Review article: panitumumab--a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer.

BACKGROUND: Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR). AIM: To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC). METHODS: Available literature identified from PubMed and conference websites was reviewed. RESULTS: In phase 2-3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8-13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44-0.66; P < 0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab--and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR approximately equal to 20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (approximately equal to 90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3-4 infusion reactions (<1%) are rare. CONCLUSION: Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS.

Topical eflornithine.

Eflornithine is a specific, irreversible inhibitor of the enzyme ornithine decarboxylase which is thought to slow hair growth by inhibiting this enzyme in hair follicles. Percutaneous absorption of eflornithine in women with unwanted facial hair (hirsutism) was < 1% when the 15% cream was applied twice daily to a shaved 50 cm2 area of skin under the chin. In clinical studies in women with excessive, unwanted facial hair, eflornithine 15% cream was superior to placebo in reducing hair growth, as demonstrated by objective and subjective methods, after 2 to 8 weeks' treatment. After 24 weeks' treatment, 58% of eflornithine and 34% of placebo recipients had at least some improvement in facial hirsutism (for the purposes of this analysis all patients not assessed at week 24 were considered to be worse or to have no improvement). In addition, 32 versus 8% of patients were judged to be successfully treated (at least marked improvement). Hair growth returned to pretreatment rates within 8 weeks of stopping treatment. Use of a self-assessment questionnaire to assess the effect of study treatment on 6 aspects of patient well-being showed that eflornithine reduced the mean level of overall discomfort and bother by 33 versus 15% in placebo recipients. Adverse events mostly affected the skin. Only burning/stinging/tingling was markedly more common with eflornithine than with placebo.

Walking difficulty, walking speed, and age as predictors of self-rated health: the women's health and aging study.

BACKGROUND: Older persons reporting disability are more likely to report poor self-rated health, but little work has been done to assess the independent relationships of reported walking difficulty and measured walking performance with self-rated health. This study examines the associations of walking difficulty, walking speed, and age with self-rated health in older women. METHODS: The data are from the baseline of the Women's Health and Aging Study. Difficulty walking one quarter mile was used as a measure of mobility in the representative population aged 65 and older screened for the study (n = 3841) and in the one third most disabled study group (n = 1002). Maximal walking speed was measured in the study sample. RESULTS: Increasing severity of walking difficulty (in the screened population and in the disabled study group), slower walking speed (in the study group), and younger age were all associated with fair or poor self-rated health, after simultaneous adjustment for these and other objective measures of physical performance and health. The associations of both measures of walking with self-rated health weakened with age. CONCLUSIONS: Both walking difficulty and walking speed are independent determinants of self-rated health. Adjusted for health and functioning, self-rated health tends to improve with age.

Telithromycin.

Telithromycin is the first member of a new family of the macrolide-lincosamide-streptogramin-B (MLS(B)) class of antimicrobials, the ketolides. It has a good spectrum of activity against respiratory pathogens, including penicillin- and erythromycin-resistant pneumococci, as well as intracellular and atypical bacteria. Furthermore, it has a low potential to select for resistance or induce cross-resistance among other MLS(B) antimicrobials. At the recommended dosage of 800 mg orally once daily, telithromycin reaches maximal plasma concentrations of about 2 mg/L. It penetrates rapidly into bronchopulmonary, tonsillar, sinus and middle ear tissues and/or fluids and achieves high concentrations at sites of infection. It also concentrates within polymorphonuclear neutrophils. In clinical trials in patients with community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) or pharyngitis/tonsillitis caused by group A beta-haemolytic streptococci, telithromycin 800 mg once daily achieved clinical cure rates of 86 to 95%. In acute maxillary sinusitis (AMS), cure rates were 73 to 91%. A 7- to 10-day regimen of telithromycin was as effective as a 10-day course of amoxicillin 1000 mg 3 times daily, clarithromycin 500 mg twice daily or a 7- to 10-day course of trovafloxacin 200 mg once daily for treating CAP. A 5-day regimen of telithromycin was as effective as a 10-day regimen of cefuroxime axetil 500 mg twice daily or amoxicillin/clavulanic acid 500/125 mg 3 times daily in AECB. A 5-day regimen of telithromycin was as effective as a 10-day regimen of clarithromycin 250 mg twice daily or phenoxymethylpenicillin 500 mg 3 times daily in pharyngitis/tonsillitis, or a 10-day regimen of amoxicillin/clavulanic acid 500/125 mg 3 times daily in patients with AMS. Telithromycin was well tolerated across all patient populations. Adverse events associated with telithromycin were generally mild to moderate in intensity and seldom led to treatment discontinuation. The most frequent adverse events were diarrhoea (13.3%) and nausea (8.1%). Other adverse events included dizziness and vomiting.

