months. Clinical trials of oral formulations are underway. The challenges of dose, haemorrhage and thrombocytopenia must be surmounted before oral antagonists can be incorporated into clinical practice. Despite enrolment of thousands of patients in randomised trials of GPIIb/IIIa antagonists, much additional information is needed to refine the use of this therapy in practice. Application of this drug class will advance a new therapeutic standard for ischaemic heart disease. [ABSTRACT FROM AUTHOR]

Aspergillus infections have a very high mortality rate. Their incidence is growing because of the increasing number of immunocompromised patients. Treatment of Aspergillus infection is difficult, and the agents used have numerous adverse effects and toxicities. Recently, new and less nephrotoxic formulations of amphotericin B have come onto the market and other new drugs, such as voriconazole and terbinafine, are under evaluation for this infection. Restoration of host immune defences by tapering of immunosuppressive therapy in transplant patients or correction of granulocytopenia in haematological disease is the cornerstone of modern treatment of aspergillosis in immunocompromised patients. In patients with invasive aspergillosis it is very important to achieve therapeutic concentrations of antimycotic drugs as quickly as possible. Patients at high risk of developing aspergillosis (e.g. those with granulocytopenia) should be treated on the basis of clinical or radiological criteria alone if microbiological or histological diagnosis would significantly delay treatment. Conventional amphotericin B is still the first-line treatment for patients with invasive aspergillosis. In transplant patients receiving other nephrotoxic drugs, particularly cyclosporin, first-line therapy with one of the new amphotericin B formulations should be considered. If the emergence of renal toxicity in any patient precludes aggressive treatment, the patient should be switched to one of the new formulations of amphotericin B. For patients cured with amphotericin B, secondary prophylaxis is needed at the end of the intravenous therapy. Amphotericin B by aerosol or itraconazole are possible solutions. In non-invasive forms of aspergillosis, such as suppurative bronchitis, patients could be treated either with amphotericin B or itraconazole as first-line therapy. [ABSTRACT FROM AUTHOR]

▴ Exemestane is a steroidal agent which causes inactivation of the aromatase enzyme by binding irreversibly to the substrate binding site. ▴ Oral exemestane 25 mg/day inactivates peripheral aromatase activity (~98% inactivation) and reduces basal plasma estrone, estradiol and estrone sulphate levels by 85 to 95% in postmenopausal women with advanced breast cancer. ▴ Phase II trials indicate that oral exemestane 25 mg/day is an effective second- or third-line agent in the treatment of postmenopausal women with advanced breast cancer (achieving an objective response in up to 28 and 26% of patients, respectively). ▴ Results from a phase III trial indicate that exemestane achieves a similar objective response rate to megestrol as a second-line therapy; however, exemestane achieved a significantly longer duration of overall success, time to disease progression and survival time. ▴ Exemestane is at least as well tolerated as megestrol, but is associated with significantly fewer bodyweight changes, mainly bodyweight gain (≥10%). Other common adverse events are hot flushes, nausea and fatigue. [ABSTRACT FROM AUTHOR]

The classification of rotaviruses as well as the pathogenesis and the diagnosis of rotavirus infections are briefly reviewed. Treatment of rotavirus disease consists mainly of oral or intravenous rehydration, using World Health Organization-recommended oral rehydration solutions or lactated Ringer's solutions, respectively. Specific antivirals have been tried in animal models but are not used for human treatment at present. The epidemiology of rotaviruses is complex as at any one time and in any geographical area different types co-circulate. The development of rotavirus candidate vaccines is reviewed, one of which, the tetravalent, rhesus rotavirus-based human reassortant vaccine, was licensed for universal use in the US in 1998. Its implementation requires careful surveillance of co-circulating rotavirus types (molecular epidemiology) as well as of any potential adverse effects not previously detected. [ABSTRACT FROM AUTHOR]

▴ Adefovir dipivoxil is an ester prodrug of the nucleoside reverse transcriptase inhibitor adefovir (PMEA), the prototype compound of the acyclic nucleoside phosphonates. It has better oral bioavailability than the parent compound. ▴ Adefovir dipivoxil 120mg once daily significantly reduced viral load compared with placebo when added to standard antiretroviral therapy in a 6-month, double-blind study in patients with HIV infection. Viral suppression was maintained during an additional 6-month nonblind extension phase. ▴ The drug was most effective in patients with baseline isolates containing the M184V lamivudine resistance mutation according to data from a virological substudy of a large placebo-controlled trial. ▴ Adefovir dipivoxil 60mg was as effective as 120mg (both once daily) after 20 weeks' treatment in a randomised double-blind study in antiretroviral-experienced (protease inhibitor-naive) patients. ▴ Viral suppression was generally maintained in patients who developed new reverse transcriptase mutations during adefovir dipivoxil monotherapy or combination therapy for up to 12 months. No clear pattern of particular clinical resistance mutations has emerged. ▴ GI disturbances, hepatic effects and delayed renal abnormalities are the principal adverse events seen with adefovir dipivoxil. Reductions in serum free carnitine levels may occur and coadministration of L-carnitine is recommended. [ABSTRACT FROM AUTHOR]

▴ Tegaserod is a serotonin (5-hydroxytryptamine; 5-HT) receptor partial agonist which has been investigated for the treatment of irritable bowel syndrome (IBS). Specifically, it binds with high affinity to human 5-HT receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex in vitro. ▴ Small bowel transit (increased colonic filling over 6 hours) was accelerated in patients with constipation-predominant irritable bowel syndrome (IBS) receiving oral tegaserod 2mg twice daily for 1 week compared with those receiving placebo. In addition, there was a mean 20% increase of proximal colonic emptying in these patients. ▴ Oral tegaserod 2 (p < 0.05) or 6mg twice daily improved symptoms of abdominal discomfort, bloating and constipation (assessed using a Subjects' Global Assessment Scale) compared with placebo in patients with constipation-predominant IBS in a double-blind, dose-ranging study. ▴ The most frequent adverse events in patients with constipation-predominant IBS receiving oral tegaserod were transient diarrhoea and flatulence. ▴ No clinically relevant changes in blood pressure, pulse rate, QRS or QT interval were reported with tegaserod doses of 25 to 100mg. [ABSTRACT FROM AUTHOR]

General anaesthesia has become, thanks to recently developed drugs, monitoring devices and delivery systems, a very well tolerated method of making the great surgical opportunities of the last few years available to all ages of patient. With a balanced and rational use of drug profiles, general anaesthesia allows even frail and very ill patients a margin of tolerability inconceivable just a few years ago. For the vast majority of patients, the risk from the general anaesthetic technique is so small it can be considered negligible. However, the majority of general anaesthetic drugs are both highly potent and very toxic, with many of the volatile agents still having a therapeutic ratio of about 4 : 1. The anaesthetic staff have to continually upgrade their skills and knowledge to ensure that harm does not result. It is, however, reasonable to offer some practical guidelines from the current literature on when to choose a general anaesthetic technique, either alone or with a regional local anaesthetic method, and when to avoid loss of consciousness. The complications expected from the use of general anaesthesia are reviewed, and the basis for these complications investigated. The currently available drugs and their place in anaesthetic practice are also assessed. Recent developments in the area of total intravenous anaesthesia and monitoring for potential awareness using bispectral analysis suggest that this technique should now be included in the choice of anaesthetic. Recommendations are made on both the selection of the technique, and the appropriate agents for a given group of patients. [ABSTRACT FROM AUTHOR]

