329. DRUG PROFILE

DRUG   PROFILE

Cetirizine hydrochloride

INTRODUCTION:

A potent second-generation histamine H1 antagonist that is effective in the treatment of allergic rhinitis, chronic urticaria, and pollen-induced asthma.

STRUCTURE:

IUPAC NAME: (±)[2-[4-[(4-chlorophenyl) phenyl methyl] -1-piperazinyl]ethoxy]acetic acid dihydrochloride

Synonyms:

Cetirizina [Spanish]

Cetirizinum [Latin]

Cetrizine Hcl

Pharmacologic class: Potent second-generation histamine H1 antagonist

Category: Antihistamine, Anti allergic drug

PHYSICOCHEMICAL PROFILE

Empirical formula: C₂₁H₂₅Cl N₂O₃•2HCl

Molecular weight:  461.82g/mol

Description  : White, crystalline powder 

Solubility: Soluble in water insoluble in acetone and dichloromethane

Clinical Pharmacology:

Mechanism   of   Action:   Cetirizine,   a   human   metabolite   of   hydroxyzine,   is   an antihistamine; its principal effects are mediated via selective inhibition of peripheral H₁ receptors. The antihistaminic activity of cetirizine has been clearly documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth was more common with cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity for other than H₁ receptors.

Pharmacokinetics

Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (T_max) of approximately 1 hour following oral administration of tablets, chewable tablets or syrup in adults.  Comparable bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers were administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311ng/mL was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of exposure (AUC) of the cetirizine tablet or chewable tablet, but Tmax was delayed  by1.7 hours and 2.8 hours  respectively,  and  Cmax  was  decreased  by  23%  and  37%,  respectively  in  the presence of food.

Distribution: The mean plasma protein binding of cetirizine is 93%, independent of concentration in the range of 25-1000 ng/ml, which includes the therapeutic plasma levels observed.

Metabolism: A mass balance study in 6 healthy male volunteers indicated that 70% of the  administered  radioactivity  was  recovered  in  the  urine  and  10%  in the faeces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

Elimination: The mean elimination half life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for cetirizine was approximately 53 ml/min.

Pharmacodynamics:

Cetirizine hydrochloride at doses of 5 and 10 mg strongly inhibited the wheal and flare caused by intradermal injection of histamine in 19 pediatric volunteers (aged 5 to 12 years) and the activity persisted for at least 24 hours. In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic (suppression of wheal and flare response) effects of Cetirizine hydrochloride was found. In 10 infants 7 to 25 months of age who received 4 to 9 days of Cetirizine in an oral solution (0.25 mg/kg bid), there was a 90% inhibition of  histamine-induced  (10 mg/ml)  cutaneous  wheal  and  87%  inhibition  of  the  flare 12 hours after administration of the last dose. The clinical relevance of this suppression of histamine-induced wheal and flare response on skin testing is unknown.

The effects of intradermal injection of various other mediators or histamine releasers were also inhibited by cetirizine, as was response to a cold challenge in patients with cold-induced urticaria. In a four-week clinical trial in pediatric patients aged 6 to 11 years, results of randomly obtained ECG measurements before treatment and after 2 weeks of treatment showed that Cetirizine hydrochloride 5 or 10 mg did not increase QTc versus placebo.

In a one week clinical trial (N=86) of cetirizine hydrochloride syrup (0.25 mg/kg bid) compared with placebo in pediatric patients 6 to 11 months of age, ECG measurements taken within 3 hours of the last dose did not show any ECG abnormalities or increases in QTc interval in either group compared to baseline assessments. Data from other studies where Cetirizine hydrochloride was administered to patients 6-23 months of age were consistent with the findings in this study. The effects of cetirizine hydrochloride on the QTc interval at doses higher than 10 mg have not been studied in children less than 12 years of age. In a six-week, placebo-controlled study of 186 patients (aged 12 to 64 years) with allergic rhinitis  and   mild   to  moderate  asthma,  cetirizine  hydrochloride  10 mg  once  daily improved  rhinitis  symptoms  and  did  not  alter  pulmonary  function.  In  a  two-week, placebo-controlled clinical trial, a subset analysis of 65 pediatric (aged 6 to 11 years) allergic rhinitis  patients  with  asthma  showed  cetirizine  hydrochloride  did  not  alter pulmonary   function.  These  studies  support  the  safety  of  administering  cetirizine hydrochloride  to  pediatric  and  adult  allergic  rhinitis  patients  with  mild  to  moderate asthma.

