GABAA receptor positive allosteric modulator

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Gamma-Aminobuttersaure - gamma-aminobutyric acid.svg
Fig 1. Chemical structure of gamma-aminobutyric acid or GABA
GABAA-receptor-protein-example.png
Fig 2. Schematic diagram of a GABAA receptor protein ((α1)2(β2)2(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl-) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, [1] are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

Contents

GABA is a major inhibitory neurotransmitter in the central nervous system. Upon binding, it triggers the GABAA receptor to open its chloride channel to allow chloride ions into the neuron, making the cell hyperpolarized and less likely to fire. GABAA PAMs increase the effect of GABA by making the channel open more frequently or for longer periods. However, they have no effect if GABA or another agonist is not present.

Unlike GABAA receptor agonists, GABAA PAMs do not bind at the same active site as the γ-aminobutyric acid (GABA) neurotransmitter molecule: they affect the receptor by binding at a different site on the protein. This is called allosteric modulation.

In psychopharmacology, GABAA receptor PAMs used as drugs have mainly sedative and anxiolytic effects. Examples of GABAA PAMs include alcohol (ethanol), benzodiazepines such as diazepam (Valium) and alprazolam (Xanax), Z-drugs such as zolpidem (Ambien) and the barbiturate drugs.

History

The GABAA receptors have historically been a target of drug treatment research. The earliest compounds were ionic compounds, such as bromide.

Barbiturates

In 1903, the first psychoactive derivative of barbituric acid was synthesized and marketed for headaches. Within 30 years, many other barbiturates were developed and found use as sedatives, sleep aids and general anesthetics. Although barbiturates fell out of favor, they continue to serve as a short-acting anesthetic and anti-epileptic drugs.

Benzodiazepines

Benzodiazepines were discovered in 1955 and largely replaced the barbiturates because of their larger therapeutic index. [2] At first benzodiazepines were considered to be safe and efficient minor tranquilizers but then were criticized for their dependence producing effects. Several efficient benzodiazepines offer choices about dosage form, length of action, metabolic interaction and safety.

Benzodiazepines function by binding to the benzodiazepine site on most, but not all, GABAA receptors. GABAA modulation by benzodiazepine site agonists is self-limiting. The channel conductance is not higher in the presence of benzodiazepine and GABA than the conductance with the presence of only high GABA concentrations. Additionally, in the absence of GABA the presence of benzodiazepines alone does not open the chloride channel. [3]

Neurosteroids

Certain metabolites of progesterone and deoxycorticosterone are potent and selective positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor. [4] Hans Selye demonstrated in 1940 that certain pregnane steroids could cause both anesthesia and sedation, [5] but 40 years later the molecular mechanism emerged to explain their depressant effect. In a rat brain slice preparation, the synthetic steroidal anesthetic alphaxalone (5α-pregnan-3α-ol-11,20 dione) enhanced both stimulus-evoked inhibition and the effects of exogenously applied muscimol, which is a GABAA selective agonist. [6]

Receptor

Fig 3. Binding sites of different therapeutic chemical groups on a GABAA receptor GABAA receptor binding sites.jpg
Fig 3. Binding sites of different therapeutic chemical groups on a GABAA receptor

The GABAA receptors are made up of subunits which form a receptor complex. Humans have 19 receptor subunits and are classified into α (1–6), β (1–3), γ (1–3), δ, ε, π, θ, and ρ (1−3). The function of the receptor is different according to how the pentameric complex is put together. The most common complex that includes around 40% of the GABAA receptors is the α1β2γ2 combination. The expression of the subunits can be very different depending on brain region. [7] The combination of the subunits influences how the receptor acts. For example, if the α1 and β2 subunits are expressed together they have high sensitivity to GABA, but low channel conductance. But if the γ2 is expressed with α1 and β2 the sensitivity is low and channel conductance is high. [8] γ2 subunit has to be present for high affinity binding of benzodiazepine. Little is known about where different complexes are located in the brain, complicating drug discovery. [7] For example, the binding site of neurosteroids in the GABAA receptor is not known [9] and barbiturates bind at a beta subunit that is distinct from the benzodiazepine binding site.

