Biomedical subjects

David P Figgitt

Publications and source records attributed to David P Figgitt.

16 recordsLinked to original sources

PubMed2003

Memantine.

Memantine, an uncompetitive antagonist with moderate affinity for NMDA receptors, demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Memantine 20 mg/day significantly slowed the rate of deterioration in outpatients with moderate to severe Alzheimer's disease in a 28-week US randomised, double-blind, placebo-controlled, multicentre study. Memantine 10 mg/day improved measures of dementia in care-dependent inpatients with Alzheimer's disease or vascular dementia in a 12-week randomised, double-blind study. Significantly more memantine than placebo recipients were responders according to Clinical Global Impression of Change scores and the Behavioural Rating Scale for Geriatric Patients Care Dependence subscale. Memantine 20 mg/day significantly improved cognition-related outcomes (cognitive subscale of the Alzheimer's Disease Assessment Scale) in patients with vascular dementia in two 28-week randomised, double-blind, placebo-controlled, multicentre trials. No statistically significant between-group difference was seen in other primary endpoints. Adverse events (incidence in memantine recipients greater than in placebo recipients) occurring in patients with moderately severe to severe dementia included diarrhoea, insomnia, dizziness, headache and hallucination.

Alzheimer Disease↗

PubMed2003

Combined two-dose hepatitis A and B vaccine (AmBirix).

One month after the last dose (i.e. at month 7), geometric mean titres (GMTs) of antibodies directed against hepatitis A virus (anti-HAV) were generally greater in participants (aged 12-15 years) receiving combined two-dose (0 and 6 months) hepatitis A and B vaccine (AmBirix) compared with the three-dose (containing one half the dose of the two active components per dose, given at 0, 1 and 6 months; Twinrix Paediatric) schedule. Moreover, at month 7 all patients had seroconverted to anti-HAV. GMTs of antibodies directed against hepatitis B surface antigen greatly exceeded the threshold for seroprotection (>/=10 mIU/mL) 1 month after the last dose of vaccine. Seroprotection rates against hepatitis B virus (HBV) were similar 1 month after completion of either a two- (97.9%) or three-dose (100%) vaccination schedule. At 24 months' follow-up, all patients tested remained positive for anti-HAV, and 93.3% and 96.2% of those treated with the two- and three-dose schedules, respectively, remained above the threshold for seroprotection against HBV. Administering the second dose in the two-dose series at 12 months rather than at 6 months did not compromise the immune response to the combined vaccine in adolescents aged 12-15 years in a randomised, multicentre trial. Local adverse events reported in the 4 days following administration of combined two-dose hepatitis A and B vaccine include pain or soreness, redness and swelling; systemic symptoms included headache, fatigue, gastrointestinal events and fever.

Adolescent↗

PubMed2003

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months. Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)

Antibodies, Monoclonal↗

PubMed2003

Tipranavir.

Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.

Clinical Trials as Topic↗

PubMed2003

Topical 3% diclofenac in 2.5% hyaluronic acid gel: a review of its use in patients with actinic keratoses.

Topical 3% diclofenac in 2.5% hyaluronic acid (HA) gel (diclofenac HA gel; Solaraze) is an NSAID approved for the treatment of actinic keratoses (AK). The efficacy of diclofenac HA gel (0.5g applied twice daily to each 5cm x 5cm treatment area) in patients with AK has been evaluated in three randomized, double-blind, HA gel vehicle-controlled trials. In each trial, efficacy was assessed 30 days after the end of treatment because an earlier study revealed that resolution of lesions was greater when measured after a 4 week interval, rather than at the end of treatment. In two fully published multicenter trials, there was no difference in baseline characteristics of the study groups. In a further single center study (not yet published), patients randomized to diclofenac HA gel had a significantly higher mean number of target lesions at baseline compared with HA gel vehicle. In the two published studies, the efficacy of diclofenac HA gel increased with increased treatment duration. When compared with HA gel vehicle recipients, significant improvements in total lesion number scores (TLNS), cumulative lesion number scores (CLNS), patient global improvement indices (PGII) and investigator global improvement indices (IGII) were obtained in patients treated for 60 and 90 but not 30 days with diclofenac HA gel. Fifty percent of patients treated for 90 days with diclofenac HA gel (vs 20% in HA gel vehicle recipients) and 33% of those treated for 60 days (vs 10%) had TLNS and CLNS of zero at the end of follow-up. In the third trial, in which treatment was applied for 90 days, there was no statistically significant difference in the proportion of patients with TLNS or CLNS of zero at the end of follow-up. However, when controlling for the significant difference in mean baseline target lesion scores by calculating the mean change from baseline in lesion counts, TLNS and CLNS were significantly lower in recipients of diclofenac HA gel than HA gel vehicle at the end of follow-up. Pruritus was the most frequently reported adverse event in all trials and the incidence was generally similar or lower in patients treated with diclofenac HA gel than HA gel vehicle. In conclusion, diclofenac HA gel produces significant reductions in the number of AK lesions, and can produce complete clearance of lesions when applied twice daily for 60 or 90 days. The product is well tolerated and did not produce serious adverse cosmetic effects in clinical trials. Thus, diclofenac HA gel represents a useful addition to the array of pharmacologic treatments available for AK.