Interaction Studies

Pharmacokinetic interaction studies with cetirizine in adults were conducted with pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and cetirizine (20 mg once daily for 3 days), a 16% decrease in the clearance of  cetirizine was  observed. The disposition of theophylline was not altered by concomitant cetirizine administration.

Indications and usage

Seasonal Allergic Rhinitis: Cetirizine is indicated for the relief of symptoms associated with seasonal allergic rhinitis due to allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes.

Perennial Allergic Rhinitis: Cetirizine is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in adults and children 6 months of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.

Chronic Urticaria: Cetirizine is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.  It  significantly  reduces  the  occurrence,  severity,  and  duration  of  hives  and significantly reduces pruritus.

Contraindications:

Cetirizine is contraindicated in those patients with a known hypersensitivity to it or any of its ingredients or hydroxyzine.

Precautions

Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has been reported in some patients taking cetirizine; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use  of  cetirizine  with  alcohol  or  other  CNS depressants  should  be  avoided  because additional reductions in alertness and additional  impairment of CNS performance may occur.

Drug-Drug Interactions: No clinically significant drug interactions have been found with theophylline at low dose azithromycin, pseudodephidrine, ketoconazoleor erythromycin. There was a small decrease in the clearance of cetirizine caused by a 400mg dose of theophylline it is possible that larger theophylline doses could have a greater effect.

Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year carcinogenicity study in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg.  In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg.  No increase in the incidence of liver tumors was observed in mice at a dietary dose of 4 mg/kg  (approximately 2 times the maximum recommended daily oral dose in adults on a mg/m² basis, or  approximately equivalent  to  the  maximum  recommended  daily  oral  dose  in  infants  on  a  mg/m² basis).Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats. In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg.

Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults on a mg/m² basis). There are, however, no adequate and well-controlled studies in pregnant women.

Nursing Mothers: In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis).  Studies in beagle dogs indicated that approximately 3% of the dose was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because many drugs are excreted in human milk, use of cetirizine in nursing mothers is not recommended.

Geriatric Use: Of the total number of patients in clinical studies of cetirizine, 186 patients were 65 years and older, and 39 patients were 75 years and older. No overall differences in safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. With regard to efficacy, clinical  studies  of  cetirizine  for  each  approved  indication  did  not  include  sufficient numbers  of  patients  aged  65  years  and  older  to  determine  whether  they  respond differently than younger patients.

Cetirizine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse reactions

Controlled and uncontrolled clinical trials conducted in the United States and Canada included more than 6000 patients aged 12 years and older, with more than 3900 receiving cetirizine at doses of 5 to 20 mg per day. The duration of treatment ranged from 1 week to 6 months, with a mean exposure of 30 days. Most adverse reactions reported during therapy with cetirizine were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in patients receiving cetirizine 5 or 10 mg was not significantly different from placebo (2.9% vs. 2.4%, respectively).The most common adverse reaction in patients aged 12 years and older that occurred more frequently on cetirizine than placebo was somnolence. The incidence of somnolence associated with cetirizine was dose related, 6% in placebo, 11% at 5 mg and 14% at 10 mg. Discontinuations due to somnolence for cetirizine were uncommon (1.0% on cetirizine vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be treatment related adverse reactions. There were no differences by age, race, and gender or by body weight with regard to the incidence of adverse reactions.

Autonomic Nervous System: Anorexia, flushing, increased salivation, urinary retention.

Cardiovascular: Cardiac failure, hypertension, palpitation, tachycardia.

Central and Peripheral Nervous Systems: Abnormal coordination, ataxia, confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine, myelitis, paralysis,  paresthesia, ptosis, syncope, tremor, twitching, vertigo, visual field defect.

Gastrointestinal: Abnormal hepatic  function,  aggravated  tooth  caries,  constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids, increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative stomatitis, tongue  discoloration,  tongue edema.

Genitourinary: Cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary tract infection.

