HIV (Human immunodeficiency virus)

HIV (Human immunodeficiency virus)

Human immunodeficiency virus. The term "HIV" has been internationally accepted in the scientific community as the appropriate name for the retrovirus that is the causative agent of AIDS.
HIV is a virus which attacks the immune system and prevents it from functioning. It can be transferred from human to human via blood and bodily fluids.
Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which progressive letdown of the immune system allows life-threatening opportunistic infections and cancers to prosper. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four most important routes of transmission are unsafe sex, unhygienic needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission).
HIV infection in humans is considered pandemic by the World Health Organization (WHO). Nevertheless, satisfaction about HIV may play a key role in HIV risk. From its discovery in 1981 to 2006, AIDS killed over 25 million people. HIV infects about 0.6% of the world's population. In 2009, AIDS claimed an estimated 1.8 million lives, down from a global peak of 2.1 million in 2004. In the order of 260,000 children died of AIDS in 2009. A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and growing poverty. In 2005, it was estimated that HIV would infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.

History of HIV

The history of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) dates back to 1981, when homosexual men with symptoms of a disease that now are considered typical of AIDS were primary described in Los Angeles and New York. The men had an unusual type of lung infection (pneumonia) called Pneumocystis carinii (now known as Pneumocystis jiroveci) pneumonia (PCP) and rare skin tumors called Kaposi's sarcomas. The patients were renowned to have a severe reduction in a type of cell in the blood (CD4 cells) that is a vital part of the immune system. These cells, often referred to as T cells, help the body fight infections. Shortly thereafter, this disease was familiar throughout the United States, Western Europe, and Africa. In 1983, researchers in the United States and France described the virus that causes AIDS, now known as HIV, belonging to the group of viruses called retroviruses. While HIV infection is required to develop AIDS, the actual definition of AIDS is the development of a low CD4 cell count (<200 cells/mm3) or any one of a long list of complications of HIV infection ranging from a variety of so-called "opportunistic infections," cancers, neurologic symptoms, and wasting syndromes.

AIDS

When CD4+ T cell numbers decline lower a dangerous level of 200 cells per µL, cell-mediated immunity is vanished, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations.
Common opportunistic infections and tumors, the greater parts of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is vanished early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma.
HIV spread (transmitted)
HIV is present to changeable degrees in the blood and genital secretions of virtually all individuals infected with HIV, regardless of whether or not they have symptoms. The spread of HIV can occur when these secretions come in contact with tissues such as those lining the vagina, anal area, mouth, eyes (the mucus membranes), or with a break in the skin, such as from a cut or puncture by a needle. The most common ways in which HIV is spreading throughout the world include sexual contact, sharing needles, and by transmission from infected mothers to their newborns during pregnancy, labor (the delivery process), or breastfeeding. (See the section below on treatment during pregnancy for a discussion on reducing the risk of transmission to the newborn.)
Sexual transmission of HIV has been described from men to men, men to women, women to men, and women to women through vaginal, anal, and oral sex. The best way to avoid sexual transmission is abstinence from sex until it is certain that both partners in a monogamous relationship are not HIV-infected. Because the HIV antibody test can take months to turn positive after infection occurs, both partners would need to investigation negative for at least 12 and up to 24 weeks after their last potential exposure to HIV.
The spread of HIV by exposure to infected blood usually results from sharing needles, as in those used for illicit drugs. HIV also can be spread by sharing needles for anabolic steroids to increase muscle, tattooing, and body piercing. To prevent the spread of HIV, as well as other diseases including hepatitis, needles should never be shared. At the beginning of the HIV epidemic, many individuals acquired HIV infection from blood transfusions or blood products, such as those used for hemophiliacs. At present, however, because blood is tested for both antibodies to HIV and the actual virus before transfusion, the risk of acquiring HIV from a blood transfusion in the United States is extremely small and is considered insignificant.

There is small evidence that HIV can be transferred by casual exposure, as might occur in a household setting. For example, unless there are open sores or blood in the mouth, kissing is generally considered not to be a risk factor for transmitting HIV. This is because saliva, in contrast to genital secretions, has been shown to contain very little HIV. Still, theoretical risks are associated with the sharing of toothbrushes and shaving razors because they can cause bleeding, and blood can contain large amounts of HIV. Consequently, these items should not be shared with infected people. Similarly, without sexual exposure or direct contact with blood, there is little if any risk of HIV contagion in the workplace or classroom.