Therapeutic angiogenesis, in the form of growth factor protein administration or gene therapy, has emerged as a new method of treatment for patients with severe, inoperable coronary artery disease. Improved myocardial perfusion and function after the administration of angiogenic growth factors has been demonstrated in animal models of chronic myocardial ischaemia. Recently, preliminary clinical trials using growth factor proteins or genes encoding these angiogenic factors have demonstrated clinical and other objective evidence of relevant angiogenesis. Thus, therapeutic angiogenesis has the potential to extend treatment options to patients who are not optimal candidates for conventional methods of myocardial revascularisation. [ABSTRACT FROM AUTHOR]

There is now considerable clinical trial data to support the use of β-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a “new wave” of clinical trials have been conducted to definitively determine the mortality benefits of β-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its β-blocking properties alone or to a combination of the β-blocking and ancillary effects of the drug; whether β-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether β-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with β-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHF. Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of β-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of β-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of β-blockers as part of the design of such studies. In conclusion, β-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment. [ABSTRACT FROM AUTHOR]

The goal of hormone therapy is to deprive breast tumours of estrogens, since estrogens have been implicated in the development or progression of tumours. This can be accomplished by the use of antiestrogens that block estrogen action or by inhibiting aromatase, the enzyme that catalyses the final and rate-limiting step in estrogen biosynthesis. A number of steroidal and nonsteroidal compounds have been developed as aromatase inhibitors. This review highlights the valuable role that a few of these aromatase inhibitors have played, and continue to play, in the treatment of breast cancer. Following background information regarding the biochemistry of aromatase, the rationale for its inhibition, and an outline of the test systems for evaluating and characterising aromatase inhibitors, the discussion focuses on the new generation of aromatase inhibitors that are in clinical trials or clinically available. Specifically, it discusses the pharmacology and clinical efficacy of formestane, exemestane, rogletimide, fadrozole, vorozole, anastrozole and letrozole. The role of these agents as the optimal second-line agents (after tamoxifen) for the treatment of advanced breast cancer has been established; their prospects in other clinical settings and as potential breast cancer chemopreventives are warranted but are yet to be fully determined. [ABSTRACT FROM AUTHOR]

▴ The humanised monoclonal antibody palivizumab has been developed for prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in infants at high risk; RSV is the most common cause of lower respiratory tract infections in infants. ▴ Palivizumab specifically inhibits an epitope at the A antigenic site of the F protein of RSV subtypes A and B. RSV replication was inhibited in nasal and tracheal aspirates from infants receiving palivizumab 15 mg/kg. ▴ Mean 30-day trough serum concentrations of palivizumab were consistently about 70 mg/L in infants receiving repeated intramuscular or intravenous palivizumab 15 mg/kg. This is above the target serum concentration of 40 mg/L estimated to reduce pulmonary RSV replication by >99% in animal studies. ▴ In a large multicentre trial in 1502 infants at high risk of RSV infection, intramuscular palivizumab 15 mg/kg more than halved the incidence of RSV-attributable hospitalisation to 4.8% compared with 10.6% in placebo recipients. ▴ In the same group of high-risk infants, palivizumab significantly decreased total days in hospital attributable to RSV infection, days with increased supplemental oxygen requirement, days with moderate to severe lower respiratory tract infections and the incidence of admissions to intensive care. It had no effect on the incidence or total number of days of ventilation. ▴ Palivizumab was well tolerated during clinical trials in infants at risk of RSV infection. The incidence of adverse events was similar in placebo (10%) and palivizumab (11%) groups. Fever, irritability and injection site reaction were the most commonly reported adverse events. [ABSTRACT FROM AUTHOR]

▴ Rosiglitazone, a thiazolidinedione antidiabetic agent, improves insulin resistance, a key underlying metabolic abnormality in most patients with type 2 (non-insulin-dependent) diabetes mellitus. ▴ In animal models of insulin resistance, rosiglitazone decreased plasma glucose, insulin and triglyceride levels and also attenuated or prevented diabetic nephropathy and pancreatic islet cell degeneration. ▴ In contrast with troglitazone, rosiglitazone does not induce cytochrome P4503A4 metabolism. It does not interact significantly with nifedipine, oral contraceptives, metformin, digoxin, ranitidine or acarbose. ▴ In clinical trials in patients with type 2 diabetes mellitus, rosiglitazone 2 to 12 mg/day (as a single daily dose or 2 divided daily doses) improved glycaemic control, as shown by decreases in fasting plasma glucose and glycosylated haemoglobin (HbA). ▴ Addition of rosiglitazone 2 to 8 mg/day to existing sulphonylurea, metformin or insulin therapy achieved further reductions in fasting plasma glucose and HbA. Oral combinations improved insulin sensitivity and β-cell function according to a homeostasis model assessment. ▴ Consistent with its mechanism of action, rosiglitazone appears to be associated with a low risk of hypoglycaemia (<2% of patients receiving monotherapy). There is no evidence to date that rosiglitazone shares the hepatotoxicity of troglitazone. [ABSTRACT FROM AUTHOR]

▴ Insulin aspart is a recombinant analogue of human insulin. Following subcutaneous insulin injection (0.15 to 0.2 U/kg), significantly higher serum insulin concentrations are achieved in a shorter time with insulin aspart than with human insulin. The subsequent decline in serum insulin concentrations is also more rapid with insulin aspart. ▴ In healthy individuals undergoing euglycaemic glucose clamp testing, glucose infusion rates were higher and reached maximum concentrations significantly earlier after insulin aspart than after human insulin. ▴ Interindividual variability in pharmacodynamic and pharmacokinetic parameters with insulin aspart was generally less than that with human insulin, whereas the intraindividual variability in these parameters was similar after each insulin. ▴ In patients with type 1 diabetes postprandial glucose excursions were less pronounced with insulin aspart than human insulin. Daytime glucose control was better and minimum glucose levels during the night were not as low with insulin aspart as with human insulin. ▴ In diabetic patients treated with insulin aspart there was generally a lower frequency of hypoglycaemic events than in patients treated with human insulin. [ABSTRACT FROM AUTHOR]

Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific examples of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment. Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766. Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent-generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy. Further randomised trials are required to identify the optimal role of chemoprotectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors. [ABSTRACT FROM AUTHOR]