Hearing and Vestibular: Deafness, earache, ototoxicity, tinnitus.

Metabolic/Nutritional: Dehydration, diabetes mellitus, thirst.

Musculoskeletal: Arthralgia, arthritis, arthrosis, muscle weakness, myalgia.

Psychiatric:   Abnormal thinking, agitation,  amnesia, anxiety, decreased    libido.

Respiratory      System:    Bronchitis,    dyspnea,    hyperventilation,    increased    sputum, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection. Reproductive: Dysmenorrhea, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, vaginitis.

Reticuloendothelial: Lymphadenopathy.

Skin:  Acne, alopecia, angioedema, bullous eruption,  dermatitis,  dry  skin,  eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis, increased  sweating, maculopapular rash,  photosensitivity reaction, photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin disorder, skin nodule, urticaria.

Special Senses: Taste loss, tastes perversion.

Vision: Blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation, ocular hemorrhage, exophthalmia.

Body as a Whole: Accidental injury, asthenia, back pain, chest pain, enlarged abdomen, face edema, fever, generalized edema, hot flashes, increased weight, leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral edema, rigors.Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy. Hepatitis with significant transaminase elevation and elevated bilirubin in association with the use of cetirizine has been reported.

Post-Marketing Experience

In the post-marketing period, the following additional rare, but potentially severe adverse events have been reported: aggressive reaction, anaphylaxis, cholestasis, convulsions, glomerulonephritis, hallucinations, hemolytic  anemia,  hepatitis,  or facial  dyskinesia, severe hypotension, stillbirth, suicidal ideation, suicide and thrombocytopenia.

1.4.7 Dosage and administration

Cetirizine is available as 5 mg and 10 mg capsules, 5 mg and 10 mg tablets, 1 mg/ml syrup, and 5 mg and 10 mg chewable tablets which can be taken with or without water.

328. Bleeding edge

Bleeding edge

Bleeding edge is a term that refers to technology that is so new (and thus, presumably, not perfected) that the user is required to risk reductions in stability and productivity in order to use it. It also refers to the tendency of the latest technology to be extremely expensive.

The term is formed as an allusion to "leading edge" and its synonym cutting edge, but implying a greater degree of risk: the "bleeding edge" is in front of the "cutting edge".

A technology may be considered bleeding edge under the following conditions:

• Lack of consensus — competing ways of doing some new thing exist and no one really knows for certain which way the market is going to go.
• Lack of knowledge — organizations are trying to implement a new technology or product that the trade journals have not even started talking about yet, either for or against.
• Industry resistance to change — trade journals and industry leaders have spoken against a new technology or product but some organizations are trying to implement it anyway because they are convinced it is technically superior.

The rewards for successful early adoption of new technologies can be great; unfortunately, the penalties for "betting on the wrong horse" (e.g. in a format war) or choosing the wrong product are equally large. Whenever an organization decides to take a chance on bleeding edge technology there is a good chance that they will be stuck with a white elephant or worse.

Recently however, the term bleeding edge has been increasingly used by the general public to mean "ahead of cutting edge" largely without the negative, risk-associated connotation concurrent with the term's use in more specific fields. An apt quotation concerning this issue is, "But when you’re living on the bleeding edge, you should not be surprised when you do, in fact, bleed."

The term is often used in discussions on the internet among users of computer software, especially open source software. It is common practice for open source developers to release new versions of their software fairly frequently, sometimes in a rather unpolished state. Therefore users who want features that have not been implemented in older, more stable releases of the software are able to choose the "bleeding edge" version.^[3] In such cases the user is willing to sacrifice stability or ease of use for the sake of increased functionality.

327. ANTIPARTICLE

ANTIPARTICLE

Particle and antiparticle;  electron/positron, proton/antiproton, neutron/antineutron.

