Cilostazol

Cilostazol

Cilostazol, is a antiplatelet drug that inhibits phosphodiesterase 3.

Application of cilostazol was reported to ameliorate vasospasm and improve outcomes in series and clinical trials. But the effectiveness and feasibility of cilostazol on aneurysmal subarachnoid hemorrhage remained controversial.


Kim et al. from the Asan Medical Center retrospectively analyzed the data of 427 patients with unruptured intracranial aneurysms who underwent endovascular treatment between July 2011 and June 2014. When clopidogrel resistance was confirmed via platelet reactivity unit (PRU) assay after dual antiplatelet therapy (aspirin plus clopidogrel) administration for 5 days, triple antiplatelet therapy with cilostazol was administered (Group I, 274 patients). The other group was placed on standard dual antiplatelet therapy (Group II, 153 patients). All patients underwent magnetic resonance diffusion-weighted imaging within 2 days after endovascular coiling.

No significant associations with the occurrence of a thromboembolic event and microembolic event were found between the groups. The occurrence of thromboembolic and microembolic events showed no statistical difference between groups I and II (p = 0.725 for thromboembolic events and p = 0.109 for microembolic events). Also, the PRU value and the occurrence of microembolic events, using a PRU cutoff value of 240, showed no statistical difference (p = 0.114 in group I and 0.064 in group II). There was significant increase in microembolic events after the use of a stent-assisted endovascular procedure. As the PRU value increased, there was a trend toward an increase in the mean number of microembolic lesions without statistical significance.

Even though there is a presumed anti-thromboembolic effect for clopidogrel resistance in other literature, the clinical efficacy of adjustment of additional cilostazol for endovascular coiling of unruptured aneurysms may be limited due to the unspecified cutoff value of the PRU assay for evaluating the resistance 1).

A total of 454 articles were identified using the search criteria. Six articles were selected for systematic review and the 4 randomized controlled trials were included in the meta-analysis. The pooled odds ratio for symptomatic vasospasm, new-onset infarct, and angiographic vasospasm was 0.35 (95% confidence interval [CI], 0.21-0.59; P < 0.0001), 0.38 (95% CI, 0.21-0.66; P = 0.0007) and 0.49 (95% CI, 0.31-0.80; P = 0.004), respectively. The pooled risk ratio for unfavorable outcome was 0.52 (95% CI, 0.37-0.74; P = 0.0003).

Cilostazol decreases the prevalence of symptomatic vasospasm, new-onset infarct, and angiographic vasospasm when administered after aSAH. Trial sequential analysis increased the precision of our results because the defined thresholds of effect were met by the available studies. However, further studies involving patients from other geographic areas are required to confirm the generalization of the results 2)

Shan et al., performed a systematic review to clarify this issue.

PubMed, Ovid and Cochrane library database were systematically searched up to May 2018 for eligible publications in English. Quality assessment was conducted for included studies. Meta-analysis was conducted to evaluate the overall effect on events of interest. Subgroup analyses and sensitivity analyses were used to check whether the results were robust. Publication bias was evaluated with the funnel plot.

Pooled analyses found cilostazol significantly reduced incidences of severe angiographic vasospasm (p = 0.0001), symptomatic vasospasm (p < 0.00001), new cerebral infarction (p < 0.00001) and the poor outcome (p < 0.0001). Subgroup and sensitivity analyses achieved consistent results. There was no statistical difference between cilostazol and the control group in reducing mortality (p = 0.07). But sensitivity analysis changed the result after excluding one study. Under the prescribed dosage, complication was few and non-lethal.

Cilostazol was effective and safe to reduce incidences of severe angiographic vasospasm, symptomatic vasospasm, new cerebral infarction and poor outcome in patients after aneurysmal subarachnoid hemorrhage. However, its effect on mortality and the interactive effect with nimodipine warranted further research 3).

Beneficial for patients with atherothrombosis. In contrast to other anti-platelet drugs such as aspirin and thienopyridines, little information is available on the relationship between platelet responses to cilostazol and clinical outcomes.

Ikeda et al. from the Ehime University Graduate School of Medicine in Japan, conducted a prospective study on patients with cerebral infarction who were treated with cilostazol. The platelet response to cilostazol was assessed with a new assay for the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) subsequent to the pharmacological action of cilostazol. Patients were followed up for 2 years and the relationship between VASP assay results and the recurrence of thrombotic events was examined. We also investigated the effects of CYP3A5 and CYP2C19 genotypes involved in the metabolism of cilostazol on the platelet response to cilostazol.