Available agents

Applications

Barbiturates

Barbiturates' precise action sites have not yet been defined. The second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β-subunit methionine 286 as well as α-subunit methionine 236. [10]

Insomnia

Barbiturates were introduced as hypnotics for patients with schizophrenia. It induced a state of deep and prolonged sleep. But this was not used for long because of adverse side effects. [2]

Anticonvulsant

Phenobarbital was the first truly effective drug against epilepsy. It was discovered by accident when given to epileptic patients to help them sleep. The positive side effects were anticonvulsant properties that reduced seizure number and intensity. [2]

Sedation

Pentobarbital is used as a hypnotic when analgesia is not required. It´s often used in CT imaging when sedation is needed. It is efficient, safe and the recovery time is short. [11] In 2013 the barbiturates phenobarbital and butabarbital are still used as sedatives in certain cases as well as to antagonize the effects of drugs as ephedrine and theophylline. Phenobarbital is used in cases of drug withdrawal syndromes. It is used as normal and emergency treatment in some cases of epilepsy. [2]

Fig 4. GABAergic synapse. The synaptic anchoring protein Gephyrin is indirectly linked to the GABAA receptors. GABA synapse.jpg
Fig 4. GABAergic synapse. The synaptic anchoring protein Gephyrin is indirectly linked to the GABAA receptors.

Benzodiazepine

Synaptic action of benzodiazepines: GABAA receptors located at synapses are activated when they are exposed to high concentration of GABA. Benzodiazepines enhance the receptor affinity for GABA by increasing the decay of spontaneous miniature inhibitory postsynaptic currents (mIPSC). [12] [13]

Analgesia

Sedative actions of benzodiazepines limit their usefulness as analgesic agents and they are therefore generally not considered to be appropriate. This limitation can be bypassed by intrathecal administration. GABAA receptors in the periaqueductal gray are pro-nociceptive at supraspinal sites while GABAA that are found in the spinal cord are anti-hyperalgesic. Spinal α2 and α3 containing GABAA receptors are responsible for the anti-hyperalgesic action of intrathecal diazepam. This was shown when the anti-hyperalgesic action was reduced when administered in α2 and α3 mice in inflammatory pain and in neuropathic pain. Additionally, studies in α5 mice showed that the spinal α5-containing GABAA receptor has a minor role in inflammatory pain. An α2, α3 and/or α5 selective positive allosteric agonist, like L-838,417 for example, might be useful as an analgesic drug against inflammatory or neuropathic pain. [3] Further studies in animal neuropathic pain models have shown that stabilizing the potassium chloride cotransporter 2 (KCC2) at neuronal membranes could not only potentiate the L-838,417-induced analgesia but also rescue its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAA receptor subtypes (i.e. α2, α3) and restoring Cl− homeostasis. [14]

Schizophrenia

Benzodiazepines are used as a supporting treatment in patients with schizophrenia. [3]

Depression

A GABAergic hypothesis for depression has been proposed which places the GABA system in a central role in the pathophysiology of depression. Clinical studies have shown that alprazolam and adinazolam have antidepressant activities in patients with major depressive disorder. Unfortunately, it is not known which receptor subtype is responsible for the antidepressant activities.

Studies in y2 knockout mice have shown that they display increased anxiety and depressive-like symptoms in despair-based tests. The mice also had increased corticosterone concentration, which is a symptom in major depression in humans. The y2 subunit is associated with α1-α6 subunits, which are all known α subunits, so these studies do not show which of the α subunits are related to the depressive-like symptoms. Other studies with α2 knockout mice have displayed increased anxiety and depression-like symptoms in conflict-based feeding tests. The fact that anxiety and depression are often linked seems to indicate that the α2 subunit might be a valid target for a GABAA antidepressant. [3]

Stroke

Preclinical studies have shown that benzodiazepines can be effective in reducing the effect of strokes for up to three days after the drug has been administered. [3]

Neurosteroids

Neurosteroids can act as allosteric modulators of neurotransmitter receptors, such as the GABAA, [15] [16] [17] [18] NMDA, [19] and sigma receptors. [20] The neurosteroid progesterone (PROG) that activates progesterone receptors expressed in peripheral and central glial cells. [21] [22] [23] [24] Additionally it has been surmised that the 3α-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone increase the GABA-mediated chloride currents while pregnenolone sulfate and dehydroepiandrosterone (DHEA) sulfate on the other hand display antagonistic properties at the GABAA receptors.

