256
antagonists are emerging as potential therapeutic agents against allergic rhinitis and
atopic dermatitis (Jablonowski et al. 2004; Kiss and Keseru 2012, 2014; Martinel
Lamas et al. 2015). Pharmacological targeting of the H4 receptor, either alone or in
combination with H1 receptor antagonists, was proved effective for treating both
allergy and asthma.
Histamine receptor 1 antagonists are generally known as antihistamines. They
are broadly divided into six classes and then categorized according to the modifications over time into first, second, and third generation (Krystal et al. 2013). Firstgeneration antihistamines are one of the most extensively used drugs with
symptomatic relief from allergies and the common cold, but they have potent sedative effect on patients. This paved the way for the development of second-generation
antihistamines without the CNS side effects leading to sedation; these include terfenadine, astemizole, loratadine, and cetirizine. However, terfenadine and astemizole were found to cause potentially serious arrhythmia when plasma concentrations
became elevated subsequent to impaired metabolism. Thus, second-generation
drugs were further modified to eliminate cardiac toxicity effect. Fexofenadine (the
active metabolite of terfenadine) is the first drug marketed in this category. Thirdgeneration antihistamines, such as norastemizole and descarboethoxy loratadine,
astemizole and loratadine metabolites, respectively, are under clinical validation
and development for the treatment of allergic rhinitis and chronic urticaria (Du
Buske 1996). Clinically used H1R antagonists-based drugs are presented in
Table 10.4.
10.7.5 Complement Inhibitors
Complement is a key player in innate immune response and inflammation.
Complement activation during an inflammatory reaction contributes to inflammationdriven tissue injury, especially in ischemia/reperfusion (I/R), nephritis, and arthritis.
This persistent complement activation elicits sustained immune response which
ultimately culminates in tissue injury or organ failure. C1q component product is
found to be overactivated in lupus and RA and Alzheimer’s disease. C5a seems to
play a major role in psoriasis and complement-mediated asthma as well. Thus the
central role played by complement in the origin of certain inflammation-based diseases makes it an attractive therapeutic target. Logically, the therapeutic inhibition
of complement in these contexts may ameliorate the associated complications by
decreasing the underlying hyperimmune reactions. Blocking complement activation
can be achieved by a number of ways. The potential of inherent protein regulators
of complement activation such as CR1, CR2, etc., has been exploited for the development of complement activation blockers by generating modified soluble version
of the recombinant human CR1, CR2, etc. Soluble CR1 (sCR1) is synthesized by
removing the transmembrane and cytoplasmic domain of the endogenous CR1 protein as recombinant protein product (Ballanti et al. 2011). Trials with sCR1 reduced
the complement-induced tissue injury, lung injury, vascular injury,
B.C. Bhavya and M. Haridas
antagonists are emerging as potential therapeutic agents against allergic rhinitis and
atopic dermatitis (Jablonowski et al. 2004; Kiss and Keseru 2012, 2014; Martinel
Lamas et al. 2015). Pharmacological targeting of the H4 receptor, either alone or in
combination with H1 receptor antagonists, was proved effective for treating both
allergy and asthma.
Histamine receptor 1 antagonists are generally known as antihistamines. They
are broadly divided into six classes and then categorized according to the modifications over time into first, second, and third generation (Krystal et al. 2013). Firstgeneration antihistamines are one of the most extensively used drugs with
symptomatic relief from allergies and the common cold, but they have potent sedative effect on patients. This paved the way for the development of second-generation
antihistamines without the CNS side effects leading to sedation; these include terfenadine, astemizole, loratadine, and cetirizine. However, terfenadine and astemizole were found to cause potentially serious arrhythmia when plasma concentrations
became elevated subsequent to impaired metabolism. Thus, second-generation
drugs were further modified to eliminate cardiac toxicity effect. Fexofenadine (the
active metabolite of terfenadine) is the first drug marketed in this category. Thirdgeneration antihistamines, such as norastemizole and descarboethoxy loratadine,
astemizole and loratadine metabolites, respectively, are under clinical validation
and development for the treatment of allergic rhinitis and chronic urticaria (Du
Buske 1996). Clinically used H1R antagonists-based drugs are presented in
Table 10.4.
10.7.5 Complement Inhibitors
Complement is a key player in innate immune response and inflammation.
Complement activation during an inflammatory reaction contributes to inflammationdriven tissue injury, especially in ischemia/reperfusion (I/R), nephritis, and arthritis.
This persistent complement activation elicits sustained immune response which
ultimately culminates in tissue injury or organ failure. C1q component product is
found to be overactivated in lupus and RA and Alzheimer’s disease. C5a seems to
play a major role in psoriasis and complement-mediated asthma as well. Thus the
central role played by complement in the origin of certain inflammation-based diseases makes it an attractive therapeutic target. Logically, the therapeutic inhibition
of complement in these contexts may ameliorate the associated complications by
decreasing the underlying hyperimmune reactions. Blocking complement activation
can be achieved by a number of ways. The potential of inherent protein regulators
of complement activation such as CR1, CR2, etc., has been exploited for the development of complement activation blockers by generating modified soluble version
of the recombinant human CR1, CR2, etc. Soluble CR1 (sCR1) is synthesized by
removing the transmembrane and cytoplasmic domain of the endogenous CR1 protein as recombinant protein product (Ballanti et al. 2011). Trials with sCR1 reduced
the complement-induced tissue injury, lung injury, vascular injury,
B.C. Bhavya and M. Haridas