Among the 142 patients enrolled, 130 completed the 2-year follow-up and the recurrence of thrombotic events was noted in 8 (6.2%). VASP phosphorylation levels were significantly lower in patients with than in those without recurrence. The combined genotype of CYP3A51/3 and CYP2C191/1 was associated with a low level of VASP phosphorylation, while either genotype was not. A multivariate analysis showed that high residual platelet reactivity during the cilostazol treatment, which was defined by a low response of platelet VASP phosphorylation to cilostazol, was an independent risk factor for the recurrence of thrombotic events.

A low platelet response to cilostazol determined by a new platelet assay was associated with the recurrence of thrombotic events in patients with cerebral infarction 4).

established an experimental model using normal and diabetic rats at 12 months of age. The diabetic rats were assigned to 4 different diet groups, distinguished by whether they were fed plain rat feed, or the same feed supplemented by 1 of 3 antiplatelet drugs (cilostazol, aspirin, or clopidogrel: all 0.1%) for 2 weeks, and the carotid artery was perforated by an embolization coil (“carotid coil model”). We monitored the process by which vascular endothelial cells formed the new endothelium on the surface of the coil by sampling and evaluating the region at 1, 2, and 4 weeks after placement. This repair process was also compared among 3 groups treated with different antiplatelet drugs (i.e. aspirin, clopidogrel, and cilostazol). One-way analysis of variance tests were performed to evaluate the differences in vascular thickness between groups, and P < .05 was considered statistically significant.

Results: The diabetic rats showed delayed neoendothelialization and marked intimal hyperplasia. Cilostazol and clopidogrel effectively counteracted this delayed endothelial repair process. Flk1 immunostaining revealed greater expression in the diabetic rats administered cilostazol, second only to normal rats, suggesting that this agent acted to recruit EPCs.

Conclusion: Neoendothelialization is delayed when vascular endothelial cells fail to function normally, which consequently leads to the formation of hyperplastic tissue. Cilostazol may remedy this dysfunction by recruiting EPCs to the site of injury 5).


1)

Kim GJ, Heo Y, Moon EJ, Park W, Ahn JS, Lee DH, Park JC. Thromboembolic events during endovascular coiling for unruptured intracranial aneurysms: Clinical significance of platelet reactivity unit and adjunctive cilostazol. Clin Neurol Neurosurg. 2022 Jan 15;213:107133. doi: 10.1016/j.clineuro.2022.107133. Epub ahead of print. PMID: 35065532.
2)

Bohara S, Garg K, Singh Rajpal PM, Kasliwal M. Role of Cilostazol in Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage-A Systematic Review, Meta-Analysis, and Trial Sequential Analysis. World Neurosurg. 2021 Jun;150:161-170. doi: 10.1016/j.wneu.2021.02.069. Epub 2021 Feb 23. PMID: 33631387.
3)

Shan T, Zhang T, Qian W, Ma L, Li H, You C, Xie X. Effectiveness and feasibility of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurol. 2019 Feb 9. doi: 10.1007/s00415-019-09198-z. [Epub ahead of print] Review. PubMed PMID: 30739182.
4)

Ikeda Y, Yamanouchi J, Kumon Y, Yasukawa M, Hato T. Association of platelet response to cilostazol with clinical outcome and CYP genotype in patients with cerebral infarction. Thromb Res. 2018 Oct 10;172:14-20. doi: 10.1016/j.thromres.2018.10.003. [Epub ahead of print] PubMed PMID: 30342278.
5)

Fukawa N, Ueda T, Ogoshi T, Kitazawa Y, Takahashi J. Vascular Endothelial Repair and the Influence of Circulating Antiplatelet Drugs in a Carotid Coil Model. J Cent Nerv Syst Dis. 2021 May 20;13:11795735211011786. doi: 10.1177/11795735211011786. PMID: 34104032; PMCID: PMC8145582.

Somatostatin Analogs in Acromegaly

Somatostatin Analogs in Acromegaly

In vitro, native somatostatin retains its inhibitory effect on GH secretion in many GH-secreting tumors, and this led to the development of analogs of somatostatin for clinical use in the treatment of acromegaly 1).

The two analogs of somatostatin available for clinical use are the cyclic octapeptides octreotide (Dphe-cys-phe-Dtrp-lys-thr-cys-thr-ol) and lanreotide (Dnal-cys-tyr-Dtrp-lys-val-cys-thr) (1, 5–7). Octreotide is the only analog currently available for clinical use in the treatment of acromegaly in the United States.


Clinically available somatostatin analogs control GH or IGF-I excess in about 50–60% of patients whether used as primary or secondary therapy. Signs and symptoms of the disease improve in most patients. Tumor shrinkage occurs with somatostatin analogs used as adjunctive therapy in about 30% of patients and with their use as primary therapy in about 48% of patients. The shrinkage in most patients is greater than 20%, but less than 50% of tumor size 2).