Synthesis

Barbituric acid

Original synthesis of Barbituric acid.jpg
Fig 5. Original synthesis of Barbituric acid
Current synthesis of barbituric acid.jpg
Fig 6. Current synthesis of barbituric acid

Barbituric acid is the parent compound of barbiturate drugs although barbituric acid itself is not pharmacologically active. Barbiturates were synthesized in 1864 by Adolf von Baeyer by combining urea and malonic acid (Figure 5). A synthesis process was later developed and perfected by French chemist Edouard Grimaux in 1879, making possible the subsequent widespread development of barbiturate derivatives. [25] Malonic acid was later replaced by diethyl malonate, as using the ester avoids the need to deal with the acidity of the carboxylic acid and its unreactive carboxylate (see figure 6). Barbituric acid can form a large variety of barbiturate drugs by using the Knoevenagel condensation reaction. [26]

Fig 7. Synthesis and discovery of chlordiazepoxide Synthesis and discovery of chlordiazepoxide.jpg
Fig 7. Synthesis and discovery of chlordiazepoxide

Benzodiazepines

The structure that the first benzodiazepine is based on was discovered by Leo H. Sternbach. He thought the compound had a heptoxdiazine structure (Figure 7) but it was later determined to be a quinazoline-3-oxide. Possible drug candidates were then synthesized from that compound and screened for activity. One of these compounds was active, chlordiazepoxide. It was marketed in 1960 and became the first benzodiazepine drug. [27]

Biosynthesis of neurosteroids

Neurosteroids are synthesized in the central nervous system (CNS) and the peripheral nervous system (PNS) from cholesterol and steroidal precursors that are imported from the peripheral sources. These sources include 3β-hydroxy-Δ5 derivatives, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydro derivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG). After the local synthesis or from metabolism of adrenal of gonadal steroids many neurosteroids accumulate in the brain. [28] [29]

Structure-activity relationship

Barbiturates

Fig 8. R-group position of Barbiturates BarbituratesR groups.jpg
Fig 8. R-group position of Barbiturates

Barbiturates have special uses and are organized into 4 classes: ultrashort-, short-, intermediate- and long-acting. Empirically SARs of barbiturants are based on thousands of (animal) tested compounds. They have shown that R and R´ may not be H in position 5 (see figure 8). Also, position 5 confer sedative-hypnotic properties. [11] Generally alkyl branching in position 5 means less lipid solubility and less activity. Unsaturation show less activity in position 5 and alicyclic and aromatic rings show less potency. Polar substituents (-NH2, -OH, -COOH) will decrease lipid solubility but it will also eliminate activity. R´´ in position 1 is usually, H but CH3 in that position yields less lipid solubility and duration. Exchanging S for O atom in position 2 produces thiobarbiturates, which are more lipid-soluble than the oxybarbiturates. In general, the more lipid-soluble the barbiturate, the more rapid its onset, the shorter its duration and the greater the degree of hypnotic activity. Barbiturates showed some hydrolytic problems in regard to formulation of liquid dosage forms. The difficulty is -OH catalyzed degration of the ureide rings but that can be fixed if the pH is 6 in the formulation. S(-) form of barbiturate have shown more depressant activity while the R(+) isomers have an excitatory effect. [30]

Benzodiazepines

Fig 9. Common R group positions of Benzodiazepines 1,4-Benzodiazepin-2-on.png
Fig 9. Common R group positions of Benzodiazepines

According to research performed by Maddalena et al., using artificial neural networks, position 7 has the most effect on receptor affinity. When the active group in position 7 is made more lipophilic and the electronic charge is increased the receptor affinity increases. In the same study position 2´ was found to be the second-most important in affecting the affinity, but the group in that position needs to be electrophilic to have an effect. Positions 3, 6’ and 8 are of less importance. [31] Changes to 6, 8, 9 or 4´ decrease activity. If the group in position 1 is changed to N-alkyl, haloalkyl, alkynyl and small cycle or aminoalkyl the activity is increased. Position 3 hydroxylation can cause rapid conjugation and decrease duration and potency, which can be clinically useful. [31]

Fig 10. Different R-group analogs for neurosteroids. Groups 1-4 and 10 have significant therapeutic value. Neurosteroid R-group analogs.jpg
Fig 10. Different R-group analogs for neurosteroids. Groups 1–4 and 10 have significant therapeutic value.

Neurosteroids

In the mid 1980s, the neuroactive steroids 3α,5α-tetrahydroprogesterone or allopregnanolone (3α,5α-THP) and 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC) were shown to modulate neuronal excitability via their interaction with GABAA receptors. The steroids 3α,5α-THP and 3α,5α-THDOC were able to enhance the GABA-elicited Cl− current. [15] In addition, these steroids might enhance the binding of muscimol and benzodiazepines to GABAA receptors. [32] Structure- activity studies (SAR) showed that the 3alpha-OH group is essential for the anesthetic actions of these steroids, [33] they also have an optimally-placed hydrogen bond accepting group on the β face of the steroid at the C-17 position. The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space. [34] Analogues 5 and 6 (Figure 10) are weak modulators of GABAA receptor function because the flexible side chains in these analogues do not have the conformations required for high biological activity. [35]

See also

Related Research Articles

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

The GABAA-rho receptor is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. The GABAA-ρ receptor, like other GABAA receptors, is expressed in many areas of the brain, but in contrast to other GABAA receptors, the GABAA-ρ receptor has especially high expression in the retina.