Types of treatment

There are five main groups of drugs involved:
 Nucleoside reverse transcriptase inhibitors (NRTIs)
 Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
 Nucleotide reverse transcriptase inhibitors
 Protease inhibitors
 Fusion inhibitors.
Usually, three different drugs from at least two of these groups are taken together, two to four times a day. Some tablets now contain two or three dissimilar drugs. The advantage of these combination drugs is that people do not need to take as many tablets each day.

How treatment works

When the HIV virus gets into a body cell, it normally starts to make copies of itself. These copies then spread out of that cell and into another. Drug treatments control the virus by interfering with the chemicals it uses to make copies of itself inside the body cells. The fusion inhibitors stop the HIV binding onto a new cell so it can no longer enter.
Over time, the virus can become resistant to the drugs, which means that they won’t work as well. The treatment may then have to be changed to a different combination of drugs.
People taking drug treatment for HIV will probably need to take it for the rest of their lives. Stopping drug treatment, even for little periods of time, can cause the virus to become resistant to those drugs. It is not recommended that anyone interrupt drug treatment without medical advice.
Drug treatment does not work well for everyone. Even when it is working well, it cannot control all of the virus, so the person will still have HIV in their body.
Treatment does not stop someone with HIV from being able to pass on the virus through unprotected sex or sharing needles or injecting equipment.

Gemifloxacin

Gemifloxacin

Gemifloxacin mesylate is a synthetic broad spectrum antibacterial for oral administration. Gemifloxacin a compound related to the fluoroquinolone class of antibiotics is available as the mesylate salt in the sesquihydrate form.
Mode of action

Gemifloxacin is a DNA gyrase inhibitor and also inhibits topoisomerase IV. DNA gyrase (topoisomerase IV) is an essential bacterial enzyme that maintains the superhelical structure of DNA. DNA gyrase is required for DNA replication and transcription, DNA repair, recombination, and transposition, bactericidal.
Pharmacokinetics

Gemifloxacin is rapidly absorbed from the gastrointestinal tract with absolute bioavailability of about 71%. Peak plasma concentrations occur 0.5 to 2 hours after an oral dose. Gemifloxacin is widely distributed into body tissues including the bronchial mucosa and lungs, and is about 55 to75% bound to plasma proteins. It undergoes limited hepatic metabolism and has an elimination half life of about 7 hours. It excreted as unchanged drug and metabolites in the faeces and urine. Urinary excretion is by active tubular secretion and is reduce by probenecid. Distribution into milk has been found in rats.
Indications
Gemifloxacin is indicated for the treatment of infections caused by susceptible of the designated microorganisms in the condition listed below.
• Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
• Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumonia (including multi- drug resistant strains [MDRSP]), Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamybia pneumoniae, or Klebsiella pneumoniae.
• Acute sinusitis
• Uncomplicated urinary tract infections
• Acute pyelonephritis

Contraindication

Gemifloxacin is contraindicated in patients with a history of hypersensitivity to gemifloxacin, floroquinolone antibiotic agents, or any of the product components.
Use in pregnancy and Lactation
There are no adequate and well-controlled studies in pregnant women. Reports of arthropathy (observed in immature animals and reported rarely in humans) have limited the use of fluoroquinolones in pregnancy. Reversible fatal growth retardation was observed with gemifloxacin in some animal studies. Based on limited data, quinolones are not expected to be a major human teratogen. Although quinolone antibiotics should not be used as first-line agents during pregnancy, when considering treatment for life-threatening infection and/or prolonged duration of therapy, the potential risk to the fetus must be balanced against the severity of the potential illness. Excretion in breast milk is unknown. So, Gemifloxacin is not recommended in lactating women.
Side Effect
There are many serious side effects of Gemifloxacin:

