Analysis of Clinical Efficacy and Adverse Effects of β-Blocking Agents Used Clinically for Chronic Heart Failure

Abstract

Clinical efficacy and adverse effects of the β-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the β₁ and β₂ receptors (Фss^β₁ and Фss^β₂) by these drugs. Thereafter, we examined the relationship between Фss^β₁ values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Фss^β₁ value than the others. Therefore, we constructed a model under the assumption that β-blocking agents exert both indirect action of LVEF increase through the β₁ receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of β-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper β-blocking agent and its administration at a reasonable dose for successful heart failure therapy.

Chronic heart failure is a pathological condition in which sufficient cardiac output cannot be maintained due to cardiac contractile dysfunction caused by myocardial failure, which produces hemostasis in the lungs and/or systemic venous system, resulting in impairment of daily life.^1,2) Cardiac contractile function regulates ejection of blood, required by peripheral organs, from the left ventricle to aorta, with left ventricular ejection fraction (LVEF) generally employed as its parameter. Cardiac contractile dysfunction is considered to be present when LVEF falls below 40–50% of that in healthy adults.^2,3) Moreover, in clinical trials of drugs given to treat heart failure, LVEF increase is used as a parameter to indicate efficacy.

For chronic heart failure therapy, angiotensin-converting enzyme inhibitors, angiotensin 2-receptor antagonists, and β-blocking agents are used.²⁾ Although β-blocking agents were previously contraindicated for conventional treatment, because they inhibit cardiac function, their usefulness for chronic heart failure caused by dilated cardiomyopathy, such as mortality decline and improvement of heart failure, was reported in large-scale clinical trials performed in the 1990s. Thus, β-blocking agents are now utilized with positive results.^4,5) Treatment with one of these agents for chronic heart failure is likely to aggravate heart failure symptoms when a maintenance dose is given from the start of administration. Accordingly, the standard administration method calls for starting with a minimal dose that is one-eighth (0.125%) that of the maximum maintenance dose, with doubling of the dose every 1–2 weeks or longer and setting the final dosage for continued therapy after more than 4 weeks.^6,7) In such cases, heart rate decrease and bronchoconstriction are adverse effects that should be monitored. In the present study, we performed a theoretical analysis of the efficacy and adverse effects of β-blocking agents used clinically for chronic heart failure for a quantitative comparative evaluation.

MATERIALS AND METHODS

Table 1 shows the initial dose as well as minimum and maximum maintenance doses of oral β-blocking agents presented in the package inserts. Since metoprolol was not approved for treatment of chronic heart failure in Japan at present, the doses were set based on the guidelines and the clinical trial method of other two drugs.^2,6,7)

Table 1. Oral β-Blocking Agents Used Clinically for Chronic Heart Failure^2,6,7)

Drug	Initial dose (mg/d)	Maintenance dose (mg/d)		Dose ratio (initial/maximum)
		Minimum	Maximum
Carvedilol	2.5	5	20	0.125
Bisoprolol fumarate	0.625	1.25	5	0.125
Metoprolol tartrate	15	30	120	0.125

In the present study, we compared three different β-blocking agents; carvedilol, bisoprolol, and metoprolol, and their dosages.

Collection of Pharmacokinetic and Pharmacodynamic Parameters

Pharmacokinetic and pharmacodynamic parameters necessary for the present analysis were extracted from the package insert of each agent, as well as from data used for pharmaceutical product approval applications and past reports in Japanese. The parameters obtained were plasma unbound fraction (fu), area under the plasma concentration time curve (AUC_0–∞), and dissociation constant for the β₁ and β₂ receptor (K_d).

Calculation of the Average Occupancy of Target Molecules at Time of Repeated Administration of Each Agent

On the basis of the obtained data, the steady-state average β₁ and β₂ receptor occupancy (Фss^β₁ and Фss^β₂, respectively) (%) at the time of repeated administration at the doses shown in Table 1 was calculated by using Eqs. 1 and 2.   

