Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti-tumour necrosis factor agents: subanalysis of BELIEVE.

BACKGROUND: Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti-TNFs) is likely to improve psoriasis in patients with prior anti-TNF treatment. OBJECTIVE: The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti-TNF treatment. METHODS: The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16-week, double-blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1-15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti-TNFs. RESULTS: Of 730 patients enrolled, 282 (38.6%) had prior anti-TNFs and 448 (61.4%) were anti-TNF-naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti-TNFs achieved PASI 75 at week 16, compared with 71.7% of anti-TNF-naïve patients (P=0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti-TNF agent had been used, the number of prior anti-TNFs tried, or reasons for discontinuation of prior anti-TNF therapy. Adverse event incidences were similar between patients with and without prior anti-TNF therapy. CONCLUSION: Adalimumab was effective and well-tolerated in patients with psoriasis previously treated with anti-TNF therapy.

A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study.

BACKGROUND: Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. OBJECTIVES: To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. METHODS: A 16-week, randomized, vehicle-controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1-15) in addition to either topical C/B or drug-free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. RESULTS: A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14.8% for ADA + C/B vs. 5.8% for ADA + vehicle at week 2 (P < 0.001); and 40.7% vs. 32.4%, respectively, at week 4 (P = 0.021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64.8% for ADA + C/B vs. 70.9% for ADA monotherapy, P = 0.086). Safety findings were consistent with previous ADA trials. CONCLUSIONS: ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.

Thyroid cancer: incidence, mortality and histological pattern in Denmark.

In Denmark, as in many other countries, the incidence of thyroid cancer is increasing, while mortality from this disease is decreasing. The proportionate distribution of cell types is similar to that seen elsewhere. The increase in incidence in other countries has been attributed to the increased use of radiation for benign conditions of the head and neck. This cannot explain the increase in incidence in Denmark, and other factors may contribute importantly to the changing picture of thyroid cancer.

Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers.

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assessed by anti-Xa and anti-IIa activity was studied in a two-way crossover trial. In this trial, 30 healthy volunteers received a single 175 IU/kg subcutaneous administration of tinzaparin containing approximately 3.5% of the < 2000 Da fraction and a tinzaparin-like LMWH containing 18.3% of the < 2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparable at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-Xa activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzaparin injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (< 18% for both anti-Xa and anti-IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained with tinzaparin. Based on average equivalence criteria, the two LMWH preparations were determined to be bioequivalent using either anti-Xa or anti-IIa activity as biomarkers. The calculated intrasubject variabilities were low (< 14% for anti-Xa activity and < 18% for anti-IIa activity) yielding little evidence for a significant Subject x Formulation interaction. In summary, anti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent with targeted therapeutic levels derived from previous trials in adult DVT patients. Weight-based dosing for the treatment of DVT appears rational based on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Furthermore, differences in the percentage of molecules in the < 2000 Da molecular weight fraction of tinzaparin do not translate into differences in anti-Xa and anti-IIa activity in vivo.

Pharmacodynamics of intravenous and subcutaneous tinzaparin and heparin in healthy volunteers.

