Fever is a surrogate marker for disease activity in many infectious and inflammatory disorders. According to the classical view, the genesis of fever is induced by inflammatory mediators (i.e., cytokines, namely interleukin-1, interleukin-6, tumor necrosis factor, and others) that are predominantly released by activated peripheral mononuclear phagocytes and other immune cells.[12
] Due to the fact that direct access of the large hydrophilic cytokine proteins to the temperature-controlling brain structures within the pre-optic/anterior hypothalamic areas is prevented by the blood–brain barrier, the mechanisms described below have been suggested for producing pyrexia.
Cytokines which are transported by the bloodstream could act at sites lacking a tight blood–brain barrier, the so-called circumventricular organs.[14
] Alternatively, circulating cytokines could interact with their specific receptors on brain endothelial cells[15
] or perivascular cells[16
] and thereby stimulate these cells to release pyrogenic mediators into the abluminal brain tissue. It has been proposed that fever-promoting cytokines are transported from the blood into the brain via specific carriers.[17
] An assumed manifestation of a febrile response produced by these mechanisms is termed as the humoral hypothesis of fever induction. Within the brain, prostaglandin E2
), produced by cyclooxygenase (COX)-2, is regarded as the principle downstream mediator of fever[18
] acting on thermosensitive or thermointegrative hypothalamic neurons.
Fever is tightly regulated by the immune response. Inflammatory stimuli triggering the generation of pro-pyretic messages provoke the release of endogenous antipyretic substances.[18
is synthesized from arachidonic acid, which is released from cell membrane lipid by phospholipase. Arachidonic acid is metabolized by two isoforms of the COX enzyme, COX-1 and COX-2. COX-1 usually is expressed constitutively and generates prostanoids important for housekeeping functions supporting homeostasis.[19
] COX-2, on the other hand, is inducible by inflammatory signals such as the pyrogenic cytokines, IL-1b, TNF, and IL-6, as well as bacterial lipopolysaccharide. Many cells, including synoviocytes, macrophages, endothelial cells, and chondrocytes, have the capacity to rapidly up-regulate the expression of the COX-2 during inflammation.[19
] The most likely cell type in the central nervous system responsible for producing PGE2
is the microvascular endothelial cell, which expresses COX-2 exuberantly after stress. An effective febrifuge might interrupt pyrexogenesis at any step that connects peripheral inflammation with the central production of PGE2
. Stated differently, an antipyretic might blunt peripheral inflammation or depress central pyrogenic signals, or it may affect both. Inhibiting central production of PGE2
is a well-known mechanism of antipyretic agents, but activated leukocytes and endothelial cells in peripheral areas of inflammation also represent potential drug targets.
Paracetamol is an analgesic but is also an effective febrifuge. It is a poor inhibitor of cyclooxygenase in the presence of peroxides that are found in inflammatory lesions. In contrast, its antipyretic effect may be explained by its ability to inhibit cyclooxygenase in the brain, where peroxide tone is low. Further, it does not inhibit neutrophil activation. In supra-pharmacologic doses it inhibits NF-kB stimulation of inducible nitric oxide synthase.[20
In the present study, in the yeast control group the rise in temperature was consistent and significant in comparison to the initial values. In the vehicle control group also the rise in temperature was significant; however, the magnitude was slightly less in comparison to that in the yeast control group in the initial stages. Both the Guduchi Ghrita samples produced very good antipyretic effect in a dose-dependant manner and the observed effect was almost similar to that in the paracetamol-treated group.
Previous studies by Ikram et al
] and Leghari et al
] have reported the antipyretic effect of Tinospora cordifolia
in Himalayan rabbits. Vedavathy and Rao,[23
] showed water-soluble fractions of a 95% ethanolic extract of T cordifolia
plant to possess significant antipyretic activity (when given orally) against yeast-induced pyrexia. Many authors have ascribed the antipyretic properties of T cordifolia
to the presence of berberine or other bitter substances.[24