Administration, Topical↗

PubMed2002

Vardenafil.

Vardenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme which hydrolyses cyclic guanosine monophosphate in the cavernosum tissue of the penis. Inhibition of PDE5 results in increased arterial blood flow leading to enlargement of the corpus cavernosum. Because of the increased tumescence, veins are compressed between the corpus cavernosum and the tunica albuginea, resulting in an erection. Vardenafil has a high bioavailabilty and is rapidly absorbed. An erection of >60% rigidity was maintained for approximately twice as long following visual stimulation in patients treated with vardenafil 10 or 20mg than in recipients of placebo. In a large, placebo-controlled trial in patients with mild to severe erectile dysfunction (ED), vardenafil 5, 10 or 20mg taken as needed over a 12-week period significantly improved the scores in questions 3 and 4 of the International Index of Erectile Function (IIEF). The rate of successful attempts at intercourse with ejaculation was also significantly higher with vardenafil (71 to 75%) than in the placebo group (39.5%), and significantly more patients treated with vardenafil than placebo responded 'yes' to a Global Assessment Question (GAQ) asking if treatment had improved erections. In a 26-week trial in 736 men with ED of varied aetiologies and severity patients receiving vardenafil 5, 10 or 20mg experienced significantly improved erections with 85% of vardenafil 20mg recipients reporting improved erectile function (assessed using the GAQ) compared with 28% of placebo recipients. Treatment with vardenafil also significantly improved scores in response to questions 3 and 4 of the IIEF compared with placebo. A 12-week trial in 452 men with ED associated with diabetes mellitus demonstrated that treatment with vardenafil 20mg compared with placebo significantly improved IIEF erectile function domain scores and the rate of positive responders to the erectile improvement GAQ. Similar results were reported in a placebo-controlled trial of vardenafil 10 to 20mg involving 440 patients with ED after radical prostatectomy. Adverse events associated with vardenafil were those commonly associated with PDE5 inhibitors: headache, flushing, dyspepsia and rhinitis. These were mostly dose-dependent and mild to moderate in intensity.

Clinical Trials as Topic↗

PubMed2002

Almotriptan: a review of its use in migraine.