Bendamustine.

Bendamustine is a bifunctional alkylating agent with cytotoxic activity against human ovarian and breast cancers in vitro. It shows only partial in vitro cross-resistance with cyclophosphamide, melphalan, carmustine and cisplatin. Bendamustine as monotherapy or as part of combination chemotherapy protocols for first-line or subsequent treatment produced objective response rates of 61 to 97% in patients with Hodgkin's disease or non-Hodgkin's lymphoma (NHL) [41 to 48% in high grade NHL]. In patients with multiple myeloma, a bendamustine/prednisone regimen produced a higher rate of complete response (32 vs 11%) and more durable responses than a melphalan/prednisone regimen. Substitution of bendamustine for cyclophosphamide in a standard first-line COP regimen (cyclophosphamide, vincristine and prednisolone) yielded similar response rates in patients with advanced low grade NHL. Substituting bendamustine for cyclophosphamide in the CMF protocol (cyclophosphamide, methotrexate and fluorouracil) prolonged remission from 6.2 to 15.2 months in patients with metastatic breast cancer. The most common adverse events in patients receiving bendamustine are haematological events and gastrointestinal disturbances. Bendamustine has a relatively low propensity to induce alopecia.

Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women's health and aging study.

BACKGROUND: Systemic chronic inflammation has been found to be related to all-cause mortality risk in older persons. We investigated whether specific chronic conditions, particularly cardiovascular disease (CVD), affect the association between high interleukin (IL)-6 level and mortality in a sample of disabled older women. METHODS AND RESULTS: IL-6 serum level was measured at baseline in 620 women >/=65 years old. The presence and severity of medical conditions was ascertained by standard criteria that used multiple sources of information. The sample was surveyed over the 3-year follow-up. After adjustment for potential confounders, compared with those in the lowest tertile, women in the highest IL-6 tertile were at higher risk of all-cause mortality. The presence of CVD, however, strongly affected the risk of mortality associated with high IL-6. Among women with prevalent CVD, those with high IL-6 levels had >4-fold risk of death (RR 4.6; 95% CI 2.0 to 10.5) compared with women in the lowest tertile, whereas the relative risk associated with high IL-6 among those without CVD was much lower and not significant (RR 1.8; 95% CI 0.7 to 4.2). Adjustment for all chronic diseases and disease severity measures, including ankle-brachial index, forced expiratory volume, and exercise tolerance, did not change the results. CONCLUSIONS: IL-6 level is helpful in identifying a subgroup of older CVD patients with high risk of death over a period of 3 years. Systemic inflammation, as measured by IL-6, may be related to the clinical evolution of older patients with CVD.

Progressive versus catastrophic loss of the ability to walk: implications for the prevention of mobility loss.

