Biomedical subjects

S Noble

Publications and source records attributed to S Noble.

At least 55 records · Page 3Linked to original sources

PubMed1998

Re-engineering the elective surgical service of a tertiary hospital: a historical controlled trial.

OBJECTIVE: To study the clinical effects of re-engineering the processes associated with elective surgery. DESIGN: A prospective, historical controlled trial. Control patients were enrolled from March 1995 to January 1996, and postintervention patients from February 1996 to October 1996. SETTING: A major teaching, tertiary care hospital (Prince of Wales Hospital, Sydney). PATIENTS: 224 patients (123 before and 101 after the intervention) undergoing elective herniorrhaphy of laparoscopic cholecystectomy who lived in the local area. INTERVENTION: Introduction of a re-engineered surgical service consisting of preadmission assessment and education, admission on day of surgery, and postacute care after discharge. There were no changes to the operative methods or infection control procedures. MAIN OUTCOME MEASURES: Length of stay, operative complications, pain scores and patient satisfaction. RESULTS: The risk of a patient suffering one or more complications was reduced in the postintervention group (postintervention v. control patients: 25.7% v. 38.2%; relative risk [RR], 0.66; 95% confidence interval [CI], 0.44-0.98; P = 0.035) because of a reduced risk of wound infections (5.0% v. 16.3%; RR, 0.30; 95% CI, 0.12-0.78; P = 0.0075). Other complications (perioperative or postoperative) and pain scores were unchanged. Patients treated by the re-engineered service had a significantly shorter length of stay, reported a higher level of satisfaction with the preoperative and postdischarge care, and were more likely to say that they would have the same treatment again (92.9% v 82.6%; P = 0.037). CONCLUSIONS: Re-engineering surgical services, with an associated reduction in length of stay, does not lead to a deterioration in care and may decrease postoperative complications and increase patient satisfaction.

Australia↗

PubMed1998

Assessment of intubating conditions in adults after induction with propofol and varying doses of remifentanil.

We have assessed intubating conditions in three groups of 60 ASA I or II patients after induction of anaesthesia with propofol 2 mg kg-1 and remifentanil 0.5, 1.0 or 2.0 micrograms kg-1. Tracheal intubation was graded according to ease of laryn-goscopy, position of the vocal cords, coughing, jaw relaxation and movement of the limbs. Intubation was successful in 80%, 90% and 100% of patients after remifentanil 0.5, 1.0 or 2.0 micrograms kg-1, respectively. Overall intubating conditions were regarded as acceptable in 20%, 50% and 80% of patients, respectively. All three groups had a decrease in arterial pressure after induction but there was no difference between groups. The decrease in arterial pressure was not regarded as clinically significant. Intubating conditions were best after induction with remifentanil 2 micrograms kg and propofol 2 mg kg-1.

Adult↗

PubMed1998

Rivastigmine. A review of its use in Alzheimer's disease.

UNLABELLED: Rivastigmine (SDZ ENA 713) is a carbamylating, long-acting reversible and noncompetitive carbamate acetylcholinesterase inhibitor that is indicated as an oral treatment for patients with mild to moderately severe Alzheimer's disease. The drug has been evaluated for this use in 3 well designed, adequately powered, phase II/III, 26-week clinical trials that included a total of 1479 rivastigmine and 647 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. Individual and pooled results of these trials indicate that rivastigmine 6 to 12 mg/day usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild to moderately severe Alzheimer's disease. Individual results of the 2 pivotal trials and pooled analysis also show that, compared with placebo recipients, significantly more rivastigmine 6 to 12 mg/day recipients respond to therapy. Indeed, after 26 weeks of therapy in the 2 pivotal trials, significantly more rivastigmine 6 to 12 mg/day than placebo recipients achieved clinically meaningful improvements as defined by 3 separate response criteria. The lower dosage range of 1 to 4 mg/day was not as effective as 6 to 12 mg/day, as measured using these criteria and other efficacy parameters. Rivastigmine causes adverse events that are generally those expected from an acetylcholinesterase inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction. Unpublished data from 3989 patients indicate that rivastigmine and placebo were associated with similar incidences of serious adverse events and changes in laboratory parameters, ECG and cardiorespiratory vital signs. The most common events were gastrointestinal, central and peripheral nervous system and whole body adverse events. However, compared with placebo, rivastigmine more commonly caused adverse events resulting in treatment withdrawal. These events were most frequently gastrointestinal and were more common in women. CONCLUSION: Rivastigmine is a useful option for the treatment of patients with mild to moderately severe Alzheimer's disease. Although only short term (6- month) comparisons with placebo are available, given the lack of established treatment options it should be considered for first-line use in this population.