1. fast or pounding heartbeats
2. feeling light-headed, fainting, drowsiness, dizziness
3. seizure (convulsions)
4. confusion, and feeling restless or anxious
5. a red, blistering, peeling skin rash, vaginal itching or discharge & mild skin itching
6. urinating less than usual or not at all
7. tremors or shaking
8. easy bruising or bleeding, unusual weakness
9. nausea, vomiting, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
10. sudden pain or swelling near your joints (especially in your arm or ankle)
11. numbness, tingling, or weakness in any part of your body
12. diarrhea that is watery or bloody


Drug Interaction

May interact with blood thinners (e.g. warfarin), corticosteroids (e.g. prednisone), diabetes medications (e.g. insulin), probenecid, live vaccines. Report the use of drug which might increase seizure risk (decrease seizure threshold) when combined with Gemifloxacin such as phenothiazines (e.g. thioridazine), tricyclic antidepressants (e.g. amitriptyline), isoniazid (INH) or theophylline.


Except those drugs more over have another drugs which are interact with previous mentions drugs:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Medications for heart arrhythmias
• Erythromycin
• Antipsychotics
• Water pills
• Steroid medications
• Antacids
• Sucralfate

• Didanosine
Gemifloxacin may interact with other medications or substances that are not listed above. In order to avoid potentially hazardous interactions, patients should talk with their doctor about the use of any other medicines, vitamins or supplements before beginning treatment with gemifloxacin.
Precautions
• Before taking Gemifloxacin, caution should be taken if you are allergic or have had a severe reaction to gemifloxacin or any other quinolone or fluoroquinolone antibiotics such as ciprofloxacin, gatifloxacin, levofloxacin, lomefloxacin , moxifloxacin; any other medications.
• You are taking antacids containing aluminum hydroxide or magnesium hydroxide or vitamin or mineral supplements that contain iron, magnesium, or zinc, take these medications 3 hours before or 2 hours after you take gemifloxacin.
• Before using this medication, tells your doctor about rain or nervous system disorder if any (e.g. Cerebral arteriosclerosis, tumors increased intracranial pressure), heart problems (e.g. Cardiomyopathy, slow heart rate, QTc prolongation), history of seizures kidney disease, muscle/joint/tendon problems.
• Gemifloxacin may make your skin sensitive to sunlight or ultraviolet light. So avoid prolong sun exposure.
• This medication should be used only when clearly needed during pregnancy. Consult your doctor before breast feeding.
Overdosage
Any signs or symptoms of overdosage should be treated symptomatically. No specific antidote is known. In the event of acute oral overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage; the patient should be carefully observed and treated symptomatically with appropriate hydration maintained. Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.
Mortality occurred at oral gemifloxacin doses of 1600 mg/kg in rats and 320 mg/kg in mice. The minimum lethal intravenous doses in these species were 160 and 80 mg/kg, respectively. Toxic signs after administration of a single high oral dose (400 mg/kg) of gemifloxacin to rodents included ataxia, lethargy, piloerection, tremor, and clonic convulsions.

Pizotifen

Pizotifen

Pizotifen is a tricyclic compound having antiserotoninergic and antihistaminergic effects together with a weak anticholinergic action, but a little or no activity on kinins or their liberators. At low concentration Pizotifen may potentiate the actions of serotonin.

Mechanism of action

Pizotifen, like all triptans, is a serotonin agonist, which means it acts like serotonin. Serotonin, also known as 5-hydroxytriptamine (5-HT), is a neurotransmitter that regulates communication between nerve cells and the widening of blood vessels. It acts by activating proteins on nerve endings and blood vessels, called 5-HT receptors. Pizotifen also activates these receptors. Activation prevents the release of chemicals that mediate pain and narrows blood vessels, which reduces their leakiness.

Pharmacology

Pizotifen is characterized by its polyvalent inhibition effect on biogenic amines, such as serotonin, histamine and tryptamine. Pizotifen also possesses appetite stimulation properties.

Indication

Pizotifen is indicated for the prophylactic treatment of vascular headaches of migraine types such classical migraine, common migraine, and cluster headaches. It is also indicated in appetite loss of somatic or psychogenic organ in underweight patients as an adjuvant to treatment of the underlying condition, such as infection or parasitic diseases (including during convalescence), chronic diarrhea, anorexia nervosa, or depressive states in the elderly and mood disturbances in the elderly.