(1)

  

(2)

Where Фss^β₁ and Фss^β₂ are the average values for β₁ and β₂ receptor occupancies (%), and K_d^β₁ and K_d^β₂ the dissociation constant (nM) values for the β₁ and β₂ receptor. Css^f is the steady-state plasma unbound concentration (nM) calculated by using fu and AUC_0–∞ at the time of a single administration, and the speculated drug concentration near the receptor. Dose proportionality was confirmed for using the AUC_0–∞ of each agent. Moreover, though the active metabolite was confirmed for each agent, it was excluded from analysis as that has been reported to not contribute to efficacy.^6–8)

Relationship between Average β₁ Receptor Occupancy and Clinical Efficacy

In clinical trials of drugs given to treat heart failure, LVEF increase is used as a parameter to indicate efficacy. Thus, the rate of LVEF increase was calculated as a parameter of clinical efficacy, in which the difference between LVEF at the time of β-blocking agent administration at the maintenance dose and the level before starting administration was divided by that before the start of administration and expressed as a percentage.^9–13) For actual LVEF values, the LVEF values of patients with New York Heart Association (NYHA) Functional Classification grade II or III chronic heart failure were obtained from clinical trial results.

We initially examined the relationship between the calculated Фss^β₁ value and LVEF increase rate by assuming that the LVEF-improving effect of a β-blocking agent is obtained by β₁ receptor blocking on the myocardial cell membrane. When no favorable relationship was observed between them, we speculated that there might be a mechanism that functions directly act on ryanodine receptor 2 in addition to action via the β₁ receptor in the LVEF-improving effect of β-blocking agents, as a study of carvedilol reported that its direct action on ryanodine receptor 2 on the sarcoplasmic reticulum membrane was partly involved in clinical efficacy.¹⁴⁾ The rate of LVEF increase by administration of β-blocking agents was then analyzed using Eq. 3 in which an additive effect was attained by β₁ receptor and ryanodine receptor 2.   

(3)

Where E_max^β₁ is the maximum efficacy obtained through the β₁ receptor, Фss^β₁ the steady-state average for β₁ receptor occupancy (%), E_max^Ry the maximum efficacy obtained by direct action of the agent on ryanodine receptor 2, Iss^Ry the steady-state average inhibition rate (%) of Ca²⁺ release from the sarcoplasmic reticulum mediated by ryanodine receptor 2, K_d^β₁ the dissociation constant (nM) for the β₁ receptor, and K_d^Ry the dissociation constant (nM) for ryanodine receptor 2 (carvedilol: K_d^Ry-Car, bisoprolol: K_d^Ry-Bis, metoprolol: K_d^Ry-Met). Equation 3 was simultaneously applied using a nonlinear least squares method to the actual value for each agent obtained by E_max^β₁, E_max^Ry, and K_d^Ry. For data analysis, the MLAB software program (Civilized Software Inc.) was used.

Relationship between β-Blocking Agent Dose and Clinical Efficacy

Based on the results of analysis obtained in “Relationship between Average β₁ Receptor Occupancy and Clinical Efficacy” above, simulated clinical efficacy at the doses shown in Table 1 was examined.

Relationship between β-Blocking Agent Dose and Adverse Effects

By using Eqs. 4 and 5 based on the ternary complex model previously reported by us, the rate of average decrease in heart rate (▲HR), which is a cardiovascular adverse effect, was predicted by using Фss^β₁ and the rate of average decrease in forced expiratory volume in 1 s (▲FEV₁), which is a respiratory adverse effect, was predicted by using Фss^β₂. These equations show nonlinear growth graph. In addition, their relationship with dose was evaluated.¹⁵⁾   

(4)

  

(5)

RESULTS

Collection of Pharmacokinetic and Pharmacodynamic Parameters

The pharmacokinetic and pharmacodynamic parameters of each agent are shown in Table 2.^{6–8,16–21)} For K_d, the values reported by Baker, who examined the three agents simultaneously, were used.²¹⁾

Table 2. Pharmacokinetic and Pharmacodynamic Data for β-Blocking Agents Used Clinically for Chronic Heart Failure^{6–8,16–21)}

Drug	Plasma unbound fraction	Area under the plasma concentration time curve per dose (ng·h/mL/mg)	Kd (nM)
			β1	β2
Carvedilol	0.0485a)	4.49b)	1.78	0.4
Bisoprolol	0.705a)	82.6	14.8	199.5
Metoprolol	0.885	6.05	56.0	128.8

a) Value in serum. b) Range from 0 to 36 h.