Alzheimer Disease↗

PubMed1998

Paroxetine. An update of its pharmacology and therapeutic use in depression and a review of its use in other disorders.

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT), which was previously reviewed as an antidepressant in Drugs in 1991. Since then, more comparative trials with other antidepressants have become available, and its use in the elderly and as long term maintenance therapy has been investigated. Paroxetine has also been studied in several other disorders with a presumed serotonergic component, primarily obsessive compulsive disorder (OCD) and panic disorder. In short term clinical trials in patients with depression, paroxetine produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with other agents including tricyclic antidepressants (TCAs), maprotiline, nefazodone and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline. Long term data suggest that paroxetine is effective in preventing relapse or recurrence of depression in patients treated for up to 1 year. In the elderly, the overall efficacy of paroxetine was at least as good as that of comparator agents. In short term clinical trials involving patients with OCD or panic disorder, paroxetine was significantly more effective than placebo and of similar efficacy to clomipramine. Limited long term data show that paroxetine is effective in maintaining a therapeutic response over periods of 1 year (OCD) and up to 6 months (panic disorder). Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache. Like the other SSRIs, paroxetine is better tolerated than the TCAs, causing few anticholinergic adverse effects. The most commonly reported adverse event associated with paroxetine treatment is nausea, although this is generally mild and subsides with continued use. Fewer withdrawals from treatment due to adverse effects occurred with paroxetine treatment than with TCAs. The adverse events profile of paroxetine appears to be broadly similar to that of other SSRIs, although data from comparative trials are limited. Serious adverse effects associated with paroxetine are very rare. In conclusion, paroxetine is effective and well tolerated, and suitable as first-line therapy for depression. It also appears to be a useful alternative to other available agents for the treatment of patients with OCD or panic disorder.

Antidepressive Agents, Second-Generation↗

PubMed1998

Zopiclone. An update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia.

Zopiclone is a non-benzodiazepine hypnotic which was first reviewed in Drugs in 1986. At that time, zopiclone had shown hypnotic efficacy superior to that of placebo, but had not been extensively compared with benzodiazepine hypnotics in patients with insomnia. A much larger body of clinical data is now available, allowing a more detailed evaluation than was previously possible. Together with results from earlier studies, subsequent clinical trials have shown that zopiclone is generally at least as effective as the benzodiazepines (regardless of duration of action) in the treatment of insomnia, although comparisons between zopiclone and flurazepam have produced inconsistent results. Tolerance to the effects of zopiclone was not seen in short term clinical trials (< or = 4 weeks); data from longer term studies are conflicting and the potential for tolerance during long term zopiclone treatment is therefore unclear. Zopiclone has a relatively low propensity to cause residual clinical effects (such as difficulty in waking or reduced morning concentration). Rebound of insomnia to a level below that at baseline can occur after withdrawal of zopiclone, but, on the basis of data from short term studies, does not appear to be common. Data from prescription-event monitoring suggest that zopiclone does not have a high dependence potential (at least in those who are not regular drug abusers/addicts). Zopiclone is well tolerated in both the elderly and younger patients with insomnia. A bitter aftertaste is usually the most common adverse event, but is relatively infrequent (3.6% in the largest available postmarketing study). Thus, zopiclone is now firmly established as an effective and well tolerated hypnotic agent. Although the available data on rebound insomnia and dependence liability are encouraging, potential differences between zopiclone and the benzodiazepines in these respects may have little clinical relevance in the context of short term intermittent use of hypnotics, as it currently recommended. A low propensity for rebound insomnia and dependence might prove valuable during long term hypnotic therapy (which, although not recommended, is a clinical reality). However, the risk-benefit profile of zopiclone in this context remains unknown. Nevertheless, zopiclone is clearly a suitable alternative to the benzodiazepines for the short term treatment of insomnia.

