药物的高剂量用法（一）

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一、氯丙嗪

氯丙嗪可用作yap抑制剂，治疗GOF型p53突变。

氯丙嗪在治疗精神疾病时，经常用远超说明书剂量的高剂量，下面是一个最高剂量达到每天2克的氯丙嗪的临床试验：

《Indications for high dose chlorpromazine therapy in chronic schizophrenia》

Describes a multihospital collaborative study involving over 800 chronic schizophrenics in which a high dose regimen of chlorpromazine (2000 mg/day) was compared with a low dose regimen (300 mg/day), a placebo, and physician's choice of treatment. Treatment followed a double-blind procedure for 24 wk. Results obtained were: (a) High dose response was related to age, length of current hospitalization, and the type of phenothiazine medication S was receiving just before the study. High dose was significantly more effective than the other treatments with Ss under 40 who had been hospitalized under 15 yr. and were receiving a nonpiperazine phenothiazine at pretreatment. High dose offered no great advantage over low dose and physician's choice among the other subgroups. (b) High dose was a particularly poor treatment for Ss over 40. These older Ss suffered a high incidence of severe side effects on the 2000-mg dose. (c) Among long-stay Ss, treatment failure on low dose and placebo was related to the dose of phenothiazine medication S was receiving just before the study. The higher the dose of prestudy medication, the greater the incidence of failure. (22 ref.) (PsycINFO Database Record (c) 2016 APA, all rights reserved)

二、替米沙坦

替米沙坦是已上市药物里与myc结合亲和力比较高的药物。

替米沙坦的说明书剂量“最大剂量为80mg，每日一次”

下面两个临床试验剂量达到了每天160毫克，一个达到了每天320毫克，耐受良好。

1、《High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-γ target genes in patients with the metabolic syndrome》

“ telmisartan 160 mg/d in 54 patients with the metabolic syndrome.”

2、《Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies》

“whereas in those administered 80 mg twice daily”

3、《Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients》

“ telmisartan 320 mg was administered orally once daily for 7 days to healthy young male subjects”

不过这个320毫克只吃了7天，不知道长期吃耐受如何。

这个临床试验里还有静脉注射替米沙坦160毫克的“ intravenous (10-160 mg) dose to young males”，这个应该比口服320毫克药效还要强。

三、缬沙坦

缬沙坦的说明剂量在每天80-160毫克，下面两个临床试验缬沙坦的剂量达到了每天320毫克和640毫克，耐受良好，治疗效果也比160毫克好。

1、《Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus》

Objective:Renin-angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients.

Patients and methods:Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20-700 microg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria.

Results:Comparable albuminuria reductions occurred in all groups at week 4 (P<0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P<0.001) versus a modest additional change with 160 mg (P=0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P<0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia.

Conclusion:High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.

2、《Effectiveness and safety of high-dose valsartan monotherapy in hypertension treatment: the ValTop study》

Early combination therapy is increasingly recommended in hypertension management because of increased risk of adverse effects with high-dose monotherapy. However, this risk is not necessarily increased for high doses of angiotensin receptor blockers (ARB). ValTop study compared efficacy and safety of high vs. conventional dose of valsartan in hypertensive patients. ValTop was a controlled, randomized, double-blind trial. Of 6035 screened subjects, 4004 mild-to-moderate hypertensive patients (mean seated diastolic blood pressure (MSDBP) 90-109 mm Hg) started 4-week open-label treatment with valsartan 160 mg. Of them, 3776 were randomized to receive valsartan 160 mg (N=1900) or 320 mg (N=1876) o.d. for 4 weeks. In 28-week open-label extension study, all participating patients (N=642) received valsartan 320 mg. Valsartan 160 mg reduced MSDBP by 10.0 mm Hg in the initial open-label phase. Further BP reductions in the double-blind phase were significantly (P<0.0001) greater in the 320 mg group than in the 160 mg group for MSDBP (1.6 ± 0.18 mm Hg vs. 0.5 ± 0.18 mm Hg) and mean seated systolic BP (3.3 ± 0.31 mm Hg vs. 0.7 ± 0.31 mm Hg). The size of the additional effect of the 320 mg dose on BP was similar in subjects controlled or not by the initial 160 mg dose. Adverse event (AE) rates were similar in both treatment groups, drug-related AEs occurring in <5% of subjects in each phase. High-dose valsartan is safe and effective in uncomplicated mild-to-moderate hypertension independently of the initial response to a moderate dose. High-dose ARB monotherapy may thus be a viable option in hypertension management.

四、艾曲波帕

艾曲波帕是已上市药物里与β-catenin 结合亲和力比较高的药物。艾曲波帕的说明书剂量是每天不超过75毫克。

下面两个临床试验艾曲波帕的剂量达到了每天200和300毫克。

1、《Phase Ib study of eltrombopag and azacitidine in patients with high-risk myelodysplastic syndromes and related disorders (the ELASTIC study)》

Treating adverse risk myelodysplastic syndromes with azacitidine exacerbates thrombocytopenia. We report a study of eltrombopag in combination with azacitidine using a 3 + 3 cohort design. Patients with baseline platelets of <150 × 109/l received eltrombopag ranging from 25 to 300 mg. An 8-day pre-phase of eltrombopag was followed by two cycles of combined therapy. Amongst 31 patients, there were no dose-limiting toxicities. The maximum tolerated dose (MTD) was 300 mg. Transient increases in bone marrow blasts at day 8 were common but no patient had protocol-defined progression following eltrombopag monotherapy. Marrow response rates after three and six treatment cycles were 32% and 29% respectively. In all, 70% of patients treated below and 36% treated at the MTD achieved a modified International Working Group 2006 platelet response at the end of cycle two. Of the platelet transfusion independent patients at baseline, 67% treated at the MTD became transfusion dependent during the first two cycles of treatment. Apart from lack of disease progression, our findings concur with a previously reported Phase III study (A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine [SUPPORT]). We conclude that eltrombopag/azacitidine is safe in terms of conventional measures defined by adverse-event reporting. However, in light of SUPPORT and our own descriptive findings regarding efficacy, further combination studies in high-risk disease should be considered with caution.

2、《A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine - PubMed》

Objectives: Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

Patients and methods: Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 10(9) /L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

Results: Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

Conclusion: The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

五、阿那曲唑

阿那曲唑跟her2的结合亲和力 ΔGbind (−9.65 kcal/mol)，跟her2靶向药拉帕替尼 (−10.65 kcal/mol) 差距不大。

以入脑好而著称的her2靶向药图卡替尼分子量是480.52，阿那曲唑分子量很小只有 293.37。因此her2型脑转移患者可以考虑用阿那曲唑。

阿那曲唑的说明书剂量是每天1毫克。

下面的临床试验阿那曲唑用到了每天10毫克，没有3-5级毒性，耐受良好。

《Anastrozole Dose Escalation for Optimal Estrogen Suppression in Postmenopausal Early-Stage Breast Cancer: A Prospective Trial》

Of the 33 patients who began the ANA10 cycle, 25 patients were adherent (reported taking ANA10 for 45–84 days) and underwent post-ANA10 E1 and E2 testing. One patient returned unopened medication and declined to continue on the study, and seven patients discontinued ANA10 early because of toxicity (one patient experienced grade 2 urinary tract infection and one patient experienced grade 2 breast and abdominal pain with grade 1 vaginal hemorrhage and palpitations) and patient decision (five patients) as per Fig. 1. Toxicities regardless of attribution for all 32 patients who began ANA10 are reported in Table 2. No severe (Common Terminology Criteria for AE grade 3–5) toxicities were reported.

[基础知识] 药物的高剂量用法（一）

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