▴ Moxifloxacin is a new fluoroquinolone antibacterial agent with a broad spectrum of activity, encompassing Gram-negative and Gram-positive bacteria. It has improved activity against Gram-positive species (including staphylococci, streptococci, enterococci) and anaerobes compared with ciprofloxacin. This is offset by slightly lower activity against pseudomonal species and Enterobacteriaceae. ▴ In common with other fluoroquinolones, moxifloxacin attains good penetration into respiratory tissues and fluids and its bioavailability is substantially reduced by coadministration with an antacid or iron preparation. However, moxifloxacin does not interact with theophylline or warfarin. ▴ In clinical trials in patients with community-acquired pneumococcal pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) or acute sinusitis, moxifloxacin 400mg once daily achieved bacteriological and/or clinical success rates of approximately 90% or higher. ▴ Moxifloxacin was as effective as amoxicillin 1g 3 times daily and clarithromycin 500mg twice daily in CAP and as effective as clarithromycin in AECB. In patients with sinusitis, a 7-day course of moxifloxacin 400mg once daily was as effective as a 10-day course of cefuroxime axetil 250mg twice daily. ▴ In contrast to some other fluoroquinolones, moxifloxacin appears to have a low propensity for causing phototoxic and CNS excitatory effects. The most common adverse events are gastrointestinal disturbances. [ABSTRACT FROM AUTHOR]

▴ Sibrafiban is the orally administered, nonpeptide, double-prodrug of Ro 44-3888 which is a selective glycoprotein IIb/IIIa receptor antagonist. It is currently undergoing clinical trials for secondary prevention of cardiac events in patients stabilised after acute coronary syndromes. ▴ In a phase II dose-finding study (TIMI 12) in patients stabilised after a myocardial infarction (MI) or an episode of unstable angina, there was a dose-dependent inhibition of platelet aggregation which correlated closely with the plasma concentration of the total active drug. ▴ An ongoing phase III study (SYMPHONY) compares the effects of sibrafiban on cardiac events with that of aspirin in patients stabilised after a Q wave MI or an episode of unstable angina. ▴ This large trial uses twice daily dosage regimens to produce the plasma concentrations which were associated with less bleeding in the earlier dose-ranging trial. ▴ A long term (minimum duration 12 months) phase III study (2nd SYMPHONY) is under way to compare the effects of sibrafiban on cardiac events with those of aspirin in patients stabilised after an MI or an episode of unstable angina. ▴ The most common adverse events associated with sibrafiban include bleeding, with minor haemorrhages occurring more often than with aspirin. [ABSTRACT FROM AUTHOR]

▴ Lamifiban is an intravenously administered, selective, reversible, nonpeptide glycoprotein IIb/IIIa receptor antagonist which inhibits platelet aggregation and thrombus formation by preventing the binding of fibrinogen to platelets. ▴ In trials in patients with non-Q wave myocardial infarction (MI) or unstable angina pectoris (PARAGON A and the Canadian Lamifiban Study), the incidence of clinical events at 30 days in patients receiving lamifiban (1 to 5 µg/min) was not significantly different from that in patients receiving aspirin plus heparin or aspirin alone. ▴ In PARAGON A, the incidence of clinical events at 6 months was significantly lower after lamifiban (with or without heparin) and aspirin therapy than after standard heparin and aspirin therapy. ▴ A large phase III trial (PARAGON B) is under way comparing lamifiban plus aspirin and heparin with standard aspirin and heparin therapy in patients with non-Q wave MI or unstable angina pectoris. ▴ In clinical trials, the most common adverse events associated with lamifiban were bleeding complications which were increased by the concomitant administration of heparin. [ABSTRACT FROM AUTHOR]

Anticancer treatment is generally associated with toxicity to health issues. One of the reasons for this unpleasant association is that anticancer agents have been mostly selected on the basis of an empirically established toxicity towards cancer cell lines and rapidly growing tumours in animal models, and not on the basis of a sophisticated intervention in tumour-specific biology. This strategy of drug development unavoidably produces drugs with toxicity towards normal cells and tissues which also have a high cell turnover and share many characteristics with tumour cells. Therefore it is a continuing challenge to design therapy which is both effective and also has high specificity for the biology of cancer and/or is efficiently targeted to tumour tissue. This article describes the mechanisms of cytotoxicity of standard chemo- and radiotherapy and discussed the possibilities of currently available cytoprotective agents to reduce or prevent these toxicities. These agents should ideally be selective for normal cells versus cancer cells, be effective in reducing or preventing toxicity, have no negative impact on anticancer therapy and have minimal adverse effects. None of the agents described in this article fulfils these criteria completely and therefore we cannot recommend these agents for standard use in daily anticancer practice. Nevertheless, there are encouraging data concerning the beneficial effects of dexrazoxane for anthracycline-induced cardiomyopathy and amifostine for platinum- and radiotherapy-induced toxicity. These date warrant further studies. [ABSTRACT FROM AUTHOR]

▴ Pexiganan acetate (MSI 78) is a synthetic cationic peptide (22 amino acids) with antibacterial activity. It is an analogue of magainin 2, which is a host defence peptide isolated from frog skin. ▴ The drug is thought to act by disturbing the permeability of the cell membrane or cell wall. ▴ Pexiganan acetate has good in vitro activity against Gram-positive and Gram-negative aerobes; 99% of strains were susceptible to the agent using a break-point of 64 mg/L. 89 to 97% of anaerobes were susceptible to pexiganan acetate using the same break-point. ▴ After 7 passages in vitro, there was no evidence of resistance to pexiganan acetate among 2 strains of Staphylococcus aureus. ▴ In 2 phase III multicentre randomised double-blind trials in diabetic patients with infected foot ulcers, both topical pexiganan acetate 1% and oral ofloxacin 800 mg/day achieved clinical cure or improvement in about 90% of patients. ▴ Eradication of pathogens in the 2 studies was achieved in 82% of ofloxacin recipients and 66% of pexiganan acetate recipients at the end of therapy. ▴ Limited data indicate that pexiganan acetate is well tolerated. [ABSTRACT FROM AUTHOR]

This paper reviews the results of 4 recent clinical trials, Platelet Receptor inhibition for Ischaemic Syndrome Management (PRISM), Platelet Receptor inhibition for Ischaemic Syndrome Management in Patients Limited to very Unstable Signs and symptoms (PRISM-PLUS), Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organisation Network (PARAGON A), and Platelet IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PURSUIT), that have investigated the use of glycoprotein (GP) IIb/IIIa inhibitors in with non-ST-segment elevation acute coronary syndromes. The PRISM trial randomised 3232 patients with non-ST-elevation acute coronary syndromes to either tirofiban or heparin. Patients receiving tirofiban had a 32% reduction in the likelihood of death, myocardial infarction (MI) or refractory ischaemia at 48 hours and a 36% reduction in death at 30 days (2.3 vs 3.6%, p = 0.02). The PRISM-PLUS trial randomised 1915 patients with severe non-ST-elevation acute coronary syndromes to either tirofiban alone, heparin alone or the combination of tirofiban and heparin. Patients treated with the combination of tirofiban and heparin had a 27% reduction in death or nonfatal MI at 30 days (8.7 vs 11.9%, p = 0.027). The PARAGON A trial randomised 2282 patients with non-ST-elevation acute coronary syndromes to either high or low dose lamifiban, with or without heparin, or heparin alone. There was no reduction in the rate of death at day 30 or nonfatal MI in patients who received lamifiban; however, at 6 months a significant treatment effect was seen in patients who received low dose lamifiban (13.7%, p = 0.02) but not high dose lamifiban (16.4%, p = 0.38) compared with those who received heparin alone (18.1%). The PURSUIT trial randomised 10 948 patients with non-ST-elevation acute coronary syndromes to either eptifibatide or placebo. Patients receiving eptifibatide had a 9.6% relative, and 1.5% absolute, reduction in death or MI at 30 days (15.7 vs 14.2%, p = 0.04). GP IIb/IIIa inhibitors are revolutionising the way we treat patients with atherosclerotic coronary artery disease. The results of these trials demonstrate that the GP IIb/IIIa inhibitors tirofiban, lamifiban, and eptifibatide are beneficial in the non-ST-elevation acute coronary syndrome population. In the future, acute therapy with an intravenous GP IIb/IIIa inhibitor followed by long term administration of an oral GP IIb/IIIa inhibitor may be the cornerstone of the management of patients with acute coronary syndromes. [ABSTRACT FROM AUTHOR]