OBJECTIVES: Loss of mobility is an important functional outcome that can have devastating effects on quality of life and the ability of older persons to remain independent in the community. Although a large amount of research has been done on risk factors for disability onset, little work has focused on the pace of disability progression. This study characterizes the development of severe walking disability over time and evaluates risk factors and subsequent mortality as they relate to mobility disability with progressive or catastrophic onset. DESIGN: Population-based prospective cohort study with annual follow-up assessments for up to 7 years SETTING: Three communities of the Established Populations for Epidemiologic Studies of the Elderly. PARTICIPANTS: There were 5,355 persons not disabled at baseline and the first follow-up who had adequate data available to classify mobility disability during subsequent follow-ups. MEASUREMENTS: Severe mobility disability was defined as the need for help from a person to walk across a room or inability to walk across a room. Those developing severe mobility disability were classified as having progressive mobility disability if they had been unable to walk half a mile in either of the prior 2 years. They were classified as having catastrophic mobility disability if they reported having been able to walk half a mile in two previous annual interviews. RESULTS: The overall incidence of severe mobility disability was 11.6 cases/1,000 person years. Those age 85 and older or having three or more chronic conditions at baseline were significantly more likely to develop progressive disability than catastrophic disability. Stroke, hip fracture, and cancer occurring during follow-up were associated with very high risk of severe mobility disability. For stroke and hip fracture, the risk was twice as high for catastrophic disability as for progressive disability, but this difference did not reach statistical significance. Risk for catastrophic disability from cancer was significantly greater than for progressive disability. Half of catastrophic disability subjects had stroke, hip fracture, or cancer in the year immediately preceding this disability. Incident heart attack did not predict severe mobility disability. Among those who developed severe mobility disability, type of disability did not influence subsequent survival for the first 3 years, but beyond 3 years those with catastrophic disability had a relative risk of death of 0.4 (95% confidence interval 0.2-0.9) compared with those with progressive disability. CONCLUSION: The observation that risk factors and mortality outcomes were both different for progressive and catastrophic mobility disability supports the value of ascertaining the pace of disability development as a useful characterization of disability. Further progress in developing prevention and treatment strategies may be made by taking the pace of disability development into account.

Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study.

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged > or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P < 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P < 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.

Molecular analysis of plant migration and refugia in the Arctic.

The arctic flora is thought to have originated during the late Tertiary, approximately 3 million years ago. Plant migration routes during colonization of the Arctic are currently unknown, and uncertainty remains over where arctic plants survived Pleistocene glaciations. A phylogenetic analysis of chloroplast DNA variation in the purple saxifrage (Saxifraga oppositifolia) indicates that this plant first occurred in the Arctic in western Beringia before it migrated east and west to achieve a circumpolar distribution. The geographical distribution of chloroplast DNA variation in the species supports the hypothesis that, during Pleistocene glaciations, some plant refugia were located in the Arctic as well as at more southern latitudes.

The ratio of older women to men: historical perspectives and cross-national comparisons.

In nearly all populations throughout the world there are substantially more older women than men. Although there are many biological explanations for why women have greater longevity than men, the higher proportion of women in the older population appears to be a phenomenon of the twentieth century. Using contemporary data on population size and life expectancy in a large number of countries and historical life table data from a diverse subset of countries, cross-national contrasts and historical trends in the female to male ratio are explored. In the 1990's, only 4 countries had fewer women than men in the age group 75 years and older. The number of women per 100 men aged 75+ in the remainder of the world's countries ranged from 100 to 355. In general, countries with a lower overall life expectancy had a lower number of women per 100 men aged 75+, while countries with higher overall life expectancy had a higher female to male ratio in this age group. A hundred years ago there were nearly equal numbers of women and men aged 75+ in many countries. In all countries studied, the female to male ratio increased as the century progressed. Historical life table data were used to calculate the probability of surviving through 5 stages of life: ages 0 to 5, 5 to 15, 15 to 40, 40 to 65, and 65 to 85. Although the probability of survival through all age intervals increased dramatically during the century, the current disparity in the size of the older populations of men and women can be explained primarily by the divergence in male and female probabilities of survival for the two older age intervals as the century progressed. Thus, with higher life expectancy, whether it be comparing countries or over time within a country, the proportion of the older population that is female is greater. Changes in survival probability in middle and late life, rather than childhood and young adulthood, have been responsible for the increased number of women compared to men in the older population.

Gender differences in disability: evidence and underlying reasons.

Women have greater longevity than men and represent a larger proportion of the expanding older population. Several health, disease, behavioral and sociodemographic factors contribute to the higher prevalence of disability in women compared to men. This paper presents a review of methodologic and epidemiologic considerations important to our understanding the gender differences in the prevalence of disability, and discusses underlying causes for these differences. Compared to men, women have a longer duration of life lived with disability, in part due to higher prevalence of non-fatal chronic conditions, constitutional factors such as lower muscle strength and lower bone density, and higher rates of life-style factors such as sedentary behavior and obesity. Several of these factors are modifiable, and provide important targets for researchers, clinicians, and public health practitioners in their efforts to reduce the burden of disability in the older population.

Alosetron.

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.

Ganirelix.