Calculation of Average Occupancy of Target Molecule at Time of Repeated Administration of Each Agent

The steady-state plasma concentration (Css), and average β₁ and β₂ receptor occupancies (Фss^β₁ and Фss^β₂, respectively) at the time of repeated administration at the initial dose, as well as the minimum and maximum maintenance doses were calculated, with the results shown in Table 3.

Table 3. Average Unbound Plasma Concentrations (Css^f), Average β₁ and β₂ Receptor Occupancies (Φss^β₁, Φss^β₂) after Administration of Initial, Minimum Maintenance and Maximum Maintenance Dose of Three β-Blocking Agents Used Clinically for Chronic Heart Failure

Drug	Cssf (nM)			Φssβ1 (%)			Φssβ2 (%)
	Initial	Minimum	Maximum	Initial	Minimum	Maximum	Initial	Minimum	Maximum
Carvedilol	0.21	0.41	1.6	10.4	18.8	48.1	34.1	50.8	80.5
Bisoprolol	4.7	9.3	37.3	24.0	38.7	71.6	2.3	4.5	15.7
Metoprolol	25.0	50.1	200.3	30.9	47.2	78.2	16.3	28.0	60.9

For Фss^β₁, bisoprolol and metoprolol showed similar levels (initial dose: 24.0 and 30.9%, minimum maintenance dose: 38.7 and 47.2%, maximum maintenance dose: 71.6 and 78.2%, respectively), whereas carvedilol showed lower levels (10.4, 18.8, 48.1%, respectively). As for Фss^β₂, the levels varied due to the differences of cardio selectivity of each agent. The level was greatest for carvedilol, followed in order by metoprolol and bisoprolol.

Relationship between Average β₁ Receptor Occupancy and Clinical Efficacy

The rates of LVEF increase at a variety of doses of each agent and Фss^β₁ were calculated, with their relationship shown in Fig. 1.^6,9–13)

Fig. 1. Relationship between Average β₁ Receptor Occupancy (Φss^β₁) and Clinical Efficacy (LVEF Increase Rate) of β-Blocking Agents Used Clinically for Chronic Heart Failure

Closed symbols actual values.^6,9–13)

For bisoprolol and carvedilol, the same relationship was noted between Фss^β₁ and LVEF increase rate. Meanwhile for carvedilol, our findings suggested that clinical efficacy was exerted with a lower Фss^β₁ value as compared to the other agents, demonstrating a different aspect of this drug. Accordingly, the actual value for each agent was applied simultaneously to Eq. 3, which takes into consideration the contribution of ryanodine receptor 2 for its analysis. Those results are shown in Fig. 2.^6,9–13)

Fig. 2. Fitted Lines Based on Relationship between β₁ Receptor Occupancy and Clinical Efficacy (LVEF Increase Rate) of β-Blocking Agents Used Clinically for Chronic Heart Failure

Black line: Carvedilol, gray line: Bisoprolol, gray dotted line: Metoprolol, closed symbols actual values.^6,9–13)

The fitted lines corresponded well with the actual values. Thus, the relationship between Фss^β₁ and clinical efficacy could be analyzed by taking into consideration the direct action on ryanodine receptor 2. Values for the parameters were obtained, as follows: E_max^β₁, 51.0%; E_max^Ry, 20.5%; K_d^Ry-Car, 0.0872 nM; K_d^Ry-Bis, 301.2 nM; K_d^Ry-Met, 3834 nM. For the increase in LVEF, based on the values for E_max^β₁ and E_max^Ry, it was suggested that the ratio of contribution of the action related to the β₁ receptor was 71.3%, while that of the direct action on ryanodine receptor 2 was 28.7%. Moreover, the ratio of K_d^Ry for the ryanodine receptor to K_d^β₁ for the β₁ receptor of each agent (K_d^β₁/K_d^Ry) was compared. Our results showed that the affinity of carvedilol for ryanodine receptor 2 was markedly higher as compared to that of the other 2 agents (carvedilol: 20.5, bisoprolol: 0.05, metoprolol: 0.015).

Relationship between Dose and Clinical Efficacy of β-Blocking Agents

The doses and clinical efficacy of the examined β-blocking agents were simulated on the basis of the parameters obtained, as noted above, with the results shown in Fig. 3.

Fig. 3. Simulated Lines of Clinical Efficacy (LVEF Increase Rate) of Carvedilol (a), Bisoprolol (b) and Metoprolol (c) Used Clinically for Chronic Heart Failure

Light gray area efficacy through ryanodine 2 receptor, dark gray area efficacy through β₁ receptor.