Corresponding to most kinds of particles, there is an associated antiparticle with the same mass and opposite electric charge. For example, the antiparticle of the electron is the positively charged antielectron, or positron, which is produced naturally in certain types of radioactive decay.
The laws of nature are very nearly symmetrical with respect to particles and antiparticles. For example, an antiproton and a positron can form an antihydrogen atom, which has almost exactly the same properties as a hydrogen atom. This leads to the question of why the formation of matter after the Big Bang resulted in a universe consisting almost entirely of matter, rather than being a half-and-half mixture of matter and antimatter.
The discovery of CP violation helped to shed light on this problem by showing that this symmetry, originally thought to be perfect, was only approximate.
Particle-antiparticle pairs can annihilate each other, producing photons; since the charges of the particle and antiparticle are opposite, total charge is conserved. For example, the positrons produced in natural radioactive decay quickly annihilate themselves with electrons, producing pairs of gamma rays, a process exploited in positron emission tomography.
Antiparticles are produced naturally in beta decay, and in the interaction of cosmic rays in the Earth's atmosphere. Because charge is conserved, it is not possible to create an antiparticle without either destroying a particle of the same charge (as in beta decay) or creating a particle of the opposite charge. The latter is seen in many processes in which both a particle and its antiparticle are created simultaneously, as in particle accelerators. This is the inverse of the particle-antiparticle annihilation process.
Although particles and their antiparticles have opposite charges, electrically neutral particles need not be identical to their antiparticles.
The neutron, for example, is made out of quarks, the antineutron from antiquarks, and they are distinguishable from one another because neutrons and antineutrons annihilate each other upon contact.
However, other neutral particles are their own antiparticles, such as photons, the hypothetical gravitons, and some WIMPs.

History

Experiment

In 1932, soon after the prediction of positrons by Paul Dirac, Carl D. Anderson found that cosmic-ray collisions produced these particles in a cloud chamber— a particle detector in which moving electrons (or positrons) leave behind trails as they move through the gas.
The electric charge-to-mass ratio of a particle can be measured by observing the radius of curling of its cloud-chamber track in a magnetic field.
Positrons, because of the direction that their paths curled, were at first mistaken for electrons travelling in the opposite direction.
Positron paths in a cloud-chamber trace the same helical path as an electron but rotate in the opposite direction with respect to the magnetic field direction due to their having the same magnitude of charge-to-mass ratio but with opposite charge and, therefore, opposite signed charge-to-mass ratios.
The antiproton and antineutron were found by Emilio Segrè and Owen Chamberlain in 1955 at the University of California, Berkeley.
Since then, the antiparticles of many other subatomic particles have been created in particle accelerator experiments.
In recent years, complete atoms of antimatter have been assembled out of antiprotons and positrons, collected in electromagnetic traps.

Hole theory

... the development of quantum field theory made the interpretation of antiparticles as holes unnecessary, even though it lingers on in many textbooks.

Solutions of the Dirac equation contained negative energy quantum states. As a result, an electron could always radiate energy and fall into a negative energy state. Even worse, it could keep radiating infinite amounts of energy because there were infinitely many negative energy states available. To prevent this unphysical situation from happening, Dirac proposed that a "sea" of negative-energy electrons fills the universe, already occupying all of the lower-energy states so that, due to the Pauli exclusion principle, no other electron could fall into them.
Sometimes, however, one of these negative-energy particles could be lifted out of this Dirac sea to become a positive-energy particle. But, when lifted out, it would leave behind a hole in the sea that would act exactly like a positive-energy electron with a reversed charge. These he interpreted as "negative-energy electrons" and attempted to identify them with protons in his 1930 paper A Theory of Electrons and Protons However, these "negative-energy electrons" turned out to be positrons, and not protons.
Dirac was aware of the problem that his picture implied an infinite negative charge for the universe. Dirac tried to argue that we would perceive this as the normal state of zero charge. Another difficulty was the difference in masses of the electron and the proton. Dirac tried to argue that this was due to the electromagnetic interactions with the sea, until Hermann Weyl proved that hole theory was completely symmetric between negative and positive charges. Dirac also predicted a reaction e− + p+ → γ + γ, where an electron and a proton annihilate to give two photons. Robert Oppenheimer and Igor Tamm proved that this would cause ordinary matter to disappear too fast. A year later, in 1931, Dirac modified his theory and postulated the positron, a new particle of the same mass as the electron. The discovery of this particle the next year removed the last two objections to his theory.
However, the problem of infinite charge of the universe remains. Also, as we now know, bosons also have antiparticles, but since bosons do not obey the Pauli Exclusion Principle (only fermions do), hole theory does not work for them. A unified interpretation of antiparticles is now available in quantum field theory, which solves both these problems.