Azabicyclo Compounds↗

PubMed1998

Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy.

Tiagabine is a gamma-aminobutyric acid (GABA) uptake inhibitor which is structurally related to nipecotic acid but has an improved ability to cross the blood-brain barrier. Clinical trials have shown that tiagabine is effective as add-on therapy in the management of patients with refractory partial epilepsy. In short term studies of this indication, tiagabine < or = 64 mg/day for 7 to 12 weeks reduced the complex partial and simple partial seizure frequency by > or = 50% in 8 to 31 and 28.2 to 37% of patients, respectively. Tiagabine appeared to produce a sustained reduction in seizure frequency in studies of up to 12 months' duration. Data from preliminary studies are currently insufficient to confirm the usefulness of tiagabine when used as monotherapy or in the treatment of children with epilepsy. Further studies are, therefore, necessary to more fully elucidate the efficacy of the drug in these settings. Adverse events associated with tiagabine are primarily CNS-related and include dizziness, asthenia, nonspecific nervousness and tremor. Skin rash or psychosis occurred with similar frequencies among tiagabine- and placebo-treated patients. With long term administration (> or = 1 year for many patients), the profile and incidence of adverse events was similar to that for short term therapy. Tiagabine does not appear to affect the hepatic metabolism of other drugs such as carbamazepine and phenytoin. Possible disadvantages of tiagabine include its short plasma elimination half-life, necessitating 2 to 4 times daily administration, and its inducible hepatic metabolism. Thus, tiagabine is a new antiepileptic agent with a novel mechanism of action, which has demonstrated efficacy in the adjunctive treatment of patients with refractory partial epilepsy. Further investigation of the efficacy of tiagabine is expected to provide a clearer definition of its place in the treatment of epilepsy and its relative merits in relation to other antiepileptic drugs.

Animals↗

PubMed1998

Saquinavir soft-gel capsule formulation. A review of its use in patients with HIV infection.

Saquinavir is an HIV protease inhibitor which, formulated as a hard-gel capsule (HGC), was the first drug of its class to become available for the treatment of patients with HIV infection. Despite the beneficial effects that saquinavir HGC-containing combination regimens have shown in the treatment of patients with HIV infection, the HGC formulation has limited oral bioavailability and has shown only modest antiviral activity in vivo. To overcome this limitation (with the aim of improving antiviral efficacy), a soft-gel capsule (SGC) formulation of the drug has been developed. At the recommended dosage of 1200 mg 3 times daily, the SGC formulation of saquinavir achieves plasma concentrations > 8 times higher than those in patients receiving saquinavir HGC 600 mg 3 times daily. Initial results of trials evaluating the therapeutic efficacy of saquinavir SGC-containing combination therapy in patients with moderate to advanced HIV infection are promising. In patients who were previously antiretroviral therapy-naive or -experienced, short term (< or = 36 weeks) treatment with saquinavir SGC in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or 2 NRTIs plus nelfinavir led to marked improvements in virological and immunological markers of HIV disease. In comparative trials, saquinavir SGC showed improved antiviral activity compared with the HGC formulation in terms of reducing viral load. Furthermore, saquinavir SGC in combination with 2 NRTIs was as effective as indinavir plus 2 NRTIs in antiretroviral-naive or -experienced patients. Available data suggest that saquinavir SGC-containing combination therapy may be of greatest benefit in patients naive to previous antiretroviral therapy. The SGC formulation of saquinavir appears to be generally well tolerated by adults with HIV infection. Gastrointestinal adverse events, notably diarrhoea, abdominal discomfort, nausea and dyspepsia, are the most common adverse events occurring during treatment with the drug. Initial results of several trials that used surrogate markers to assess treatment efficacy indicate that the SGC formulation of saquinavir, administered in combination with other antiretroviral drugs, is an effective and well-tolerated treatment for patients with moderate or advanced HIV infection. Although further data are required before definitive conclusions can be drawn regarding the comparative efficacy and tolerability of the SGC and HGC formulations, it appears likely that the SGC formulation will replace the conventional formulation as a component of combination regimens for the treatment of patients with HIV infection.