The rate of LVEF increase at the maintenance dose ranged from 26.5–44.0% for carvedilol (5–20 mg), 20.3–38.8% for bisoprolol (1.25–5 mg), and 24.3–40.9% for metoprolol (30–120 mg), demonstrating that very similar levels of efficacy were obtained at the maintenance dose. That rate associated with the β₁ receptor of carvedilol ranged from 9.6–24.5% and that with ryanodine receptor 2 ranged from 16.9–19.5%. The ratio of contribution was 36.2–55.7% for the β₁ receptor and 63.8–44.3% for ryanodine receptor 2. For bisoprolol and metoprolol, the rate of LVEF increase rate associated with ryanodine receptor 2 was markedly lower at 0.6–2.3 and 0.3–1.0%, respectively, while the contribution ratio was 3.0–5.9 and 1.2–2.4%, respectively.

Relationship between Dose and Adverse Effects of β-Blocking Agents

The relationship between the dose and adverse effects of the examined β-blocking agents, obtained by calculations with Eqs. 4 and 5, are shown in Fig. 4.

Fig. 4. The Range of Predicted Values from Initial Dose to Maximum Dose for Adverse Effects (Average ▲HR (a), Average ▲FEV₁ (b)) after Administration of Carvedilol, Bisoprolol and Metoprolol Used Clinically for Chronic Heart Failure

The average value for ▲HR at the initial dose was 0.2% for carvedilol, 0.7% for bisoprolol and 1.0% for metoprolol, demonstrating that ▲HR was suppressed at a low level. Meanwhile, the average value for ▲HR at the maximum maintenance dose was 2.2% for carvedilol, 6.0% for bisoprolol, and 8.1% for metoprolol, indicating that the heart rate decreasing effect was lower with carvedilol as compared to metoprolol and bisoprolol. In addition, the average value for ▲FEV₁ at the initial dose was 5.5% for carvedilol, 0.3% for bisoprolol, and 2.1% for metoprolol, while that at the maximum maintenance dose was 25.8, 2.1, and 14.0%, respectively, suggesting that the risk of an induced asthmatic attack was higher for carvedilol, followed in order by metoprolol and bisoprolol.

DISCUSSION

In the present study, clinical efficacy and adverse effects of the β-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure.

The Фss^β₁ value at the usual dose was nearly the same for bisoprolol and metoprolol (24.0–71.6 and 30.9–78.2%, respectively), whereas that for carvedilol was lower (10.4–48.1%). Bisoprolol and metoprolol showed the same relationship between LVEF increase rate and Фss^β₁, while our findings suggested that the LVEF increase rate with carvedilol could be attained with a lower Фss^β₁ value. These findings support previous reports that noted that a targeted action other than toward the β₁ receptor might be involved in the clinical efficacy of carvedilol.^22–25)

The action mechanism of β-blocking agents is poorly understood. Recent reports have indicated that the major mechanism is correction of the abnormal dynamic state of Ca²⁺ in myocardial cells by indirectly acting on SERCA2a (Ca²⁺-ATPase of cardiac sarcoplasmic reticulum), based on β₁ receptor blocking, to improve contractility.^{22,24,26–29)} Moreover, findings in those studies suggested that β-blocking agents might directly act on the ryanodine receptor on the membrane of the cardiac sarcoplasmic reticulum. Another study reported that only carvedilol directly acted on ryanodine receptor 2 to selectively control arrhythmia induced by Ca²⁺ release from the reticulum.¹⁴⁾ Furthermore, it has been suggested that carvedilol has no inhibitory action toward the involvement of CICR (Ca²⁺-induced Ca²⁺ release) during normal contractions, but acts on arrhythmogenic SOICR (store overload-induced Ca²⁺ release) on ryanodine receptor 2 to selectively inhibit it.²⁵⁾