Ganirelix is a synthetic third generation gonadotropin-releasing hormone (GnRH) antagonist that is administered via the subcutaneous route. The drug competitively blocks GnRH receptors in the anterior pituitary gland, preventing endogenous GnRH from inducing luteinising hormone (LH) and follicle stimulating hormone release. Ganirelix effectively inhibited LH surges during controlled ovarian stimulation in a large, multicentre clinical trial in women undergoing in vitro fertilisation. A vital pregnancy rate per embryo transfer of 40.3% was achieved at weeks 5 to 6 after treatment with the 0.25 mg/day dosage. Subcutaneous ganirelix has been generally well tolerated in clinical trials. The most common adverse events were local injection site events, asthenia, nausea, malaise, headache and fatigue.

Moxifloxacin: a review of its clinical potential in the management of community-acquired respiratory tract infections.

UNLABELLED: Moxifloxacin is an extended-spectrum fluoroquinolone which has improved coverage against gram-positive cocci and atypical pathogens compared with older fluoroquinolone agents, while retaining good activity against gram-negative bacteria. The antibacterial spectrum of moxifloxacin includes all major upper and lower respiratory tract pathogens; it is one of the most active fluoroquinolones against pneumococci, including penicillin- and macrolide-resistant strains. In in vitro studies, emergence of bacterial resistance was less common with moxifloxacin than with some other fluoroquinolones, but this requires confirmation in large-scale clinical studies. As with other fluoroquinolones, moxifloxacin achieves good penetration into respiratory tissues and fluids. It shows a low potential for drug interactions and dosage adjustment is not required for patients of advanced age or those with renal or mild hepatic impairment. The efficacy of oral moxifloxacin has been demonstrated in large, well-designed clinical trials in patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Moxifloxacin 400 mg once daily achieved bacteriological and clinical success rates of approximately 90% or higher. It was as effective as, or more effective than, comparators including clarithromycin, cefuroxime axetil and high dose amoxicillin in these trials. The most commonly reported adverse events in patients receiving moxifloxacin are gastrointestinal disturbances. Moxifloxacin is also associated with QTc prolongation in some patients; there are, as yet, no data concerning the possible clinical sequelae of this effect in high-risk patients. Moxifloxacin has a low propensity for causing phototoxic reactions relative to other fluoroquinolones, and animal data suggest that it has a low potential for causing excitatory CNS and hepatotoxic effects. CONCLUSIONS: As an extended-spectrum fluoroquinolone, moxifloxacin offers the benefits of excellent activity against pneumococci, once daily administration and a low propensity for drug interactions. Although studies are needed regarding its tolerability in at-risk patients with QT interval prolongation, available data suggest that moxifloxacin is likely to become a first-line therapy option for the treatment of community-acquired lower respiratory tract infections, particularly in areas where drug-resistant S. pneumoniae or H. influenzae are common.

Gatifloxacin.

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 > or = 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 250 mg 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 400 g 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.

Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases.

UNLABELLED: Patients with beta-thalassaemia and other transfusion-dependent diseases develop iron overload from chronic blood transfusions and require regular iron chelation to prevent potentially fatal iron-related complications. The only iron chelator currently widely available is deferoxamine, which is expensive and requires prolonged subcutaneous infusion 3 to 7 times per week or daily intramuscular injections. Moreover, some patients are unable to tolerate deferoxamine and compliance with the drug is poor in many patients. Deferiprone is the most extensively studied oral iron chelator to date. Non-comparative clinical studies mostly in patients with beta-thalassaemia have demonstrated that deferiprone 75 to 100 mg/kg/day can reduce iron burden in regularly transfused iron-overloaded patients. Serum ferritin levels are generally reduced in patients with very high pretreatment levels and are frequently maintained within an acceptable range in those who are already adequately chelated. Deferiprone is not effective in all patients (some of whom show increases in serum ferritin and/or liver iron content, particularly during long term therapy). This may reflect factors such as suboptimal dosage and/or severe degree of iron overload at baseline in some instances. Although few long term comparative data are available, deferiprone at the recommended dosage of 75 mg/kg/day appears to be less effective than deferoxamine; however, compliance is superior with deferiprone, which may partly compensate for this. Deferiprone has additive, or possibly synergistic, effects on iron excretion when combined with deferoxamine. The optimum dosage and long term efficacy of deferiprone, and its effects on survival and progression of iron-related organ damage, remain to be established. The most important adverse effects in deferiprone-treated patients are arthropathy and neutropenia/agranulocytosis. Other adverse events include gastrointestinal disturbances, ALT elevation, development of antinuclear antibodies and zinc deficiency. With deferiprone, adverse effects occur mostly in heavily iron-loaded patients, whereas with deferoxamine adverse effects occur predominantly when body iron burden is lower. CONCLUSION: Deferiprone is the most promising oral iron chelator under development at present. Further studies are required to determine the best way to use this new drug. Although it appears to be less effective than deferoxamine at the recommended dosage and there are concerns regarding its tolerability, it may nevertheless offer a therapeutic alternative in the management of patients unable or unwilling to receive the latter drug. Deferipone also shows promise as an adjunct to deferoxamine therapy in patients with insufficient response and may prove useful as a maintenance treatment to interpose between treatments.