Anti-HIV Agents↗

PubMed1998

Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients.

UNLABELLED: Ganciclovir is a nucleoside analogue which is used to treat and prevent cytomegalovirus (CMV) infection. Most recent clinical studies of ganciclovir in transplant recipients have focused on preventive approaches. When ganciclovir was last reviewed in Drugs in 1994, substantial data on post-transplantation CMV prophylaxis with this drug were available only for patients undergoing allogeneic bone marrow transplantation (BMT). Two strategies had emerged: prophylaxis for all patients or early treatment started after detection of asymptomatic CMV infection. Subsequently, a large double-blind study has shown that ganciclovir prophylaxis is more effective than early treatment in preventing early CMV disease after allogeneic BMT and is not associated with an increased incidence of neutropenia. However, mortality for the 2 strategies was similar. The efficacy of prophylactic intravenous ganciclovir in liver transplant recipients [including high risk donor seropositive/recipient seronegative (D+/R-) or antilymphocyte-treated patients] is now well established. Prophylaxis with oral ganciclovir was effective both overall and in D+/R-patients in a large placebo controlled study, and prolonged intravenous ganciclovir was significantly more effective than high dose aciclovir (acyclovir) in seropositive liver recipients. Early treatment with ganciclovir has proved useful in this setting. More limited data indicate that CMV prophylaxis with intravenous ganciclovir may be useful after heart or lung transplantation but its value in D+/-patients remains unclear. Combined chemoimmunotherapy may be valuable in these high risk patients but controlled data are lacking. Targeted prophylaxis with intravenous ganciclovir is effective in renal transplant recipients receiving antilymphocyte therapy; the role of oral ganciclovir in this setting is less clear. The value of ganciclovir in D+/- renal transplant recipients and its efficacy compared with high dose aciclovir have not been determined. CONCLUSIONS: Ganciclovir is the only antiviral chemotherapy which reduces the risk of CMV infection or disease after most types of major transplantation. Unresolved issues include the best (and most cost-effective) use of ganciclovir and aciclovir after allogeneic BMT, the efficacy of oral ganciclovir compared with other anti-CMV regiments, the potential clinical effect of viral resistance during prolonged ganciclovir exposure and the value of ganciclovir in certain high risk transplant populations. In the meantime, ganciclovir has an important role in the prevention of CMV infection and disease after bone marrow and liver transplantation and is likely to gain wider clinical use in heart, lung and kidney transplant recipients.

Acyclovir↗

PubMed1998

Enoxaparin. A review of its clinical potential in the management of coronary artery disease.