In the present study, we constructed a model under the assumption that β-blocking agents exert indirect action through the β₁ receptor and direct action on ryanodine receptor 2, both of which additively exert clinical efficacy (Eq. 3). For clinical efficacy, LVEF increase rate was used as a parameter. In Fig. 2, the fitted lines corresponded well with the actual values. Thus, the relationship between Фss^β₁ and clinical efficacy could be analyzed by taking into consideration the direct action on ryanodine receptor 2. Although there is only one LVEF increase rate value for bisoprolol and metoprolol respectively, Eq. 3 was simultaneously applied to the actual value for the six data of the three drugs, and the fitted lines corresponded well with the actual values. Thus, we thought that the relationship between Фss^β₁ and clinical efficacy could be analyzed for these drugs. Data collected from patients with NYHA cardiac functional class II or III heart failure were used for our analyses. In analysis with our model, E_max^β₁ was 51.0% and E_max^Ry was 20.5%. As for the LVEF increasing effect, the contribution ratio of the action related to the β₁ receptor was 71.3% and that of the direct action on ryanodine receptor 2 was 28.7%. Moreover, the K_d^Ry value was 0.0872 nM for carvedilol, 301.2 nM for bisoprolol, and 3.834 nM for metoprolol, thus the activity of carvedilol ranged from approximately 3500 to 44000 times greater than that of the others. Therefore, the LVEF increase rate with carvedilol was attained with a lower Фss^β₁ value than the others.

In analysis of the inhibitory effect of Ca²⁺ released from the cardiac sarcoplasmic reticulum by HEK293 cells in mice, which express ryanodine receptor 2, it was found that the IC₅₀ of carvedilol was 15.9 µM and that of metoprolol was >1000 µM.²⁵⁾ Although these results cannot be directly compared with the K_d^Ry values obtained in our study, they suggest the validity of our analysis, as nearly the same response was obtained in regard to proportion by the agents. On the basis of the parameters obtained and analyzed, LVEF increase rate could be predicted from the dose.

For the maintenance dose range, nearly the same levels were obtained for the β-blocking agents (carvedilol 26.5–44.0%, bisoprolol 20.3–38.8%, metoprolol 24.3–40.9%), suggesting the same level of clinical efficacy. For patients with NYHA functional classification class II and III, average LVEF was reported to be 42.8 and 36.3%, respectively, thus it was considered that the percentage increase in LVEF necessary for attaining the target of 50% might be 16.8 and 37.7%, respectively.³⁰⁾ Those levels agree with the levels obtained in our analysis, indicating that clinical efficacy could be evaluated by using the model constructed in the present study. The LVEF increase rate for carvedilol attained through the β₁ receptor was shown to be 9.6–24.5%, while that attained by direct involvement with ryanodine receptor 2 was 6.9–19.5%. On the other hand, the LVEF increase rate attained by involvement with ryanodine receptor 2 for bisoprolol and metoprolol was remarkably low at 0.6–2.3 and 0.3–1.0%, respectively. Our results clarified, at least theoretically, that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses.

We also investigated decreases in heart rate and FEV₁ as adverse effects of β-blocking agents using a ternary complex model. Although it was reported that β-blocking agents could improve delayed afterdepolarization and prevent arrhythmia via ryanodine receptor 2, the mechanism of decreasing heart rate via the receptor is not reported.³¹⁾ Thus, we assumed that the ▲HR could be predicted by using Фss^β₁. The average ▲HR value from administration of the initial dose to that of the maximum maintenance dose ranged from 0.2–2.2% for carvedilol, 0.7–6.0% for bisoprolol, and 1.0–8.1% for metoprolol, indicating that carvedilol is less likely to induce a heart rate decrease. The relationship between Фss^β₁ and ▲HR value is nonlinear growth.¹⁵⁾ Thus, if there was a little difference in high Фss^β₁ value (maximum dose of bisoprolol: 71.6% and metoprolol: 78.2%), ▲HR value is affected (maximum dose of bisoprolol: 6.0% and metoprolol: 8.1%). These findings were in line with past studies that found carvedilol good for chronic heart failure, as it did not decrease heart rate, and stated that bisoprolol should be used with care in patients with a lower heart rate.^13,32) Moreover, average ▲HR at the initial dose was lower by one-eighth to one-eleventh of that at the maximum maintenance dose, demonstrating quantitatively the importance of starting administration at one-eight of the maximum maintenance dose to prevent aggravation of heart failure. Meanwhile, average ▲FEV₁ from the initial to maximum maintenance dose ranged from 5.5–25.8% for carvedilol, 0.3–2.1% for bisoprolol, and 2.1–14.0% for metoprolol, providing evidence that carvedilol is contraindicated for patients with asthma, as they have a high risk of adverse effects on the respiratory system. These results were considered to support previous reports of the patients with pulmonary disease.^33,34)

The present theoretical findings suggest that carvedilol, bisoprolol, and metoprolol have no differences in regard to clinical efficacy, while their action mechanisms for producing effects vary. Moreover, evidence of adverse effects previously reported for these agents was theoretically confirmed, suggesting predictable risk. Thus, our results are considered useful for selection of a proper β-blocking agent and its administration at a reasonable dose for successful heart failure therapy.