Rituximab.

Rituximab is a chimaeric monoclonal antibody which specifically binds to the CD20 antigen on normal and malignant B lymphocytes. It produces antibody-dependent cell- and complement-mediated cytotoxicity in these cells. Rituximab reduced peripheral B lymphocyte counts by approximately 90% within 3 days in patients with relapsed indolent lymphoma. Counts remained depleted for 6 months and recovered by months 9 to 12 after 4 doses of rituximab 375 mg/m2 once weekly. Clinical response rates were 46 and 48% in 2 non-comparative trials in patients with relapsed indolent lymphoma. The rate of response to rituximab appeared to be markedly higher in patients with follicular lymphoma than in those with small lymphocytic disease (56 or 60% versus 13 or 15%). 85 to 94% of patients reported adverse events during clinical trials of rituximab; 90% of events were mild or moderate. The most common adverse event, a transient set of flu-like symptoms during the first infusion in approximately 50 to 87% of patients, generally resolved completely in < 3 hours. Diphenhydramine and/or paracetamol was administered to some patients. In 10% of patients, the flu-like symptoms during the first infusion were accompanied by bronchospasm and/or hypotension or severe cytokine release syndrome. Patients were generally able to complete treatment after these symptoms revolved.

Rosiglitazone.

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 (HbA1c). Addition of rosiglitazone 2 to 8 mg/day to existing sulphonylurea, metformin or insulin therapy achieved further reductions in fasting plasma glucose and HbA1c. Oral combinations improved insulin sensitivity and beta-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.

Moxifloxacin.

Moxilloxacin 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 400 mg once daily achieved bacteriological and/or clinical success rates of approximately 90% or higher. Moxifloxacin was as effective as amoxicillin 1 g 3 times daily and clarithromycin 500 mg 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.

Fomivirsen.

Fomivirsen (ISIS 2922) is an antisense oligonucleotide which specifically inhibits replication of human cytomegalovirus. It achieves this by binding to complementary sequences on messenger RNA transcribed from the major immediate-early transcriptional unit of the virus. It is being developed for the treatment of cytomegalovirus retinitis. Mean maximum retinal concentrations of fomivirsen occurred approximately 2 days after a single intravitreal injection in monkeys. The elimination half-life of fomivirsen (after a single 115 microg dose) in monkey retina was 78 hours. Fomivirsen, administered as an intravitreal injection, significantly delayed progression of cytomegalovirus retinitis in patients with AIDS in preliminary clinical trials. In 18 patients with newly diagnosed, unilateral, peripheral cytomegalovirus retinitis treated with fomivirsen 165 microg once weekly for 3 weeks, then 165 microg every second week, the median time to disease progression was significantly longer than in 10 patients in whom fomivirsen treatment was deferred until early disease progression (71 vs 14 days). In patients with advanced, refractory, sight-threatening disease, treatment with fomivirsen 330 microg once weekly for 3 weeks and then 330 microg every 2 weeks (n = 34) or 330 microg on days 1 and 15 and then monthly (n = 20) significantly delayed disease progression. The interpolated median time to disease progression was 90 days in both treatment groups. The most common adverse events reported in clinical trials of fomivirsen were increased intraocular pressure and mild to moderate intraocular inflammation. These events were generally transient or reversible with topical steroid treatment.