Particle-antiparticle annihilation

An example of a virtual pion pair that influences the propagation of a kaon, causing a neutral kaon to mix with the antikaon. This is an example of renormalization in quantum field theory— the field theory being necessary because the number of particles changes from one to two and back again.

If a particle and antiparticle are in the appropriate quantum states, then they can annihilate each other and produce other particles. Reactions such as e− + e+ →  γ + γ (the two-photon annihilation of an electron-positron pair) are an example. The single-photon annihilation of an electron-positron pair, e− + e+ → γ, cannot occur in free space because it is impossible to conserve energy and momentum together in this process. However, in the Coulomb field of a nucleus the translational invariance is broken and single-photon annihilation may occur. The reverse reaction (in free space, without an atomic nucleus) is also impossible for this reason. In quantum field theory, this process is allowed only as an intermediate quantum state for times short enough that the violation of energy conservation can be accommodated by the uncertainty principle. This opens the way for virtual pair production or annihilation in which a one particle quantum state may fluctuate into a two particle state and back. These processes are important in the vacuum state and renormalization of a quantum field theory. It also opens the way for neutral particle mixing through processes such as the one pictured here, which is a complicated example of mass renormalization.

Properties of antiparticles

Quantum states of a particle and an antiparticle can be interchanged by applying the charge conjugation (C), parity (P), and time reversal (T) operators. If denotes the quantum state of a particle (n) with momentum p, spin J whose component in the z-direction is σ, then one has where n^c denotes the charge conjugate state, i.e., the antiparticle. This behaviour under CPT is the same as the statement that the particle and its antiparticle lie in the same irreducible representation of the Poincaré group. Properties of antiparticles can be related to those of particles through this. If T is a good symmetry of the dynamics, then where the proportionality sign indicates that there might be a phase on the right hand side.
In other words, particle and antiparticle must have

• the same mass m
• the same spin state J
• opposite electric charges q and -q.

Quantum field theory

One may try to quantize an electron field without mixing the annihilation and creation operators by writing where we use the symbol k to denote the quantum numbers p and σ of the previous section and the sign of the energy, E(k), and a_k denotes the corresponding annihilation operators. Of course, since we are dealing with fermions, we have to have the operators satisfy canonical anti-commutation relations. However, if one now writes down the Hamiltonian then one sees immediately that the expectation value of H need not be positive. This is because E(k) can have any sign whatsoever, and the combination of creation and annihilation operators has expectation value 1 or 0.
So one has to introduce the charge conjugate antiparticle field, with its own creation and annihilation operators satisfying the relations where k has the same p, and opposite σ and sign of the energy. Then one can rewrite the field in the form where the first sum is over positive energy states and the second over those of negative energy. The energy becomes where E₀ is an infinite negative constant.
The vacuum state is  defined as the state with no particle or antiparticle, i.e., and. Then the energy of the vacuum is exactly E₀. Since all energies are measured relative to the vacuum, H is positive definite. Analysis of the properties of a_k and b_k shows that one is the annihilation operator for particles and the other for antiparticles. This is the case of a fermion.
This approach is due to Vladimir Fock, Wendell Furry and Robert Oppenheimer. If one quantizes a real scalar field, then one finds that there is only one kind of annihilation operator; therefore, real scalar fields describe neutral bosons.
Since complex scalar fields admit two different kinds of annihilation operators, which are related by conjugation, such fields describe charged bosons.

Feynman–Stueckelberg interpretation

By considering the propagation of the negative energy modes of the electron field backward in time, Ernst Stueckelberg reached a pictorial understanding of the fact that the particle and antiparticle have equal mass m and spin J but opposite charges q. This allowed him to rewrite perturbation theory precisely in the form of diagrams. Richard Feynman later gave an independent systematic derivation of these diagrams from a particle formalism, and they are now called Feynman diagrams. Each line of a diagram represents a particle propagating either backward or forward in time. This technique is the most widespread method of computing amplitudes in quantum field theory today.
Since this picture was first developed by Ernst Stueckelberg, and acquired its modern form in Feynman's work, it is called the Feynman-Stueckelberg interpretation of antiparticles to honor both scientists.