Conflict of Interest

The authors declare no conflict of interest.

REFERENCES

• 1) Brian RW, Nicki RC, Stuart HR. Davidson’s Principles and Practice of Medicine, 21st Edition. CHURCHILL, LIVINGSTONE, ELSEVIER, London (2010).
• 2) “Guidelines for Treatment of Chronic Heart Failure (JCS 2010).”: ‹http://www.j-circ.or.jp/guideline/pdf/JCS2010_matsuzaki_h.pdf›. accessed 13 September 2016.
• 3) Longo LD, Fauci SA, Kasper LD, Hauser LS, Jameson LJ, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th Edition. The McGraw-Hill Companies, Inc., New York (2011).
• 4) Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br. Heart J., 37, 1022–1036 (1975).
• 5) Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A, Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet, 342, 1441–1446 (1993).
• 6) “Summary basis of approval of ARCHIST.”: ‹http://www.pmda.go.jp/drugs/2015/P20150812001/430574000_20500AMZ00009_A100_1.pdf›. accessed 13 September, 2016.
• 7) “Summary basis of approval of MAINTATE.”: ‹http://www.pmda.go.jp/drugs/2011/P201100095/400315000_20200AMZ00948_A100_1.pdf›. accessed 13 September, 2016.
• 8) “Interviewform of SELOKEN 11th Edition.”: ‹http://www.info.pmda.go.jp/go/interview/1/670227_2149010F1025_1_111_1F›. accessed 13 September, 2016.
• 9) Kohno T, Yoshikawa T, Yoshizawa A, Nakamura I, Anzai T, Satoh T, Ogawa S. Carvedilol exerts more potent antiadrenergic effect than metoprolol in heart failure. Cardiovasc. Drugs Ther., 19, 347–355 (2005).
• 10) Hori M, Nagai R, Izumi T, Matsuzaki M. Efficacy and safety of bisoprolol fumarate compared with carvedilol in Japanese patients with chronic heart failure: results of the randomized, controlled, double-blind, Multistep Administration of bisoprolol IN Chronic Heart Failure II (MAIN-CHF II) study. Heart Vessels, 29, 238–247 (2014).
• 11) Hori M, Sasayama S, Kitabatake A, Toyo-oka T, Handa S, Yokoyama M, Matsuzaki M, Takeshita A, Origasa H, Matsui K, Hosoda S; MUCHA Investigators. Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial. Am. Heart J., 147, 324–330 (2004).
• 12) Okamoto H, Hori M, Matsuzaki M, Tsutsui H, Yamazaki T, Nagai R, Yoshikawa T, Fujio Y, Nonen S, Azuma J, Izumi T, Ohashi Y, Kitabatake A; J-CHF Investigators. Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study. Int. J. Cardiol., 164, 238–244 (2013).
• 13) Miyagishima K, Hiramitsu S, Kimura H, Mori K, Ishikawa S, Yoda R, Sugiura A, Kato Y, Kato S, Iwase M, Morimoto S, Ozaki Y. Effectiveness of β₁-selective β-blocker bisoprolol in Japanese patients with chronic heart failure. SHINZO, 44, 132–139 (2012).
• 14) Zhou Q, Xiao J, Jiang D, Wang R, Vembaiyan K, Wang A, Smith CD, Xie C, Chen W, Zhang J, Tian X, Jones PP, Zhong X, Guo A, Chen H, Zhang L, Zhu W, Yang D, Li X, Chen J, Gillis AM, Duff HJ, Cheng H, Feldman AM, Song LS, Fill M, Back TG, Chen SR. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca²⁺ release. Nat. Med., 17, 1003–1009 (2011).
• 15) Yamada Y, Matsuyama K, Ito K, Sawada Y, Iga T. Risk assessment of adverse pulmonary effects induced by adrenaline β-receptor antagonists and rational drug dosage regimen based on receptor occupancy. J. Pharmacokinet. Biopharm., 23, 463–478 (1995).