UNLABELLED: Almotriptan is a selective serotonin 5-HT(1B/1D) receptor agonist ('triptan'). Its efficacy and tolerability have been assessed in a number of randomised, controlled trials in over 4800 adults with moderate or severe attacks of migraine. Oral almotriptan has a rapid onset of action (significant headache relief is observed 0.5 hours after administration of a 12.5mg dose) and efficacy is sustained in most patients who respond by 2 hours. The drug is significantly more effective than placebo as measured by a number of parameters including 2-hour headache response and pain-free response rates. Other symptoms of migraine, including nausea, photophobia and phonophobia, are also alleviated by almotriptan. The efficacy of oral almotriptan appears to be maintained over repeated doses for multiple attacks of migraine treated over a long period (up to 1 year). High headache response rates were reported over all attacks without tachyphylaxis. For the relief of single attacks of migraine, oral almotriptan 12.5mg had similar efficacy to oral sumatriptan 50mg. Patients given almotriptan report less concern with adverse effects than patients given sumatriptan. The lower incidence of chest pain following treatment with almotriptan than with sumatriptan may lead to a reduction in direct costs, with fewer patients requiring management of chest pain. Almotriptan is well tolerated. Most adverse events were of mild or moderate intensity, transient, and generally resolved without intervention or the need for treatment withdrawal. The most common adverse events associated with oral almotriptan 12.5mg treatment were dizziness, paraesthesia, nausea, fatigue, headache, somnolence, skeletal pain, vomiting and chest symptoms. The incidence of adverse events did not differ from placebo and decreased in the longer term. Almotriptan can be coadministered with drugs that share a common hepatic metabolic path; in addition, dosage reduction is required only in the presence of severe renal or hepatic impairment. CONCLUSIONS: Almotriptan is an effective drug for the acute treatment of moderate or severe attacks of migraine in adults. An oral dose of almotriptan 12.5mg has shown greater efficacy than placebo; current data indicate that efficacy is similar to that of oral sumatriptan 50mg, and is maintained in the long term (<or=1 year). Almotriptan has a good adverse event profile and a generally similar overall tolerability profile to sumatriptan; of note, almotriptan is associated with a significantly lower incidence of chest pain than sumatriptan. However, further clinical experience is required to clearly define the place of almotriptan among the other currently available triptans. Nevertheless, because triptans have an important place in various management regimens, and because the nature of individual patient response to triptans is idiosyncratic, almotriptan is likely to become a useful treatment option in the management of adults with moderate or severe migraine headaches.

Animals↗

PubMed2002

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia.

UNLABELLED: Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles. Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient- assessed pain and patient-/physician-assessed global improvement ratings. In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a > or =20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%). Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. CONCLUSIONS: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.

Animals↗

PubMed2002

Ceftriaxone: an update of its use in the management of community-acquired and nosocomial infections.

UNLABELLED: Ceftriaxone is a parenteral third-generation cephalosporin with a long elimination half-life which permits once-daily administration. It has good activity against Streptococcus pneumoniae, methicillin-susceptible staphylococci, Haemophilus influenzae, Moraxella catarrhalis and Neisseria spp. Although active against Enterobacteriaceae, the recent spread of derepressed mutants which hyperproduce chromosomal beta-lactamases and extended-spectrum beta-lactamases has diminished the activity of all third-generation cephalosporins against these pathogens necessitating careful attention to sensitivity studies. Extensive data from randomised clinical trials confirm the efficacy of ceftriaxone in serious and difficult-to-treat community-acquired infections including meningitis, pneumonia and nonresponsive acute otitis media. Ceftriaxone also has efficacy in other community-acquired infections including uncomplicated gonorrhoea, acute pyelonephritis and various infections in children. In the nosocomial setting, extensive data also confirm the efficacy of ceftriaxone with or without an aminoglycoside in serious Gram-negative infections, pneumonia, spontaneous bacterial peritonitis and as surgical prophylaxis. Outpatient use of ceftriaxone, either as part of a step-down regimen or parenterally, is a distinguishing feature of the data gathered on the agent over the last decade. The review focuses on new applications of the drug and its use in infections in which the causative pathogens or their resistance patterns have changed over the past decade. Ceftriaxone has a good tolerability profile, the most common events being diarrhoea, nausea, vomiting, candidiasis and rash. Ceftriaxone may cause reversible biliary pseudolithiasis, notably at higher dosages of the drug (>/=2 g/day); however, the incidence of true lithiasis is <0.1%. Injection site discomfort or phlebitis can occur after intramuscular or intravenous administration. CONCLUSIONS: As a result of its strong activity against S. pneumoniae, ceftriaxone holds an important place, either alone or as part of a combination regimen, in the treatment of invasive pneumococcal infections, including those with reduced beta-lactam susceptibility. Its once-daily administration schedule allows simplification of otherwise complex regimens in a hospital setting and has also contributed to its popularity as a parenteral agent in an ambulatory setting. These properties, together with a well characterised tolerability profile, mean that ceftriaxone is likely to retain its place as an important third-generation cephalosporin in the treatment of serious community-acquired and nosocomial infections.

Animals↗

PubMed2002

ET-743.

ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.

Antineoplastic Agents, Alkylating↗

PubMed2002

Dexmethylphenidate.