▴ Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT receptor subtype without affecting other receptor systems involved in cardiovascular regulation. ▴ Oral telmisartan dose-dependently reduced blood pressure (BP) in various animal models of hypertension. In transgenic rats, telmisartan reduced cardiac hypertrophy and glomerulosclerosis. ▴ When administered at dosages of 40 to 160mg once daily to patients with mild to moderate hypertension, telmisartan significantly reduced systolic and diastolic BP compared with placebo and was at least as effective as atenolol 50 or 100mg and lisinopril 10 to 40mg. One study showed telmisartan 80 mg/day to be more effective than enalapril 20 mg/day. ▴ In 2 studies that used ambulatory BP monitoring, once daily telmisartan provided better control of diastolic BP for the full dosing interval than losartan potassium 50mg or amlodipine 5 or 10mg. ▴ In a single study in patients with severe hypertension, a telmisartan-based regimen had antihypertensive efficacy similar to that of an enalapril-based regimen. ▴ Telmisartan had a tolerability profile similar to that of placebo in clinical studies. [ABSTRACT FROM AUTHOR]

Anastrozole, letrozole and vorozole are new aromatase inhibitors with a non-steroidal structure (NSS), and have been demonstrated to be highly effective and better tolerated than standard endocrine therapy with megestrol (megestrol acetate) and aminoglutethimide (AG). These agents are very potent and selective: all of them are capable of suppressing estrone (E1) and estradiol (E2) to the limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also suppressed. However, the fact that this potency has not led to any greater clinical efficacy, and that there is no relationship between estrogen suppression and clinical response, suggests that aromatase inhibitors may have additional mechanisms of action. A number of international, multicentre clinical trials have compared anastrozole, letrozole and vorozole with megestrol 160 mg/day or AG 500 mg/day plus hydrocortisone in patients with advanced breast cancer. Letrozole proved to be significantly more effective than megestrol but anastrozole had a greater effect on survival than either agent. However, letrozole therapy led to longer survival than that observed in patients treated with AG. The activity of vorozole was similar to that of megestrol and AG. These results have raised a number of questions. The first is how should the clinical results be evaluated, given that ‘disease stabilisation lasting ≥6 months’ has been considered a response? The second is how should these drugs be used, and whether there is a rationale for using them in combination or sequentially in the treatment of patients with advanced breast cancer? Finally, is the possible effect of formestane and vorozole on intratumoral aromatase an alternative or concomitant mechanism of action? Anastrozole, letrozole and vorozole will be compared with tamoxifen in postmenopausal patients with breast cancer in adjuvant and primary settings. However, we feel that concomitant biological and clinical studies should also be carried out in order to clarify the properties of these drugs and avoid possible risks for patients over time. [ABSTRACT FROM AUTHOR]

Influenza infection is an acute respiratory disease with a high morbidity and significant mortality, particularly among the elderly and individuals with chronic diseases. The majority of countries now recommend annual influenza vaccination for all people aged 65 years or older, and for those with high risk conditions. Most commercially available influenza vaccines are administered systemically and while these are effective in children and young adults, efficacy levels in elderly individuals have been reported to be much lower. Mucosal vaccines may offer an improved vaccine strategy for protection of the elderly. As the influenza virus causes a respiratory infection, it is potentially more beneficial to administer a vaccine that will boost protection in the mucosal surfaces of the upper and lower respiratory tract. Mucosal influenza vaccines are aimed at stimulating protective immunity in the respiratory tract via oral or intranasal immunisation. This review examines our present knowledge of mucosal immunity and current strategies for mucosal vaccination. It also stresses that the use of serum antibody levels as a ‘surrogate marker’ for protection against influenza is potentially misleading; serum antibody, for example, may be a quite inappropriate marker to assess a mucosal vaccine. This marker does not reflect other immune responses to vaccination that are crucial for protection. [ABSTRACT FROM AUTHOR]

▴ Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug. ▴ Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. ▴ Complete response rates were 18 and 29% in patients with carcinoma in situ of the bladder which was refractory to intravesical BCG in 2 noncomparative trials of prophylactic intravesical valrubicin. In patients with recurrent superficial papillary tumours, the complete response rate was 46%. ▴ Adverse events were generally transient in patients who received intravesical valrubicin. Bladder irritation occurred in 88% of patients. Systemic absorption of intravesically administered valrubicin was minimal. Accordingly, systemic adverse events generally occurred in ≤5% of patients. ▴ Valrubicin was less toxic to chick embryos and haematopoietic stem cells in vitro and produced a lower incidence of cardiotoxicity in rabbits, compared with doxorubicin. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disorder with an impact on public health which continues to increase with the increasing longevity of the population. The disease is characterised clinically by a progressive loss of cognitive and behavioural function. These deficits are thought to result from decreased cholinergic transmission; therefore, restoring cholinergic function has been the main focus in the development of drugs for AD. Several pharmacological approaches to enhancing cholinergic function have been developed for symptomatic or palliative therapy of AD. Although these strategies have resulted in modest cognitive and behavioural improvements in patients with AD, they do not address the underlying progression of the disease. New strategies will be required to slow, stop or reverse the effects of neurodegeneration in AD. A number of potential therapies are currently under investigation, including estrogen replacement, anti-inflammatory agents, free radical scavengers and antioxidants, and monoamine oxidase-B (MAO-B) inhibitors. The evidence for a protective effect of estrogens or nonsteroidal anti-inflammatory drugs (NSAIDs) is controversial, and largely based on retrospective studies. More controlled prospective studies are needed to definitively demonstrate the benefits of long term estrogen or NSAID use in the prevention of AD. Free radical scavengers/antioxidants such as idebenone, and selective prevention MAO-B inhibitors such as lazabemide are well tolerated, but require additional studies in order to demonstrate preventative effects. In addition, other approaches, such as anti-amyloid treatments that affect beta-amylase secretion, aggregation and toxicity, appear promising; treatments that hinder neurofibrillary tangle construction and nerve growth factor (NGF) induction are in the very early stages of development. [ABSTRACT FROM AUTHOR]

