ABSTRACT
Upregulation of Toll-like receptor 2 (TLR2) plays a critical role in inflammation associated with ischemia/reperfusion-induced tissue damage. OPN-305 is the first humanized IgG4 monoclonal antibody against TLR2 in development and is intended for the prevention of reperfusion injury following renal transplantation and other indications. A phase I, single-center, prospective randomized, double-blind, placebo-controlled study was performed to evaluate single ascending doses of OPN-305 in 41 healthy male subjects (age range: 19-58 years) randomized to OPN-305 or placebo across six cohorts. OPN-305 was well tolerated across all doses, with no elevations in endogenous cytokines. A dose-proportional increase in maximum serum concentration (Cmax) was observed, with area under the curve increasing in a greater-than-dose-proportional manner with increasing elimination half-life. OPN-305 produced full TLR2 receptor blockade on CD14(+)CD45(+) cells (monocytes), from 14 (0.5 mg/kg) to >90 (10 mg/kg) days, with a linear effect on the duration of inhibition of interleukin-6 release after TLR2 stimulation.
Subject(s)
Antibodies, Monoclonal/pharmacology , Toll-Like Receptor 2/immunology , Adolescent , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Dose-Response Relationship, Immunologic , Double-Blind Method , Humans , Infusions, Intravenous , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Leukocyte Count , Male , Middle Aged , Young AdultABSTRACT
We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease (COPD). After a 2-wk run-in period, 780 patients with COPD were randomized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily, ipratropium bromide 40 microg four times daily, or placebo in a multicenter, double-blind, parallel-group study. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s (FEV(1)) measured over 12 h after 12 wk of treatment. Secondary variables included diary symptoms and quality of life. Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1) in comparison with placebo (all p < 0.001). Both doses of formoterol were also significantly superior to ipratropium (all p < 0.025). Compared with placebo, both doses of formoterol significantly improved symptoms (all p < or = 0.007) and quality of life (p < 0.01 for total scores) whereas ipratropium did not show significant effects (all p > or = 0.3). All study treatments exhibited a similar safety profile. We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD, as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive.
Subject(s)
Bronchodilator Agents/administration & dosage , Ethanolamines/administration & dosage , Ipratropium/administration & dosage , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Double-Blind Method , Female , Forced Expiratory Volume , Formoterol Fumarate , Humans , Male , Middle Aged , Powders , Pulmonary Disease, Chronic Obstructive/physiopathologyABSTRACT
A study of ganciclovir used on compassionate grounds in the treatment of severe cytomegalovirus disease in iatrogenically immunosuppressed and AIDS patients in Europe, commenced in June 1985. The results of 120 iatrogenically immunosuppressed patients treated between May 1986 and February 1988 are reported. Patients presented with systemic infection (58), pneumonia (58), retinitis (9) and infection of other organs (9). There was a favourable clinical response (as rated by the local physician) in 40 of 57 (70%) evaluable patients with systemic infection, 38/58 (65%) with pneumonia, 6/8 (75%) with retinitis, and 4/9 (44%) of those with CMV infection of other organs. Of particular note was the relatively high rate of short term survival (up to 12 days post therapy) in bone marrow transplant patients with CMV pneumonia, 10/19 (52%), compared to the 10% survival reported by Shepp et al., (1985). Adverse events were frequent (26%) and haematological effects necessitated discontinuation of treatment in 13/120 (11%) patients. The use of ganciclovir should be confined, therefore, to the treatment of severe cytomegalovirus disease.
Subject(s)
Acyclovir/analogs & derivatives , Antiviral Agents/therapeutic use , Cytomegalovirus Infections/drug therapy , Immunosuppression Therapy/adverse effects , Acyclovir/adverse effects , Acyclovir/therapeutic use , Antiviral Agents/adverse effects , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/mortality , Drug Therapy, Combination , Ganciclovir , Humans , Pneumonia, Viral/etiologyABSTRACT
The effect of different dosages of ganciclovir on proved cytomegalovirus chorioretinitis was tested in a randomized trial on 11 homosexual men with AIDS. The effect of 5 mg/kg/day was as good as 10 mg/kg/day. The lower dosage had less toxicity.