<span class="mw-page-title-main">Neurosteroid</span> Compounds that affect neuronal excitability through modulation of specific ionotropic receptors

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Allopregnanolone</span> Endogenous inhibitory neurosteroid

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.

<span class="mw-page-title-main">Alfaxalone</span> Chemical compound

Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable anesthetic. Though it is more expensive than other induction agents, it often preferred due to the lack of depressive effects on the cardiovascular system. The most common side effect seen in current veterinary practice is respiratory depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; when premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up.

<span class="mw-page-title-main">L-838,417</span> Chemical compound

L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme.

<span class="mw-page-title-main">Pregnanolone</span> Chemical compound

Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties.

<span class="mw-page-title-main">L-655,708</span> Chemical compound

L-655,708 (FG-8094) is a nootropic drug invented in 1996 by a team working for Merck, Sharp and Dohme, that was the first compound developed which acts as a subtype-selective inverse agonist at the α5 subtype of the benzodiazepine binding site on the GABAA receptor. It acts as an inverse agonist at the α1, α2, α3 and α5 subtypes, but with much higher affinity for α5, and unlike newer α5 inverse agonists such as α5IA, L-655,708 exerts its subtype selectivity purely via higher binding affinity for this receptor subtype, with its efficacy as an inverse agonist being around the same at all the subtypes it binds to.

<span class="mw-page-title-main">Tetrahydrodeoxycorticosterone</span> Chemical compound

Tetrahydrodeoxycorticosterone, also referred to as allotetrahydrocorticosterone, is an endogenous neurosteroid. It is synthesized from the adrenal hormone deoxycorticosterone by the action of two enzymes, 5α-reductase type I and 3α-hydroxysteroid dehydrogenase. THDOC is a potent positive allosteric modulator of the GABAA receptor, and has sedative, anxiolytic and anticonvulsant effects. Changes in the normal levels of this steroid particularly during pregnancy and menstruation may be involved in some types of epilepsy and premenstrual syndrome, as well as stress, anxiety and depression.

<span class="mw-page-title-main">3α-Androstanediol</span> Chemical compound

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).

<span class="mw-page-title-main">5α-Dihydroprogesterone</span> Chemical compound

5α-Dihydroprogesterone is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone.

<span class="mw-page-title-main">17-Phenylandrostenol</span> Chemical compound

17-Phenylandrostenol (17-PA), or (3α,5α)-17-phenylandrost-16-en-3-ol, is a steroid drug which binds to GABAA receptors. It acts as an antagonist against the sedative effects of neuroactive steroids, but has little effect when administered by itself, and does not block the effects of benzodiazepines or barbiturates.

<span class="mw-page-title-main">Isopregnanolone</span> Chemical compound

Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone, and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of allopregnanolone. It has been reported to act as a subunit-selective negative allosteric modulator of the GABAA receptor, and antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as anesthesia, sedation, and reduced saccadic eye movements, but not learning impairment. Isopregnanolone has no hormonal effects and appears to have no effect on the GABAA receptor by itself; it selectively antagonizes allopregnanolone and does not affect the effects of other types of GABAA receptor positive allosteric modulators such as benzodiazepines or barbiturates.

<span class="mw-page-title-main">Epipregnanolone</span> Chemical compound

Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiators like allopregnanolone. Epipregnanolone is biosynthesized from progesterone by the actions of 5β-reductase and 3β-hydroxysteroid dehydrogenase, with 5β-dihydroprogesterone as the intermediate in this two-step transformation.

<span class="mw-page-title-main">5β-Dihydroprogesterone</span> Chemical compound

5β-Dihydroprogesterone is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone. It is synthesized from progesterone by the enzyme 5β-reductase.

<span class="mw-page-title-main">3α-Dihydroprogesterone</span> Chemical compound

3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid. It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone. 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action. In accordance, it has anxiolytic effects in animals. 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties. Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride. No data were available on the progestogenic activity of 3α-DHP as of 1977. Levels of 5α-DHP have been quantified.

A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.

<span class="mw-page-title-main">Darigabat</span> Chemical compound

Darigabat is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders. It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued. It is taken via oral administration.

References

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