UNLABELLED: Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) that is widely used in the prevention of deep venous thrombosis and pulmonary embolism in patients undergoing orthopaedic or general surgery. Its efficacy in these indications has led to study of its use in patients with coronary artery disease, particularly those with unstable angina, who have a high risk of myocardial infarction and death. A double-blind multicentre study [ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events)] showed that subcutaneous enoxaparin was more effective than intravenous unfractionated heparin (UFH) in reducing the incidence of the composite end-point of death, myocardial infarction or recurrent angina after 14 days in 3171 patients with recent-onset resting angina (i.e. unstable angina). There were no statistically significant between-group differences for the secondary end-point of death or myocardial infarction. Preliminary reports of long term follow-up data indicate that the clinical benefit of enoxaparin over UFH is maintained after 1 year. The only significant difference in tolerability between enoxaparin and UFH in ESSENCE was for minor haemorrhage (mostly injection-site ecchymosis), which was more common with the LMWH. Prospective pharmacoeconomic substudies of the ESSENCE trial suggest that total medical costs (including those for subsequent revascularisation procedures) for enoxaparin treatment are lower than those for UFH. The ESSENCE study is the first double-blind trial to show that a LMWH is more effective than UFH in patients with unstable angina. The superiority of enoxaparin was attributable mainly to its effects on recurrent angina. The level of anticoagulation achieved in the UFH group raises a number of issues which might have affected the apparent relative efficacy of enoxaparin and UFH. Preliminary data suggest that enoxaparin is at least as effective as UFH in reducing the incidence of subsequent cardiac events in patients receiving thrombolysis for acute myocardial infarction, and a randomised comparison with no additional treatment (other than aspirin) has demonstrated its efficacy in this indication. Enoxaparin has been ineffective in preventing restenosis after angioplasty CONCLUSIONS: The ESSENCE study has shown that enoxaparin is more effective than UFH in patients with unstable angina. Although clarification of some methodological issues would be beneficial, the available efficacy data, together with the practical advantages of LMWHs in general, suggest that enoxaparin is an effective and convenient means of treating unstable angina and should provide cost savings compared with UFH.

Angina, Unstable↗

PubMed1998

Trandolapril. An update of its pharmacology and therapeutic use in cardiovascular disorders.

UNLABELLED: Trandolapril is an orally administered angiotensin converting enzyme (ACE) inhibitor that has been used in the treatment of patients with hypertension and congestive heart failure (CHF), and after myocardial infarction (MI). Trandolapril is a nonsulfhydryl prodrug that is hydrolysed to the active diacid trandolaprilat. Trandolapril 2 mg once daily provides effective control of blood pressure (BP) over 24 hours in patients with mild to moderate hypertension, with a trough/peak ratio of BP reduction (as determined by 24-hour ambulatory monitoring) consistently > or = 50%. Trandolapril has similar antihypertensive efficacy to enalapril as indicated by several clinical trials. Combined therapy with trandolapril and sustained-release verapamil has a significantly greater antihypertensive effect than either agent alone. Only limited data are available on the use of trandolapril in patients with CHF, although ACE inhibitors as a class are recommended as first line therapy in such patients. In the Trandolapril Cardiac Evaluation (TRACE) study, trandolapril 1 to 4 mg once daily resulted in an early and long term reduction in all-cause mortality, including cardiovascular mortality, in patients with left ventricular (LV) dysfunction after an MI. Trandolapril therapy was commenced a mean 4.5 days after acute MI and continued for 24 to 50 months. At study end, the relative risk of death from any cause with trandolapril versus placebo was 0.78 (p = 0.001). The tolerability profile of trandolapril is similar to that of other ACE inhibitors. Most adverse events are mild and transient in nature, and include cough, asthenia, dizziness, headache and nausea. Trandolapril has no adverse effect on lipid or carbohydrate metabolism. CONCLUSIONS: trandolapril has a favourable pharmacological profile and an antihypertensive efficacy at least comparable to that of other ACE inhibitors. The pharmacological characteristics of trandolapril allow it to provide good 24-hour control of BP with once-daily administration. Trandolapril has also demonstrated some efficacy in a small number of patients with CHF. In addition, trandolapril provides long term protection against all-cause mortality in patients with LV dysfunction after MI. The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) study will determine its potential as a cardioprotective agent in patients with coronary artery disease and preserved LV function. Thus, trandolapril represents an effective, well-tolerated and convenient treatment option for patients with mild to moderate hypertension or LV systolic dysfunction after MI.

Aged↗

PubMed1998

Efavirenz.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.