Dexmethylphenidate comprises only the d-enantiomer (the pharmacologically effective isomer) of racemic methylphenidate and is indicated for the treatment of patients aged > or =6 years with attention deficit hyperactivity disorder (ADHD). In a 4-week, double-blind trial in 132 children with ADHD, significantly greater improvements from baseline in teacher-rated Swanson, Nolan and Pelham (SNAP)-ADHD scores were seen in dexmethylphenidate and methylphenidate recipients, compared with placebo recipients. In addition, significantly more dexmethylphenidate and methylphenidate recipients, compared with placebo recipients, were much improved or very much improved according to Clinical Global Impression-Improvement of Illness scale scores. In the same study, parent-rated SNAP-ADHD scores had decreased by a significantly greater extent in dexmethylphenidate recipients at 3pm and 6pm and in methylphenidate recipients at 3pm, compared with placebo recipients. Significantly fewer dexmethylphenidate than placebo recipients failed treatment in a double-blind, treatment-withdrawal trial in 75 children with ADHD (17.1 vs 61.5%). In a noncomparative study in 22 children with ADHD, symptoms of ADHD, as assessed by teachers and parents, were controlled during the entire school day in 68 and 86% of dexmethylphenidate recipients, respectively, with a median duration of effect of 6.3 and 7.5 hours, respectively. Dexmethylphenidate was generally well tolerated in children with ADHD; adverse events were consistent with those known to be associated with agents containing methylphenidate.

Absorption↗

PubMed2002

Levofloxacin: an updated review of its use in the treatment of bacterial infections.

UNLABELLED: Levofloxacin is the L-form of the fluoroquinolone antibacterial agent, ofloxacin. In in vitro studies, levofloxacin demonstrated a broad range of activity against Gram-positive and -negative organisms and anaerobes. The drug is more active against Gram-positive organisms than ciprofloxacin, but less active than newer fluoroquinolones such as gatifloxacin. Its activity against Streptococcus pneumoniae is unaffected by the presence of penicillin resistance. In several randomised controlled trails, 5 to 14 days' treatment with intravenous and/or oral levofloxacin proved an effective therapy for upper and lower respiratory tract infections. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once or twice daily was as effective as intravenous and/or oral gatifloxacin, clarithromycin, azithromycin or amoxicillin/clavulanic acid. Overall, clinical response rates with levofloxacin ranged from 86 to 95% versus 88 to 96% with comparator agents; bacteriological response rates were 88 to 95% and 86 to 98%, respectively. Sequential (intravenous +/- oral switch) therapy with levofloxacin 750mg once daily was as effective as intravenous imipenem/cilastatin (+/- oral switch to ciprofloxacin) in patients with severe nosocomial pneumonia. Generally, oral levofloxacin 250 or 500mg once daily was at least as effective as oral cefaclor, cefuroxime axetil, clarithromycin or moxifloxacin in patients with acute exacerbations of chronic bronchitis as assessed by either clinical or bacteriological response rates. This approach also provided similar efficacy to amoxicillin/ clavulanic acid or clarithromycin in patients with acute sinusitis. Sequential therapy with levofloxacin 500mg twice daily for 7 to 14 days' was as effective as intravenous imipenem/cilastatin in patients with suspected bacteraemia. Oral levofloxacin 500mg once daily for 7 to 10 days was also an effective treatment in patients with uncomplicated skin and skin structure infections, and in those with complicated urinary tract infections. A higher dosage of sequential levofloxacin 750mg once daily proved as effective as intravenous ticarcillin/clavulanic acid (+/- oral switch to amoxicillin/clavulanic acid) in the treatment of complicated skin and skin structure infections. Pharmacoeconomic studies suggest that levofloxacin may be cost-saving in comparison to conventional therapies. CONCLUSIONS: Levofloxacin continues to demonstrate good clinical efficacy in the treatment of a range of infections, including those in which S. pneumoniae is a potential pathogen. Importantly, it has efficacy in CAP similar to that of gatifloxacin and at least as good as that of the third generation cephalosporins. Extensive clinical data confirm the good tolerability profile of this agent without the phototoxicity, hepatic and cardiac events evident with some of the other newer fluoroquinolone agents. Levofloxacin therefore offers a unique combination of documented efficacy and tolerability, and provides an important option for the treatment of bacterial infections.

Bacterial Infections↗

PubMed2002

Bicalutamide: in early-stage prostate cancer.