The pharmacodynamics of i.v. and subcutaneous (s.c.) tinzaparin sodium compared with heparin in healthy volunteers were studied. A randomized, open-label, five-treatment, five-period-crossover study with a Latin square design was performed in 30 healthy men to estimate tinzaparin pharmacodynamics (anti-Xa and anti-IIa activities) after single-dose i.v. and s.c. administration, to evaluate absolute bioavailability, to determine the effect of a preservative (benzyl alcohol), to evaluate the dose-activity relationship, and to compare tinzaparin with unfractionated heparin. Treatments were (1) heparin 5,000 units s.c., (2) tinzaparin 4,500 anti-Xa IU without preservative s.c., (3) tinzaparin 4,500 anti-Xa IU without preservative i.v., (4) tinzaparin 12,250 anti-Xa IU with preservative s.c., and (5) tinzaparin 4,500 anti-Xa IU with preservative s.c. Blood samples for the measurement of anti-Xa and anti-IIa activities were drawn over 24 hours. Anti-Xa and anti-IIa activities were determined by chromogenic methods; data were analyzed by using a noncompartmental approach. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr. The volume of distribution was 3.1-5.0 L, suggesting that the molecular entities responsible for anti-Xa and anti-IIa activities are confined to the intravascular space. Mean peak anti-Xa activity occurred three to four hours after s.c. injection, independent of the dose. The mean half-life of anti-Xa activity after s.c. injection ranged from 3.41 to 4.13 hours and was independent of the dose. The mean absolute bioavailability of s.c. tinzaparin was 86.7%. Intersubject pharmacodynamic variability was low for tinzaparin compared with heparin. Benzyl alcohol did not affect tinzaparin pharmacodynamics. A clear dose-activity relationship was seen for the two fixed doses of tinzaparin (12,250 and 4,500 IU). Single doses of tinzaparin were safe and well tolerated after administration by either route. The anti-Xa profile of tinzaparin supports the pharmacodynamic superiority of low-molecular-weight heparins over standard i.v. heparin administration. This pharmacodynamic study in healthy volunteers indicates that s.c. tinzaparin sodium was well absorbed; the presence of a preservative, benzyl alcohol, did not affect the activity of tinzaparin; and tinzaparin activity is dose-related.

[Multiple primary cancer. Presence of more than 4 primary cancers]. / Multipel primaer cancer. Forekomst af flere end 4 primaere kancere.

The presence of more than four primary malignant tumours in a single patient was investigated in the Danish Cancer Registry. Four patients with five primary malignancies and one patient with six primary malignancies were found. All of the tumours were verified histologically and there was convincing evidence that none of the tumours were secondaries. In some of the cases, clustering of tobacco-associated cancers was observed. The anticipated number of cases with more than four primary malignancies was computed and it was found that less than one case would be anticipated. It is concluded that some cancer patients have an increased risk of developing a new primary malignancy.

Aetiological parallel between anal cancer and cervical cancer.

It has been postulated that an infectious agent and/or specific sexual behaviour is involved in the aetiology of anal cancer, in analogy with the aetiology established for cancer of the cervix. A case-control study of 29,648 women with cancers registered in the Danish Cancer Registry during 1968-87 tested the hypothesis that anal cancer patients were more likely than patients with colon, stomach, or vulva cancer to have had a previous diagnosis of cervical intraepithelial neoplasia (CIN) or invasive cervical cancer. The odds ratio of CIN, adjusted for age and year of diagnosis, for anal vs colon cancer was 5.2 (95% confidence interval [CI] 3.3-8.3), that for anal vs stomach cancer 3.6 (2.1-6.0), and that for anal vs vulva cancer 1.6 (0.9-2.9). The median time from diagnosis of CIN to diagnosis of the registered cancer was 151 months for anal, 112 months for vulva, 114 months for colon, and 126 months for stomach cancer. The association with previous invasive cervical cancer was also investigated; no patient with cervical cancer in this second analysis had been included in the CIN analysis. The odds ratios were similar. In addition, anal cancer patients were significantly more likely to have had cervical cancer than were patients with vulva cancer (odds ratio 1.8 [1.0-3.9]). The strong association between anal cancer and CIN/invasive cervical cancer suggests that these cancers share common risk factors. The association is at least as strong as that between cervical and vulva cancer.

Cancer of the lung and urinary bladder in Denmark, 1943-87: a cohort analysis.

National data from 1943 to 1987 on the two most frequent tobacco-related cancers in Denmark, lung and bladder cancer, were analyzed with multiplicative Poisson models. The temporal trends in the cohort-specific risks for both sites and sexes were similar: the risks increased in the beginning of the period covered by the analysis, but then levelled off; and there was no increase among cohorts born after circa 1930. Women experienced a smaller increase during the period covered by the analysis in the cohort-specific risk for bladder cancer than men (3.7 cf 6.1 times), whereas the overall increase in lung-cancer cohort-specific risk was the same for both sexes. The difference could not be explained by trends in tobacco consumption, types of tobacco consumed, or occupational exposures. On the basis of these findings, it is suggested that women may be less susceptible than men to developing bladder cancer from tobacco smoking.