Observations of the pharmacology of tamoxifen and related compounds have lead to the concept of selective estrogen receptor modulators (SERMs). This new class of drug displays estrogen agonist or antagonist effects in a tissue-dependent manner and appears to offer an alternative to hormone replacement therapy for the prevention and treatment of osteoporosis and cardiovascular disease in postmenopausal women. Moreover, the estrogen antagonist actions of SERMs on breast tissue may also provide a protective effect against breast cancer. Although tamoxifen therapy reduces plasma cholesterol levels and maintains bone density, it is also associated with an increased risk of endometrial cancer, pulmonary embolism and deep vein thrombosis. This has lead to the development of newer SERMs which will hopefully lack these adverse effects of tamoxifen. These compounds promise a new era of disease prevention in the aging woman and their therapeutic potential is currently being evaluated in large-scale clinical trials. [ABSTRACT FROM AUTHOR]

Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available. Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 µg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including β-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes. Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative syndrome which primarily affects dopamine-producing neurons of the substantia nigra, resulting in poverty and slowness of movement, instability of gait and posture, and tremor at rest in individuals with the disease. While symptoms of the disease can be effectively managed for several years with available drugs, the syndrome is progressive and the efficacy of standard drugs wanes with time. One experimental approach to therapy is to use natural and synthetic molecules which promote survival and growth of dopaminergic neurons, so-called ‘neurotrophic factors’, to stabilise the diminishing population of dopaminergic neurons and stimulate compensation and growth in these cells. In this review, we examine the available evidence on 29 molecules with neurotrophic properties for dopaminergic neurons. The properties of these molecules provide ample reasons for optimism that a neurotrophic strategy can be developed that would provide a significant treatment option for patients with PD. While the search continues for even more specific, potent and long-lasting agents, the single greatest challenge is the development of techniques for targeted delivery of these molecules. [ABSTRACT FROM AUTHOR]

▴ Topical gel containing 3% diclofenac in 2.5% hyaluronic acid (HYAL CT1101) is used for the treatment of actinic keratosis. ▴ In animal models, diclofenac in hyaluronic acid inhibited angiogenesis and induced neovascular regression in inflammatory tissue, and depleted substance P content in snout tissue. ▴ Diclofenac delivered in hyaluronic acid appears to accumulate in the epidermis of human skin in vitro and mice in vivo. ▴ Results of clinical trials indicate that topical HYAL CT1101 is effective in the treatment of actinic keratosis. A clinical cure (all lesions fully resolved) was seen in 47% of 108 patients using HYAL CT1101 compared with 19% of patients using placebo after 3 months in 1 randomised, double-blind study. ▴ Mild to moderate skin irritation has been reported in up to 72% of patients treated with HYAL CT1101 in clinical studies. [ABSTRACT FROM AUTHOR]

Gene therapy for breast cancer initially involves local or systemic delivery. Local delivery may be intrapleural or via direct injection to lesions. However, systemic delivery remains the greatest challenge with targeting, although methods using antibodies or growth factor receptor ligands have been demonstrated in preclinical models. This review focuses on the next step of using tissue-specific promoters such as Muc-1, CEA, PSA, HER-2, Myc, L-plastin and secretory leukoproteinase inhibitor promoters. All of these have demonstrated differential upregulation in breast cancer and additional specificity may be obtained by using physiological stimuli that are more frequently expressed in cancers, such as glucose regulated promoters and hypoxia response elements or radiation inducible elements. Amongst the later are the EGR-1, p21 and tissue type plaminogen activator promoters. Potential therapy genes include the prodrug activation system 5-fluorocytosine and other analogues of antimetabolites, but all of these need gap junctions to transfer the phosphorylated metabolites. Other approaches involving more freely diffusible products include cyclophosphamide, ifosfamide and thymidine phosphorylase to activate 5-deoxy-5-fluoruridine to fluorouracil. The bystander effect is important both for cell killing and for immunological and antivascular effects. Breast cancer is one type of tumour where a major clinical research effort is underway using local delivery methods. For prodrug activation systems, the use of human enzymes is desirable to prevent an immunological response that would eventually eliminate cells producing the prodrug activation system. The use of alkylating agents has an advantage over antimetabolites in that they are cytotoxic to cycling and noncycling cells, and the cytotoxic products can diffuse across cell membranes without the need for gap junctions. They also have a much steeper dose response curve than antimetabolites. [ABSTRACT FROM AUTHOR]

Despite advances in antimicrobial chemotherapy over recent decades, morbidity and mortality secondary to infection continues to rise. In addition, the incidence of infection caused by resistant organisms has also increased. Concurrently, the elderly are living longer than prior generations, often with disabling chronic diseases. The more debilitated of the geriatric population are at greater risk for infection, and more likely to acquire or develop antimicrobial resistant organisms. Gram-positive organisms are a source of resistance and commonly cause infection in older patients. Whereas resistance is a concern in all patients, in the elderly this is magnified by limitations in treatment options because of differences in pharmacokinetics and tolerance as compared with younger counterparts. Pharmacokinetic differences include changes in drug distribution and may arise as a result of diminished end organ function. Age-related decreases in renal function often impact on commonly prescribed antimicrobials. In addition, the elderly are more susceptible to drug-drug interactions because polypharmacy is common in this patient population. Streptogramins may offer a useful alternative in the treatment of infections in the elderly due to their coverage of organisms commonly causing infections in this population and because of their favourable pharmacokinetic profiles. While published experience is limited, streptogramins are not appreciably eliminated by the kidney and, therefore, they are less subject to age-related changes in renal elimination. What is required is multi-dose pharmacokinetic analysis of streptogramins in geriatric populations and subset analysis of patient use data on file. The following will provide the reader with the most recently presented data on streptogramin use and their potential. While focusing on potential use in the elderly, we have cited data and issues which we believe will be relevant in the geriatric population. [ABSTRACT FROM AUTHOR]

Nutritional strategies of overfeeding, ingesting carbohydrate/protein before and after exercise, and dietary supplementation of various nutrients [e.g. protein, glutamine, branched-chain amino acid, creatine, leucine, β-hydroxy β-methylbutyrate (β-HMB), chromium, vanadyl sulfate, boron, prasterone (dehydroepiandrosterone [DHEA]) and androstenedione] have been purported to promote gains in fat-free mass during resistance training. Most studies indicate that chromium, vanadyl sulfate and boron supplementation do not affect muscle growth. However, there is evidence that ingesting carbohydrate/protein prior to exercise may reduce catabolism during exercise and that ingesting carbohydrate/protein following resistance-exercise may promote a more anabolic hormonal profile. Furthermore, glutamine, creatine, leucine, and calcium β-HMB may affect protein synthesis. Creatine and calcium β-HMB supplementation during resistance training have been reported to increase fat-free mass in athletic and nonathletic populations. Prasterone supplementation has been reported to increase testosterone and fat-free mass in nontrained populations. However, results are equivocal, studies have yet to be conducted on athletes, and prasterone is considered a banned substance by some athletic organisations. This paper discusses rationale and effectiveness of these nutritional strategies in promoting lean tissue accretion during resistance training. [ABSTRACT FROM AUTHOR]