Bicalutamide is an oral, once-daily nonsteroidal antiandrogen. Its efficacy in localised or locally advanced prostate cancer is currently being investigated as part of the Early Prostate Cancer (EPC) programme. In the EPC programme, bicalutamide 150 mg/day, as an adjunct to radiotherapy, radical prostatectomy or watchful waiting, significantly reduced the risk of objective disease progression, the incidence of bone metastases and the risk of prostate specific antigen progression compared with placebo (p < 0.0001 for all three parameters) after a median follow-up of 3 years. Survival data are currently immature, with an overall mortality rate of 6% in both treatment arms. On two nonblind, randomised trials, bicalutamide 150 mg/day monotherapy was as effective as medical or surgical castration in terms of overall survival in patients with locally advanced nonmetastatic prostate cancer. After a median follow-up of 6.3 years, median survival was 63.5 and 69.9 months for bicalutamide and castration, respectively; time to disease progression was also similar between treatment groups. Bicalutamide recipients reported a significantly smaller loss in sexual interest and a better physical capacity than recipients of castration (p <or= 0.05 for both parameters). Bicalutamide is well tolerated in studies of up to 6.3 years' duration.

Administration, Oral↗

PubMed2002

Spotlight on fluvoxamine in anxiety disorders in children and adolescents.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which may be used for the management of anxiety disorders in children and adolescents. Absorption of fluvoxamine was similar in adolescents to that in adults, which suggests that the maximum dosage of the drug for patients aged between 12 and 17 years can be as high as 300 mg/day. However, steady-state plasma fluvoxamine concentrations were 2 to 3 times higher in children (aged between 6 and 11 years) than in adolescents; thus, the maximum fluvoxamine dosage recommended for children is 200 mg/day. Fluvoxamine (50 to 300 mg/day) for 8 to 16 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) [measured across multiple assessment scales] compared with placebo in a well controlled trial in paediatric patients (n = 120) or from baseline in noncomparative trials in adolescent (n = 20) or paediatric (n = 16) patients. Improvements with fluvoxamine (up to 200 mg/day) were observed for up to 1 year in 98 patients with OCD in a noncomparative trial. The drug (up to 250 or 300 mg/day) also improved symptoms of anxiety compared with placebo in an 8-week well controlled trial in 128 paediatric patients with social phobia, separation anxiety disorder or generalised anxiety disorder (GAD). Fluvoxamine (50 to 300 mg/day) appears to be well tolerated in paediatric patients, with most adverse events with the drug (except abdominal discomfort, which occurred more often in patients receiving fluvoxamine) occurring with a similar incidence to those with placebo. The most common adverse events involved the CNS or gastrointestinal system. Most adverse events reported by paediatric patients with OCD were similar to those reported by adults. In conclusion, fluvoxamine is generally well tolerated and has demonstrated short-term efficacy compared with placebo in the treatment of OCD, and social phobia, separation anxiety disorder or GAD in well controlled trials in paediatric patients. Reductions in symptoms of anxiety with fluvoxamine have been observed for up to 1 year in children and adolescents with OCD. However, there are currently no comparative trials of fluvoxamine with other pharmacological agents. In the absence of such trials, current consensus opinion recommends that when pharmacotherapy is indicated, fluvoxamine, like other SSRIs, can be used as first-line treatment for anxiety disorders, particularly OCD, in paediatric patients. However, direct comparisons are required to assess the relative efficacy and tolerability of pharmacological agents in order to make firm recommendations for the treatment of anxiety disorders in this patient group.

Adolescent↗

PubMed2002

Spotlight on almotriptan in migraine.