Administration, Oral↗

PubMed1997

Core protein mu2 is a second determinant of nucleoside triphosphatase activities by reovirus cores.

NTPase activities in mammalian reovirus cores were examined under various conditions that permitted several new differences to be identified between strains type 1 Lang (T1L) and type 3 Dearing (T3D). One difference concerned the ratio (at pH 8.5) of ATP hydrolysis at 50 degrees C to that at 35 degrees C. A genetic analysis using T1L x T3D reassortant viruses implicated the L3 and M1 gene segments in this difference, with M1 influencing ATPase activity most strongly at high temperatures. L3 and M1 encode the core proteins lambda1 and mu2, respectively. Another difference concerned the absolute levels of GTP hydrolysis by cores at 45 degrees C and pH 6.5. A genetic analysis using T1L x T3D reassortants implicated the M1 gene as the sole determinant of this difference. The results of these experiments, coupled with previous findings (S. Noble and M. L. Nibert, J. Virol. 71:2182-2191, 1997), suggest either that a single type of NTPase in cores is strongly influenced by two different core proteins--lambda1 and mu2--or that cores contain two different types of NTPase influenced by the two proteins. The findings appear relevant for understanding the complex functions of reovirus cores in RNA synthesis and capping.

Acid Anhydride Hydrolases↗

PubMed1997

Characterization of an ATPase activity in reovirus cores and its genetic association with core-shell protein lambda1.

A previously identified nucleoside triphosphatase activity in mammalian reovirus cores was further characterized by comparing two reovirus strains whose cores differ in their efficiencies of ATP hydrolysis. In assays using a panel of reassortant viruses derived from these strains, the difference in ATPase activity at standard conditions was genetically associated with viral genome segment L3, encoding protein lambda1, a major constituent of the core shell that possesses sequence motifs characteristic of other ATPases. The ATPase activity of cores was affected by several other reaction components, including temperature, pH, nature and concentration of monovalent and divalent cations, and nature and concentration of anions. A strain difference in the response of core ATPase activity to monovalent acetate salts was also mapped to L3/lambda1 by using reassortant viruses. Experiments with different nucleoside triphosphates demonstrated that ATP is the preferred ribonucleotide substrate for cores of both strains. Other experiments suggested that the ATPase is latent in reovirus virions and infectious subviral particles but undergoes activation during production of cores in close association with the protease-mediated degradation of outer-capsid protein mu1 and its cleavage products, suggesting that mu1 may play a role in regulating the ATPase.

Adenosine Triphosphatases↗

PubMed1997

Octreotide long-acting release (LAR). A review of its pharmacological properties and therapeutic use in the management of acromegaly.

Octreotide is a somatostatin analogue: a long-acting release (LAR) formulation of octreotide is designed for once-monthly intramuscular administration. As with native somatostatin, octreotide LAR exerts potent inhibitory effects on the secretion of growth hormone and on various peptides of the gastroenteropancreatic endocrine system. When patients with acromegaly who show a positive response to treatment with subcutaneous octreotide 300 to 600 micrograms/day are switched to octreotide LAR 20 or 30 mg, the resulting decrease in growth hormone levels is stable and sustained. Reductions in growth hormone levels to < 5 micrograms/L for about 4 weeks are seen in 86 to 100% of patients, to < 2 to 2.5 micrograms/L in 39 to 75% and to < 1 microgram/L in 24 to 40%. Levels of insulin-like growth factor-1 (IGF-1) decrease in parallel and are often normalised with repeated drug treatment. There is no evidence of tachyphylaxis with long term therapy (up to 34 months). Treatment with octreotide LAR improves facial appearance and soft tissue thickening, and eliminates or reduces the incidence of symptoms such as headache, fatigue, arthralgia and excessive perspiration. Tumour shrinkage has been noted in some, but not all, patients receiving octreotide LAR, although this has not been widely evaluated in clinical studies. Overall, octreotide LAR is well tolerated, and the mild to moderate gastrointestinal events experienced by up to 50% of patients are of short duration and often subside with continued drug administration. The incidence of gallbladder abnormalities (sediment, sludge, microlithiasis and gallstones) increases in patients receiving long term therapy with subcutaneous octreotide, although most patients remain asymptomatic. The incidence of gallbladder abnormalities in patients receiving octreotide LAR compares favourably with that during subcutaneous administration. Glycaemic control is not usually altered during octreotide LAR treatment. In summary, octreotide continues to be the principal pharmacological option for most patients with acromegaly. Octreotide LAR offers the convenience of once-monthly administration compared with daily subcutaneous drug administration. In addition, the good efficacy and tolerability profile of octreotide LAR should enhance patient compliance and acceptability of octreotide therapy and contribute to an improvement in patient quality of life.