Cytokines are small proteins with the properties of locally acting hormones. They are essential for the healing of connective tissues following injury. Various cytokines are expressed endogenously during the healing responses of those ligaments and tendons which possess them, and there is evidence that the exogenous application of certain cytokines promotes healing. Because healing is a multistep process, several different cytokines may need to be applied at different times to achieve a satisfactory response. Sustained, localised delivery of the appropriate cytokines presents a technical challenge to their clinical use in the repair of ligaments and tendons. Slow release devices and gene transfer are being evaluated as strategies for obviating this limitation. [ABSTRACT FROM AUTHOR]

Calfactant (Infasurf) is a natural bovine surfactant which has been evaluated for intratracheal use in the prevention and rescue treatment of respiratory distress syndrome (RDS) in preterm infants. In 2 randomised, double-blind, multicentre clinical trials of prophylactic use, calfactant 100 or 105mg phospholipid per kg bodyweight (mg/kg) reduced RDS incidence, RDS severity and mortality rates to a greater extent than colfosceril palmitate (Exosurf Neonatal) 67.5 mg/kg and was generally similar to beractant (Survanta) 100 mg/kg. Although the rate of mortality before discharge from hospital was significantly higher in infants with birthweights <600g who received calfactant than in those who received beractant, this may not be a typical result. As rescue treatment, calfactant 100 or 105 mg/kg reduced RDS severity, but not mortality rates, significantly more than colfosceril palmitate 67.5 mg/kg or beractant 100 mg/kg in 2 randomised, doubleblind, multicentre clinical trials. In addition, the duration of effect of calfactant as prophylaxis or rescue treatment appeared to be longer than that of beractant. In other randomised trials, prophylaxis was more effective than rescue treatment with calfactant, particularly in infants of ≤29 weeks gestational age. The incidence of pulmonary air leak events was lower with calfactant than with colfosceril palmitate (12 vs 22%) but was identical with calfactant and beractant (15% with either agent). The incidence of other complications associated with RDS was usually similar with all 3 agents in clinical trials in preterm infants. The incidence of intraventricular haemorrhage was significantly higher in 1 clinical trial, and that of septicaemia was significantly lower in another, with calfactant versus colfosceril palmitate, but the combined incidences of these complications was similar with the 2 agents when results from different trials were pooled. The incidence of acute adverse events (i.e. those which occurred during administration of the drug) with calfactant was similar to that with beractant and higher than that with colfosceril palmitate; the difference may been related to reduced RDS severity in calfactant versus colfosceril palmitate recipients. Acute adverse events were usually transient and not severe. Conclusions: Calfactant is a well tolerated natural bovine surfactant which is effective in the prevention and treatment of RDS in preterm infants. Further investigation is needed to more clearly determine the efficacy and tolerability of calfactant relative to that of other surfactant preparations. When more data are available, it is likely that calfactant will be useful as an alternative to beractant (at least in infants of birthweights >600g), and calfactant may be preferred over colfosceril palmitate in both the prophylaxis and treatment of RDS. [ABSTRACT FROM AUTHOR]

Respiratory distress syndrome (RDS) in preterm neonates is caused by a lack of alveolar surfactant, which leads to decreased pulmonary compliance and increased work of breathing. Effective therapy for RDS has reduced mortality at the expense of increasing the number of preterm survivors with chronic lung disease. Drugs such as corticosteroids, proterelin (thyrotropin-releasing hormone) and ambroxol have all been administered to mothers to promote fetal lung maturation, but of these only corticosteroids have been proven to be of benefit. The management of RDS includes assisted ventilation and surfactant replacement therapy. There are several surfactant preparations, some synthetic and others derived from animal lungs, and recent research has been directed at finding which, if any, is superior. The timing of the first dose has also been studied. Prophylactic surfactant administration within the first 15 minutes of life appears to be more efficacious than later treatment for very preterm babies, but could lead to some neonates being treated unnecessarily and perhaps being exposed to adverse effects. Newer treatments for neonates with RDS are aimed at reducing the pulmonary inflammation that occurs as a result of ventilatory barotrauma and oxygen toxicity. Superoxide dismutase, along with other antioxidants, may be beneficial as a free radical scavenger to reduce oxygen toxicity. Inhaled nitric oxide may reduce oxygen requirements by reducing ventilation-perfusion mismatching, and early treatment with corticosteroids may reduce pulmonary inflammation. All of these treatments are currently undergoing clinical trials. [ABSTRACT FROM AUTHOR]

Objective: The results of treatment of brain tumours have been disappointing. The objective of this study was to evaluate a new treatment with antineoplastons A10 and AS2-1. Patients and Methods: This study involved a cohort of patients who had failed established therapies and were treated in private practices in the USA and Australia. Patients received daily intravenous injections of antineoplastons A10 and AS2-1 at average dosages of 7.7 and 0.36 g/kg/day, respectively. Tumour dimensions were documented by magnetic resonance imaging. Changes in tumour size were categorised as defined by the National Cancer Institute. Results: Antineoplastons A10 and AS2-1 eliminated or substantially reduced tumours in 44% of patients with brain tumours. Of the 36 evaluable patients, nine had a complete response, seven a partial response, and 12 stable disease. Progressive disease occurred in eight patients. 15 patients are alive today, 86.5% of them for over 3 years from the beginning of treatment. Complete and partial responses were documented in glioblastoma multiforme, astrocytoma, oligodendroglioma, mixed glioma, medulloblastoma, and malignant meningioma. Adverse drug experiences included easily treated abnormalities in plasma electrolytes. In a small percentage of patients additional adverse effects possibly related to antineoplastons included skin rash (19%), somnolence (17%), weakness (14%), nausea (6%), vomiting (3%), headaches (3%), slurred speech (6%), confusion (3%), fever (3%) and fluid retention (3%). Adverse effects were reversed on temporary discontinuation or dose reduction. Conclusion: Antineoplaston therapy produced complete or partial responses in 16 of 36 (44%) patients with brain tumours. Compared with standard treatment, antineoplaston therapy is associated with prolonged survival time and prolonged time to disease progression. [ABSTRACT FROM AUTHOR]

The high prevalence of respiratory tract infections (RTIs) and the increasing resistance of causative pathogens to currently available antibiotics necessitates the development of new, more powerful antimicrobial agents. Such agents must possess a broad spectrum of antibacterial activity so as to be useful for both the empirical and specific therapy of RTIs. Moxifloxacin is one such antimicrobial agent. The drug is a new 8-methoxyquinolone that has been shown to have a wide range of activity against Gram-positive and -negative bacteria as well as against anaerobes and atypical pathogens that can cause RTIs. Moxifloxacin is also effective against both β-lactam- and macrolide-resistant organisms and very rarely itself induces resistance under experimental conditions. This review summarises the in vitro evidence for the range of antibacterial activities of moxifloxacin, in terms of minimum inhibitory concentrations (MIC), time-kill kinetics and post-antibiotic effects. These in vitro findings have been confirmed by animal studies. In conclusion, moxifloxacin has an effective, appropriate spectrum of antimicrobial activity and other properties that provide a foundation for its use in the therapy of RTIs. [ABSTRACT FROM AUTHOR]