UNLABELLED: Almotriptan is a selective serotonin 5-HT(1B/1D) receptor agonist ('triptan'). Its efficacy and tolerability have been assessed in a number of randomised, controlled trials in over 4800 adults with moderate or severe attacks of migraine. Oral almotriptan has a rapid onset of action (significant headache relief is observed 0.5 hours after administration of a 12.5mg dose) and efficacy is sustained in most patients who respond by 2 hours. The drug is significantly more effective than placebo as measured by a number of parameters including 2-hour headache response and pain-free response rates. Other symptoms of migraine, including nausea, photophobia and phonophobia, are also alleviated by almotriptan. The efficacy of oral almotriptan appears to be maintained over repeated doses for multiple attacks of migraine treated over a long period (up to 1 year). High headache response rates were reported over all attacks without tachyphylaxis. For the relief of single attacks of migraine, oral almotriptan 12.5mg had similar efficacy to oral sumatriptan 50mg. Patients given almotriptan report less concern with adverse effects than patients given sumatriptan. The lower incidence of chest pain following treatment with almotriptan than with sumatriptan may lead to a reduction in direct costs, with fewer patients requiring management of chest pain. Almotriptan is well tolerated. Most adverse events were of mild or moderate intensity, transient and generally resolved without intervention or the need for treatment withdrawal. The most common adverse events associated with oral almotriptan 12.5mg treatment were dizziness, paraesthesia, nausea, fatigue, headache, somnolence, skeletal pain, vomiting and chest symptoms. The incidence of adverse events did not differ from placebo and decreased in the longer term. Almotriptan can be coadministered with drugs that share a common hepatic metabolic path; in addition, dosage reduction is required only in the presence of severe renal or hepatic impairment. CONCLUSIONS: Almotriptan is an effective drug for the acute treatment of moderate or severe attacks of migraine in adults. An oral dose of almotriptan 12.5mg has shown greater efficacy than placebo; current data indicate that efficacy is similar to that of oral sumatriptan 50mg, and is maintained in the long term (< or = 1 year). Almotriptan has a good adverse event profile and a generally similar overall tolerability profile to sumatriptan; of note, almotriptan is associated with a significantly lower incidence of chest pain than sumatriptan. However, further clinical experience is required to clearly define the place of almotriptan among the other currently available triptans. Nevertheless, because triptans have an important place in various management regimens, and because the nature of individual patient response to triptans is idiosyncratic, almotriptan is likely to become a useful treatment option in the management of adults with moderate or severe migraine headaches.

Clinical Trials as Topic↗

PubMed2002

Zidovudine: a review of its use in the management of vertically-acquired pediatric HIV infection.

UNLABELLED: Zidovudine is a thymidine analog that, after intracellular phosphorylation to zidovudine triphosphate metabolite, inhibits HIV-specific reverse transcriptase and terminates proviral DNA. Zidovudine administered to mildly symptomatic women with HIV infection in the antepartum (100mg orally 5 times/day), intrapartum (2 mg/kg intravenously over 1 hour then 1 mg/kg/h) and then to the neonate for 6 weeks (2 mg/kg), significantly reduced the rate of vertical HIV transmission by about two thirds, in the absence of breast-feeding (The Pediatric AIDS Clinical Trials Group 076 trial, standard protocol). Shorter zidovudine regimens, reduced the risk of transmission of HIV by 50% in a non-breast-feeding population and by about 37% in breast-feeding populations. Zidovudine (standard protocol) in combination with lamivudine was superior to zidovudine alone. A short oral zidovudine regimen was not as effective as a two-dose oral nevirapine regime, although the combination of short-course zidovudine plus lamivudine was as effective. Suppression of viral replication in neonates, infants and children has been achieved with zidovudine when used in triple-therapy regimens that include other antiviral drugs. Results from a trial of treatment-naive children indicate that the antiviral efficacy of combinations of zidovudine and lamivudine or abacavir, given with the protease inhibitor nelfinavir, is superior to treatment with this combination minus nelfinavir. When zidovudine was used in other highly active antiretroviral therapy regimens significant improvements in surrogate markers were consistently seen. Changing to ritonavir-containing regimens was superior to changing to treatment with two new nucleoside reverse transcriptase inhibitors. Short- and long-term (up to 5.6 years) outcomes from clinical trials showed that prenatal and neonatal exposure to zidovudine was generally well tolerated with the exception of mild anemia that resolved spontaneously after treatment cessation. Zidovudine was generally well tolerated as monotherapy in clinical trials of pediatric patients with HIV infection, and adverse events were similar to those reported in adults, with anemia and neutropenia being the most common. CONCLUSION: Zidovudine, as monotherapy or in combination with other antiretroviral agents, remains a first-choice therapy for the prophylaxis of mother-to-child HIV transmission as shown by substantial reductions in transmission rates. Where feasible, the optimal strategy to prevent vertical transmission is to combine drug therapy with Cesarean section delivery and no breast-feeding. In addition, zidovudine in combination with another nucleoside analogue and a protease inhibitor is a first- or second-choice therapy for the treatment of pediatric HIV infection as significant and sustained reductions in viral load have been shown in both plasma and cerebrospinal fluid.

Adolescent↗