• 16) Takeuchi K, Kawarabayashi T, Murai K, Kinmi T, Yasunari K, Tanizawa S, Sakamoto K, Hirota K, Tanigaki Y, Tabaru A, Hirono S, Fujisawa M, Matsushita H, Itagane H, Murakawa K, Kaneyama Y, Tanaka C, Takeda T. Phase I Study of Bisoprolol hemifumarate (TA-4708)—Oral Single Dose and Oral 7-Days Dosing Study—. Japanese Pharmacology & Therapeutics, 13, 5761–5793 (1985).
• 17) “The Japanese Pharmacopoeia 16th Edition.”: ‹https://www.pmda.go.jp/files/000152816.pdf›. accessed 13 September, 2016.
• 18) Bühring KU, Sailer H, Faro HP, Leopold G, Pabst J, Garbe A. Pharmacokinetics and metabolism of bisoprolol-¹⁴C in three animal species and in humans. J. Cardiovasc. Pharmacol., 8 (Suppl. 11), S21–S28 (1985).
• 19) Johansson KA, Appelgren C, Borg KO, Elofsson R. Binding of two adrenergic beta-receptor antagonists, alprenolol and H 93-26, to human serum proteins. Acta Pharm. Suec., 11, 333–346 (1974).
• 20) Appelgren C, Borg KO, Elofsson R, Johansson KA. Binding of adrenergic beta-receptor antagonists to human serum albumin. Acta Pharm. Suec., 11, 325–332 (1974).
• 21) Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br. J. Pharmacol., 144, 317–322 (2005).
• 22) Ogiwara T, Tsukiyama H, Matsuzaki M, Shimada K. β-Shadan-yaku no subete 3rd edition. SENTAN IGAKU-SYA, Tokyo (2009).
• 23) Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A, Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet, 362, 7–13 (2003).
• 24) Komuro K. Shinhuzen Frontier. Medical Review Co., Ltd., Osaka (2003).
• 25) Smith CD, Wang A, Vembaiyan K, Zhang J, Xie C, Zhou Q, Wu G, Chen SR, Back TG. Novel carvedilol analogues that suppress store-overload-induced Ca²⁺ release. J. Med. Chem., 56, 8626–8655 (2013).
• 26) Kubo H, Margulies KB, Piacentino V 3rd, Gaughan JP, Houser SR. Patients with end-stage congestive heart failure treated with beta-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation, 104, 1012–1018 (2001).
• 27) Gwathmey JK, Kim CS, Hajjar RJ, Khan F, DiSalvo TG, Matsumori A, Bristow MR. Cellular and molecular remodeling in a heart failure model treated with the beta-blocker carteolol. Am. J. Physiol., 276, H1678–H1690 (1999).
• 28) Arai M. “Abnorma calcium handling inducing heart failure and as a therapeutic target for the treatment of heart failure.”: ‹http://jams.med.or.jp/symposium/full/122012.pdf›. accessed 13 September 2016.
• 29) Yano M, Kobayashi S. β-Shadan-yaku wo tukaikonasu. Circulation, 3, 13–19 (2013).
• 30) Mori Y, Nishikawa Y, Iizuka T, Zenimura N, Matsumoto T, Hiramatsu K, Komiya M. Post-marketing surveillance of Artist^® tablets (carvedilol) special investigation of clinical outcomes in patients given carvedilol for chronic heart failure. J. Clin. Therap. Med., 24, 143–166 (2008).
• 31) Nakaya H. Electrophysiological basis of arrhythmias associated with heart failure and pharmacotherapy. JPN J Electrocardiology, 31, 339–345 (2011).
• 32) Higuchi Y. β-Blockers. Journal of Nihon University Medical Association, 73, 20–21 (2014).
• 33) Jabbour A, Macdonald PS, Keogh AM, Kotlyar E, Mellemkjaer S, Coleman CF, Elsik M, Krum H, Hayward CS. Differences between beta-blockers in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized crossover trial. J. Am. Coll. Cardiol., 55, 1780–1787 (2010).
• 34) Lainscak M, Podbregar M, Kovacic D, Rozman J, von Haehling S. Differences between bisoprolol and carvedilol in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized trial. Respir. Med., 105 (Suppl. 1), S44–S49 (2011).