Acromegaly↗

PubMed1997

Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer.

Gemcitabine [2'-deoxy-2',2'-difluorocytidine monohydrochloride (beta isomer); dFdC] is a novel deoxycytidine analogue which was originally investigated for its antiviral effects but has since been developed as an anticancer therapy. Gemcitabine monotherapy produced an objective tumour response in 18 to 26% of patients with advanced non-small cell lung cancer (NSCLC) and appears to have similar efficacy to cisplatin plus etoposide. Objective response rates ranging from 26 to 54% were recorded when gemcitabine was combined with cisplatin, and 1-year survival duration after such treatment ranged from 35 to 61%. Improvements in a range of NSCLC disease symptoms and/or in general performance status occurred in many patients who received gemcitabine, with or without cisplatin, in 3 clinical trials. Gemcitabine appears to be cost effective compared with best supportive care for NSCLC. In addition, direct costs associated with administration of gemcitabine monotherapy may be lower than those for some other NSCLC chemotherapy options, according to retrospective cost-minimisation analyses. The combination of gemcitabine plus cisplatin was associated with a lower cost per tumour response than cisplatin plus etoposide or cisplatin plus vinorelbine, according to a retrospective cost-effectiveness analysis. In a single comparative study in patients with advanced pancreatic cancer, gemcitabine was more effective than fluorouracil with respect to survival duration and general clinical status. It also showed modest antitumour and palliative efficacy in patients refractory to fluorouracil. Gemcitabine appears to be well tolerated, although further comparisons with other chemotherapy regimens are required. The available data indicate that gemcitabine monotherapy is better tolerated than cisplatin plus etoposide in patients with NSCLC. Data from noncomparative studies suggest that the combination of gemcitabine and cisplatin has an acceptable tolerabilty profile. In a single trial in patients with pancreatic cancer, fluorouracil was better tolerated than gemcitabine; however, gemcitabine was generally well tolerated overall in this study. Thus, gemcitabine (with or without cisplatin) may prove attractive to patients with advanced NSCLC, given their limited life expectancy and the toxicity associated with many other chemotherapy regimens. More detailed characterisation of its risk-benefit profile compared with those of current and developing regimens for NSCLC should be possible once results from several ongoing studies are available. Gemcitabine is a valuable new chemotherapy option for patients with advanced pancreatic cancer, a disease considered incurable at present. Its apparent survival and palliative benefits over fluorouracil require confirmation, but are encouraging, as the need to improve both the duration and quality of survival in these patients is well recognised.

Animals↗

PubMed1996

Hypoxia-induced amphiphiles inhibit renal Na+, K(+)-ATPase.

