The anti‐cocaine monoclonal antibody, h2E2, is a candidate for treating cocaine‐use disorder. h2E2 binds to and sequesters cocaine in the plasma compartment, effectively decreasing cocaine concentrations in the brains of rats and mice. Despite the binding of cocaine to h2E2, plasma cocaine concentrations decline rapidly in rodents over time, but there was a drastic decrease in the urinary elimination of cocaine in the presence of h2E2. Since cocaine is not being renally excreted, the apparent disappearance of cocaine from the plasma must be explained by either metabolism or distribution. However, binding of cocaine to h2E2 may restrict the availability of cocaine for hydrolysis by endogenous esterases. Therefore, the antibody would be expected to extend the elimination half‐life of cocaine. In contrast, previous studies reported h2E2 as having no effect on the rate of cocaine clearance. It is important to examine the ultimate clearance of the cocaine to ascertain its half‐life and potential for re‐intoxication. Therefore, we investigated the effects of h2E2 on cocaine hydrolysis in vitro and on cocaine metabolism and disposition in vivo over a 6‐h time course. The spontaneous and enzyme‐mediated in vitro hydrolysis of cocaine was drastically decreased in the presence of h2E2 in vitro. Additionally, in mice, h2E2 significantly increased the distribution and elimination half‐lives of cocaine relative to vehicle controls over an extended time course. Therefore, we concluded that h2E2 slowing the distribution and elimination of cocaine is the most appropriate explanation for the initial disappearance of cocaine from the plasma in vivo.

2017-09-02·Human vaccines & immunotherapeutics3区 · 医学

Tocilizumab (Actemra)

3区 · 医学

Review

作者: Hadavi, Shahryar ; Laskou, Faidra ; Sheppard, Martin ; Dasgupta, Bhaskar ; Stapleton, Philip P.

Tocilizumab (TCZ), is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ including looking into the past at the discovery of interleukin-6 (IL-6) as a pro-inflammatory cytokine. It also looks at how tocilizumab was developed, manufactured and tested to ensure both safety and efficacy in a human population. The article then explores the advantages and disadvantages of using TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and large vessel vasculitis (LVV).

2010-10-01·Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association2区 · 医学

Prospective study of TNF blockade with adalimumab in ANCA-associated systemic vasculitis with renal involvement

2区 · 医学

Article

作者: Giuseppe Conte ; Simona Laurino ; Afzal Chaudhry ; Anthony Booth ; David Jayne

BACKGROUND:

Tumour necrosis factor alpha (TNFα) is implicated in the pathogenesis of ANCA-associated systemic vasculitis (AASV). There is a need for more effective and safer induction therapies for AASV. Uncontrolled studies have pointed to the efficacy of TNFα blockade with infliximab in the induction of remission in systemic vasculitides. We have hypothesized that adjunctive treatment with the humanized anti-TNFα monoclonal antibody, adalimumab, will permit more rapid remission and reduced prednisolone exposure in AASV.

METHODS:

This Phase II, open-label, prospective study enrolled 14 patients with acute flares of AASV either as first manifestation of disease or relapse. The Birmingham Vasculitis Activity Score (BVAS) was used to assess the activity of the disease and the response to treatment. Adalimumab (40 mg s.c.) was given every 2 weeks for 3 months, in combination with intravenous cyclophosphamide and a reducing course of prednisolone. Primary endpoints were: (i) induction of remission within the first 14 weeks (BVAS = 0); (ii) time taken to achieve remission; (iii) safety and tolerability.

RESULTS:

Mean age was 58 years and eight patients were male; all had kidney involvement. Eleven (78.5%) achieved remission within 14 weeks (mean, 12 weeks). BVAS decreased from 11.9 (mean; 95% CI, 9.3-14.4) at baseline to 2.0 (mean; 95% CI, 0-4.4) at Week 14 (P < 0.01). Prednisolone dose (in milligrammes per day) decreased from 37.1 (mean; 95% CI, 28.8-45.3) at entry to 8.1 (mean; 95% CI, 5.1-11.1) at Week 14 (P < 0.01). Estimated glomerular filtration rate (in millilitres per minute per 1.73 m(2)) increased from 17.1 (mean; 95% CI, 8.9-25.2) at entry to 30.1 (mean; 95% CI, 18-42.2) at 12 weeks (P < 0.01). One patient died and three infections occurred.

CONCLUSIONS:

The addition of adalimumab to prednisolone and cyclophosphamide for the treatment of severe AASV was associated with response rates and adverse events similar to standard therapy alone but with a reduced prednisolone exposure. Further study is required to demonstrate whether the addition of adalimumab improves the speed of remission, the degree of renal recovery and safety.

100 项与重组人源化抗肿瘤坏死因子α单克隆抗体 (深圳万乐药业) 相关的药物交易

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