Moxifloxacin is a new 8-methoxyquinolone with enhanced activity in vitro against Gram-positive pathogens and maintenance of activity against Gram-negative organisms. It is active against common, less common and atypical respiratory tract pathogens. The drug is rapidly absorbed, with peak plasma concentrations reached within 1 to 4 hours after treatment, and the long half-life (11.4 to 15.6 hours) makes it suitable for once-daily administration. There are no significant interactions between moxifloxacin and other drugs/substances or food, although staggered dose administration is needed if iron or other divalent cation-containing substances are to be administered to patients taking moxifloxacin. Moxifloxacin accumulates in lung epithelial lining fluid, bronchial mucosa and alveolar macrophages at concentrations that are considerably higher than the minimum inhibitory concentrations (MICs) of the most common respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis). In terms of pharmacokinetic indices used to predict clinical outcome, moxifloxacin's peak serum concentration (C):MIC exceeds the recommended minimum (>8 to 10), and the area under the inhibition curve (AUIC) values found for moxifloxacin exceed the minimum value for patients with serious infections (>125 mg/L·h). Thus, the antibiotic should achieve a high clinical success rate, although the outcome of clinical trials is awaited to confirm moxifloxacin as an important new antibiotic for a range of community respiratory infections. [ABSTRACT FROM AUTHOR]

Objective: To assess the humoral response in HIV-infected adults immunised against influenza in Poland in the epidemic season 1997/98. Patients and Methods: The study was carried out in 34 HIV-infected patients in different stages of the disease, vaccinated with a single 0.5ml dose of subunit vaccine (‘Influvac’, Solvay Pharmaceuticals BV). Antihaemagglutinin (HI) antibody levels were measured by the haemagglutinin inhibition test before immunisation and then after one and six months. Results: One month after vaccination HI antibody titres significantly increased from 1.5 to 5.5 times. After six months HI antibody levels were higher than those before vaccination and also higher than those determined one month after vaccination. Before immunisation the number of patients with HI antibody titres ≥1:40 ranged from 2.9 to 50%. After vaccination, protection rates increased and ranged from 17.6 to 79.4% one month after vaccination, and from 20.6 to 82.4% six months after vaccination. Response rate values remained at similar levels during the whole study and were between 9.4 and 14.7%. No statistically significant differences were found in humoral response between patients with different CD4 counts nor between AIDS patients and those not suffering from AIDS. Significantly higher antibody titres were recorded during the whole study for the A/Wuhan/359/95 (H3N2) influenza strain than for the A(H1N1) and B strains. Conclusions: The results of this study indicated that in HIV-infected patients humoral response to influenza vaccination was poor compared with healthy people. However, in some HIV-infected patients the vaccine induced the production of HI antibodies in titres that were considered high enough to protect against the infection. [ABSTRACT FROM AUTHOR]

Objective: To assess, using duplexsonography, the pharmacodynamic effects of a venotropic substance [ruscus extract (Cyclo 3 Fort)] on superficial primary varicose veins and deep veins in patients with primary varicose vein disease. Patients and Methods: This trial was an open, non-placebo-controlled phase IV study that included 12 male patients (mean age 49.6 ± 12.9 years) with primary varicosity of the greater saphenous vein. Three patients had no evidence of chronic venous insufficiency (Widmer classification), six had venous insufficiency grade I, and three patients had venous insufficiency grade II. All patients were administered three capsules of ruscus extract per day for 7 ± 1 days. Using a duplex scanner (duplexsonography), venous diameter and parameters of venous flow (peak velocity, mean velocity and flow volume) were measured in the supine and standing positions at baseline, 2 hours after intake of three capsules of ruscus extract on the first day of the study, and at the end of the 7-day study period. The veins assessed were the common femoral vein, the popliteal vein and the greater saphenous vein. Results: Mean venous diameter measured in the popliteal vein in standing patients was significantly lower 2 hours after treatment with ruscus extract than at baseline (1.17 ± 0.22 vs 1.21 ± 0.24cm, respectively; p = 0.009). Similarly, mean venous diameter measured in the common femoral vein in standing patients was significantly lower after 1 week's treatment with ruscus extract than at baseline (1.72 ± 0.19 vs 1.75 ± 0.21cm, respectively; p = 0.02). Nonstatistically significant decreases in greater saphenous vein (p = 0.06) and common femoral vein (p = 0.08) diameters, compared with baseline, were measured in the standing position at the 2-hour assessment. Venous diameter did not change with treatment in any vein segment measured in the supine position. Mean velocity of venous flow in the popliteal vein was significantly greater in the standing position at the 2-hour visit (0.95 ± 0.79 vs 0.7 ± 0.54 cm/sec at baseline; p = 0.05). In the greater saphenous vein, parameters of venous flow (mean velocity, flow volume) measured in the standing position were non-significantly lower than baseline at the 2-hour and 1-week assessments. No adverse effects of ruscus extract treatment were observed. Conclusions: Drug effects can be quantitatively measured by duplexsonography, although assessment of veins should be conducted with the patient in the standing position. A significant decrease in the venous diameter of deep veins, together with a significant increase in flow parameters in these veins and a nonsignificant decrease in flow parameters in superficial veins, was found when patients with primary varicose vein disease treated with ruscus extract were assessed in the standing position. A large, double-blind, placebo-controlled study is needed to confirm the postulated venoconstrictive effect of ruscus extract. [ABSTRACT FROM AUTHOR]

Objective: This pilot study was developed to acquire preliminary data concerning the analgesic efficacy and tolerability of dynorphin A(1-13), a 13 amino acid fragment of the endogenous opioid peptide dynorphin A(1-17), in opioid-treated patients. Design and Setting: Randomised, double-blind, placebo-controlled, graded dose, 3-way crossover pilot study conducted in a comprehensive cancer centre. Patients: Nine chronic pain patients receiving morphine >150 mg/day for at least 2 weeks, or the equivalent dose of hydromorphone. Interventions: Each patient was given a study treatment on each of 3 successive days after the opioid regimen was stabilised. On each day, a patient received 50% of the usual oral opioid dose when pain was at least moderate, followed 15 minutes later by a brief intravenous infusion of either dynorphin A(1-13) 150 µg/kg, dynorphin A(1-13) 500 µg/kg, or saline placebo. The sequence of administration was randomly ordered. Main Outcome Measures: Pain intensity, pain relief, mood and adverse effects were recorded for 8 hours after each treatment. Blood was sampled for dynorphin levels beginning 15 minutes after the infusion. Results: The data demonstrated linear dose-response trends for most of the parameters evaluated. Using analysis of variance (ANOVA), the differences among lower dose dynorphin A(1-13), higher dose dynorphin A(1-13), and the control were strongest for the sum of pain intensity differences (categorical scale) [p = 0.08], peak relief (p = 0.10), and total mood effect (p = 0.08). Post hoc pairwise comparisons consistently demonstrated the largest differences between the higher dose dynorphin A(1-13) and control. The major adverse effect was flushing. Dynorphin was detected only in the first sample, which was drawn 15 minutes after drug administration. Conclusions: This controlled pilot study identified trends suggesting that a brief intravenous infusion of dynorphin A(1-13) could potentially augment analgesia in opioid-treated patients. Based on this experience, a larger controlled trial is warranted. A 500 µg/kg dose would be an appropriate minimum dose for such studies. [ABSTRACT FROM AUTHOR]