We have characterized the effects of hypoxia on carnitine metabolism in proximal tubules. Hypoxia for 10 minutes resulted in a significant increase in the mass of long chain acylcarnitines (LCAC) (control 53 +/- 20 vs. hypoxia 118 +/- 38 pmol. mg-1 protein). Since LCAC are proximal metabolites in the beta-oxidation of fatty acids, these data suggest that inhibition of fatty acid oxidation occurs during hypoxia in the proximal tubule. In addition to LCAC accumulation, hypoxia resulted in a significant increase in the mass of lysoplasmenylcholine LPLasCho (control 62 +/- 15 pmol/mg vs. 20 min hypoxia 146 +/- 21 pmol/mg protein, N = 4) and also in increases in the mass of monoacyl LPC (control 122 +/- 24 pmol/mg protein vs. 283 +/- 35 pmol/mg protein after 40 min of hypoxia). We tested the possibility that these compounds that accumulate during hypoxia could inhibit proximal tubule Na+, K(+)-ATPase. LPC, LPlasC, and LCAC inhibited proximal tubule nystatin-stimulated oxygen consumption (QO2) and proximal tubule Na+, K(+)-ATPase activity in a dose-dependent manner. In addition, LPC, LPlasC, and LCAC directly inhibited' (65%, 80%, and 60%, respectively) Na+, K(+)-ATPase activity purified from kidney cortex at similar concentrations at which they accumulate during hypoxia (above 25 microM). The present data suggest that amphiphile accumulation may have a potential pathophysiologic role in the proximal tubule during renal ischemia.

Animals↗

PubMed1996

Ticlopidine. A review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischaemia and stroke.

Ticlopidine is a thienopyridine derivative which reduces the risk of reversible ischaemia and stroke in patients who have previously experienced a cerebral ischaemic episode. In comparison with aspirin, ticlopidine produced a significant reduction in the risk of stroke in a multicentre clinical trial involving more than 3000 patients with previous transient or persistent minor ischaemia, and was superior to placebo for the prevention of stroke recurrence in more than 1000 patients who had experienced a major thrombotic stroke. The cost-utility ratio for ticlopidine in comparison with aspirin was estimated to be $US31 200 to 55,000 per quality-adjusted life-year gained. Diarrhoea is the most common adverse event in ticlopidine recipients (20 to 22% incidence versus about 10% with placebo), although skin rash, nausea, dyspepsia, bleeding events, abnormal liver function and haematological disturbances were also observed in clinical trials. Severe neutropenia is the most serious event: this developed in 0.85% of patients receiving ticlopidine in 2 large clinical studies (n = 4098) but resolved after treatment withdrawal. Fatal neutropenia, although rare, has been reported in some patients receiving ticlopidine. Thus, ticlopidine is effective in reducing the risk of recurrent cerebral ischaemia and stroke. It appears to provide a gain over aspirin for the prevention of stroke after reversible ischaemia, particularly during the first year of treatment (when the risk of stroke is greatest), although further data on its absolute relative benefit would be useful. The extent to which ticlopidine is prescribed will probably depend on individual clinicians' perception of its risk/benefit and cost-effectiveness profiles. Ticlopidine is likely to be particularly useful for stroke prophylaxis in patients who do not tolerate aspirin or who have an ischaemic episode during aspirin treatment, and for the prevention of stroke recurrence in patients who have previously experienced a major stroke.

Brain Ischemia↗

PubMed1996

Meloxicam.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) developed for the treatment of rheumatoid arthritis and osteoarthritis. It has greater in vitro and in vivo inhibitory action against the inducible isoform of cyclo-oxygenase (COX-2), which is implicated in the inflammatory response, than against the constitutive form of this enzyme (COX-1), inhibition of which is associated with gastric, renal and other adverse effects. It has anti-inflammatory effects similar to or better than those of other NSAIDs in animal models, and a greater therapeutic ratio (ulcerogenic potential:efficacy in adjuvant arthritis). In healthy volunteers meloxicam 7.5 or 15 mg caused less gastrointestinal mucosal damage on endoscopy than piroxicam 20 mg, with a significant difference between meloxicam 7.5 mg and piroxicam. In comparative clinical trials, meloxicam was at least as effective as piroxicam and naproxen in patients with rheumatoid arthritis, and diclofenac and piroxicam in patients with osteoarthritis. Meloxicam was at least as well tolerated as piroxicam, diclofenac or naproxen overall but had improved gastrointestinal tolerability compared with these agents.

Animals↗