Current data suggest that response to these drugs is better analyzed by taking together biochemical and tumoral effects because only the absence of both responses might be considered as a poor response or resistance. This latter evidence seems to occur in 25% of treated patients after 12 months of currently available long-acting SA 3).


Somatostatin analogues may be used when complete recovery cannot be achieved by surgical excision of GH-secreting pituitary adenomas or the patient declines surgery. This position statement is established based on the consensus of opinion among experts and evidence from published data regarding the use of somatostatin analogs in patients with acromegaly. However, this position statement cannot be considered as complete, given the clinical characteristics of acromegaly and the absence of large-scale clinical data in Korea; at this time, the clinical judgment of the physician should take precedence over this statement. This position statement will be revised as needed when additional data for Korean patients become available 4).


Shao et al. retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After Somatostatin Analogs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, the study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly 5).

Lanreotide for Acromegaly.

Octreotide for Acromegaly.


1)

Lamberts SW. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev. 1988 Nov;9(4):417-36. doi: 10.1210/edrv-9-4-417. PMID: 2905987.
2)

Freda PU. Somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2002 Jul;87(7):3013-8. doi: 10.1210/jcem.87.7.8665. PMID: 12107192.
3)

Colao A, Auriemma RS, Lombardi G, Pivonello R. Resistance to somatostatin analogs in acromegaly. Endocr Rev. 2011 Apr;32(2):247-71. doi: 10.1210/er.2010-0002. Epub 2010 Dec 1. PMID: 21123741.
4)

Chin SO, Ku CR, Kim BJ, Kim SW, Park KH, Song KH, Oh S, Yoon HK, Lee EJ, Lee JM, Lim JS, Kim JH, Kim KJ, Jin HY, Kim DJ, Lee KA, Moon SS, Lim DJ, Shin DY, Kim SH, Kwon MJ, Kim HY, Kim JH, Kim DS, Kim CH. Medical Treatment with Somatostatin Analogues in Acromegaly: Position Statement. Endocrinol Metab (Seoul). 2019 Mar;34(1):53-62. doi: 10.3803/EnM.2019.34.1.53. PMID: 30912339; PMCID: PMC6435847.
5)

Shao XQ, Chen ZY, Wang M, Yang YP, Yu YF, Liu WJ, Wang Y, Zeng FF, Gong W, Ye HY, Wang YF, Zhao Y, Zhang L, Zhang ZY, He M, Li YM. Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases. Horm Metab Res. 2022 Jan;54(1):25-32. doi: 10.1055/a-1717-9332. Epub 2022 Jan 5. PMID: 34986497.

Tirabrutinib

Tirabrutinib

Tirabrutinib (brand name Velexbru) is a drug used for the treatment of autoimmune diseases and hematological malignancies.

Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma.

In addition, tirabrutinib is in clinical development by Ono Pharmaceutical and Gilead Sciences in the United States, Europe, and Japan for autoimmune disorders, chronic lymphocytic leukemia, B cell lymphoma, Sjogren’s syndrome, pemphigus, and rheumatoid arthritis.

Tirabrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase.

The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).

Methods: Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II.

Results: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types.

Conclusion: These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL 1).

Yoshioka et al. reported that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient’s level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia 2)


A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646 3).


Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone 4).


1)

Narita Y, Nagane M, Mishima K, Terui Y, Arakawa Y, Yonezawa H, Asai K, Fukuhara N, Sugiyama K, Shinojima N, Kitagawa J, Aoi A, Nishikawa R. Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma. Neuro Oncol. 2021 Jan 30;23(1):122-133. doi: 10.1093/neuonc/noaa145. PMID: 32583848; PMCID: PMC7850159.
2)

Yoshioka H, Okuda T, Nakao T, Fujita M, Takahashi JC. Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma. Int Cancer Conf J. 2021 Jun 5;10(4):290-293. doi: 10.1007/s13691-021-00491-1. PMID: 34567940; PMCID: PMC8421486.
3)

Okita Y, Kano-Fujiwara R, Nakatsuka SI, Honma K, Kinoshita M. Histological verification of the treatment effect of tirabrutinib for relapsed/refractory primary central nervous system lymphoma. Exp Hematol Oncol. 2021 Apr 26;10(1):29. doi: 10.1186/s40164-021-00222-5. PMID: 33902692; PMCID: PMC8077707.
4)

Satow T, Horiguchi S, Komuro T. Recovery from coma of a patient having acute progression of primary central nervous system lymphoma using tirabrutinib and methylprednisolone. Neurooncol Adv. 2020 Nov 27;2(1):vdaa164. doi: 10.1093/noajnl/vdaa164. PMID: 33409497; PMCID: PMC7770517.
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