Aromatase inhibitors were first reported in the early 1970s and have been used to treat breast cancer since that time. Until recently, essentially the only agent available in this class was aminoglutethimide, a nonspecific inhibitor with multiple adverse effects and drug interactions. Selective and potent aromatase inhibitors are now available (formestane, exemestane, fadrozole, anastrozole and letrozole), and we review the risks and benefits of these agents in order to assist clinicians in making treatment decisions. Formestane is an injectable steroidal aromatase inhibitor with significant activity against metastatic breast cancer. It has been shown to have similar efficacy and superior tolerability compared with megestrol, and is similar to tamoxifen in the metastatic setting. Exemestane is an oral steroidal aromatase inhibitor. It has been shown to be effective third-line therapy after tamoxifen and megestrol in postmenopausal patients with metastatic breast cancer. All the nonsteroidal (imidazole/ triazole) aromatase inhibitors are orally available. Fadrozole has similar activity to megestrol and tamoxifen in the setting of metastasis, but has been shown in phase II trials to inhibit cortisol and aldosterone production. Anastrozole and letrozole have similar toxicity profiles. Compared with megestrol, anastrozole improves overall survival and has superior tolerability. Letrozole is superior to megestrol and aminoglutethimide in terms of overall survival and time to progression, and is also better tolerated. Although there is a strong rationale for using these agents in the treatment of breast cancer, the information presently available is insufficient to recommend any one agent over another. Direct comparative studies are lacking, and comparing agents across studies is limited by many biases and may not be valid. Formestane is only available as an injection and exemestane is not commercially available in many countries, making these agents more difficult to recommend over the other 3 agents. Fadrozole is less potent and less selective in inhibiting aromatase than letrozole. The efficacies of fadrozole, megestrol and tamoxifen appear to be similar; however, comparative data show no advantage of fadrozole over letrozole. Anastrozole and letrozole are generally considered to be similar agents. The clinical future of the selective aromatase inhibitors is promising, and these agents may change the way postmenopausal breast cancer is treated at all stages of the disease. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) retinitis is a potentially sight-threatening complication of advanced HIV infection. The acute infection can be controlled with one of several therapies, including intravenous ganciclovir, foscarnet or cidofovir, slow release ganciclovir intraocular implants or serial intraocular injections of ganciclovir or foscarnet. The initial induction course of therapy is typically followed by lifelong maintenance therapy. In addition to the aforementioned treatments, oral ganciclovir and intravitreal fomivirsen injections are other options for maintenance therapy. The choice of agent must take into consideration factors such as comparative short and long term toxicity of the agents, route of administration and the possible need for indwelling catheters, administration time, cost and protection afforded against systemic dissemination of CMV infection. Possible drug interactions and additive toxicities of other agents needed for the management of the underlying HIV infection must also be taken into consideration. These factors can affect the tolerability of therapy as well as the quality of life of the patient. Relapse or progression of CMV retinitis may be caused by either inadequate drug concentrations at the site of the infection or by drug resistance. This may necessitate either an increase in drug dosage, a change in route of administration or a change to an alternative agent. All of these approaches can increase the risk of toxicity of the therapy. With the initiation of highly active antiretroviral therapy and partial reconstitution of the immune system, some patients have been able to successfully discontinue anti-CMV maintenance therapy, thereby decreasing long term drug toxicity. Determination of the patient predictors of success of this approach is an active area of research. [ABSTRACT FROM AUTHOR]

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale - Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease.Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with a n incidence ranging between 7 to 30% For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration. [ABSTRACT FROM AUTHOR]

Interferon alfacon-1 (consensus interferon; CIFN) is a novel, recombinant interferon which has been shown to have greater biological activity in vitro than other interferons. CIFN was tested in a large, phase 3, multicentre, North American study in patients with chronic hepatitis C. Patients were treated with 9µg CIFN or 3MU interferon (IFN)-α-2b 3 times weekly for 6 months. Efficacy was assessed by changes in ALT, decrease in hepatitis C virus (HCV) RNA and improvement in histology. CIFN produced similar overall response rates to those seen with IFNα-2b. However, the response rate and decrease in HCV RNA were greater among genotype 1 patients treated with CIFN than among those treated with IFNα-2b. Patients with sustained response generally responded early in treatment, with 96% responding by week 12. There was also a better response to CIFN than to IFNα-2b in patients with a high baseline viral concentration. Although the majority of CIFN-treated patients had histological improvement in the liver, it is notable that even patients who relapsed or did not respond had histological improvement and thus benefited from CIFN treatment. Viral and histological benefits were similar in patients with and without cirrhosis although ALT levels were not as improved in those with cirrhosis. Patients who relapsed or did not respond to initial treatment with either CIFN or IFNα-2b were re-treated with a higher dose of CIFN (15µg). Patients who relapsed had a 58% sustained viral response rate with 12 months of re-treatment. The response to re-treatment with this regimen of CIFN monotherapy is similar to that reported with the standard combination regimen of IFNα-2b plus ribavirin and far superior to that observed with 3MU IFNα-2b alone. Although prior nonresponders had a lower response rate than relapsers (sustained viral response rate of 13%), it is nonetheless clinically meaningful and clearly superior to the negligible responses among nonresponders reported in previous studies using re-treatment with other interferons. The adverse effects noted with CIFN are similar to those reported for IFNα-2b and are recognised adverse effects for all interferons. Thus, CIFN is a unique interferon with enhanced antiviral activity. Providing greater benefit for the difficult-to-treat patients makes CIFN a beneficial alternative in the initial treatment and re-treatment of patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

A new technology for treating respiratory disease, respirable antisense oligonucleotides (RASONs), has recently been developed by our group. RASONs are short, single-stranded nucleic acids, generally modified to reduce degradation. They differ from traditional drugs, which usually antagonise preformed proteins already functioning in a disease process. Instead, RASONs can attenuate the expression of disease-associated genes by targeting the messenger RNA (mRNA). Delivered directly to the target tissue, the lung, they avoid the problems of ineffective delivery encountered by other routes of administration. When an adenosine A antisense oligonucleotide was delivered to the lungs of allergic rabbits with up-regulated A adenosine receptors, desensitisation to the bronchoconstrictor effects of adenosine, histamine and a common aeroallergen (dust mite) occurred. The effect on A receptors persisted on average for nearly 7 days. RASON (the phosphorothioate antisense oligonucleotide EPI-2010) administered in low dosage was evenly distributed throughout the lung (with no detectable systemic active metabolites), and was excreted primarily in urine. These results demonstrate that RASONs can be efficiently and effectively delivered to the peripheral lung. They potently and selectively attenuate the expression of disease-associated genes, an approach to therapy which is now being extended to other potentially important mediators of bronchial asthma. [ABSTRACT FROM AUTHOR]