Contraindication

It is Contraindication in patient with `a history of hypersensitivity to any components of the product. Although its achlinergic activity it’s relatively weak, Pizotifen should be probably not be administered in the presence of narrow-angle glaucoma or prostate hypertrophy. Pizotifen should not be given in to children under 2 years of age.

Side effect

The most commonly occurring side effect are drowsiness and an increase in appetite, which may lead to increase in body weight. Other side effects such as dizziness, dry mouth nausea and constipation have been reported infrequency. In children, CNS stimulation may occur.

Pregnancy and lactation

As clinical data with Pizotifen in Pregnancy is very limited, although no ill effects have been reported. The drug should therefore only be given during pregnancy if the potential benefit to mother justifies the potential risk to the fetus. The safety of Pizotifen during lactation has not been established, so mother should avoid taking it when breast feeling.

Caution

Urinary retention, renal impairment, pregnancy and beast feeding should be taken in consideration. Drowsiness may affect the performance of skilled task (e.g. Dividing), effect of alcohol is enhances.

Precaution

Patient should be warned about the possibility of drowsiness and its significance in the driving of vehicle and the operation of machinery.

Drug interaction

Tolerance to alcohol may be lowered. Prolong the drowsiness that occurs as adverse effect of concurrently used tranquilizers, hypnotics and antidepressant. It should not be used in patients receiving monoamine oxidize inhibitors.

Dose and Administration

The recommended dose is as followings:

Adult: the initial dose is 1.5mg daily; this may be taken at bedtime as a single dose or in three divided dose. Dosage can be adjusted according to the individual patient requirement up to a maximum of 4.5mg daily. Up to 3mg may be given as a single daily dose.

Children: up to 1.5mg daily, usually as a divide dose. Use of 1.5mg at a time is not recommended, but up to 1mg can be given as a single daily dose at night. Children below two years of age should not be given Pizotifen.

Or, a directed by the registered physician.

Pharmaceuticals precaution

Store in a cool dry place protected from light. Keep out of reach of children.

Market competitors

Serial no.	Company Name	Brand name	Pack size	Unite per price	Selling price(per year)
01	Square	Migranil	Box containing 5×10 tablet Or 5×1 tablets in blister pack	3tk	TK. 22,751,915
02	Bexcimco	Avidro	Box containing 1×10 tablet Or 10×10 tablets in blister pack	3tk	TK. 5,938,344 tk
03	Drug International Ltd.	De-fen	Box containing 10×10 tablet Or 1×10 tablets in blister pack	2tk	TK. 6,580,221
04	Aristopharma Ltd.	Zofen	Box containing 10×10 tablet in blister pack	3tk	TK. 18,752,830
05	Opsonin Pharm	Pifen	Box containing 5×10 tablet in blister pack	2tk	TK. 2,503,136

SWOT analysis:

Seiral no.	Strength(Pizotifen)	Weakness(Rizatriptan)
01	It required low dose of Pizotifen as 1.5mg daily for acute treatment. So it active therapeutic effect at low dose	Rizatriptan required high dose as 5mg or 10mg daily for acute treatment it’s given low at high dose.
02	Children above 2 years it should be given	It is not recommended in children.
03	The bioavailability of this drug is 75%	The bioavailability of this drug is 45%
04	About 90% bound to plasma proteins. Peak plasma concentrations occur about 5 hr after a single oral dose.	About 5% bound to plasma proteins. Peak plasma concentrations occur about 10-15 hr after a single oral dose.

MICROMERITICS AND POWDER RHEOLOGY

MICROMERITICS AND POWDER RHEOLOGY

Importance of micromeritics in pharmacy

Size and size range of particles are very important in pharmacy.

1. Size and surface area of particles are related to physical, chemical and physiological properties of a drug.

2. The necessary flow properties of solid powders in tablet and capsule manufacture depends on the particle size, size distribution and size distribution.

3. Particle size of a drug affects the release from a dosage form administered orally, parenterally, rectally, and topically. Dissolution rate is faster from smaller particle size due to its high specific surface area.

4. Rate of sedimentation in suspension and rate of creaming in emulsion is faster with larger particles. Hence, to make a stable suspension or emulsion the particle size must be controlled.

5. For accurate determination of pore size of filters the size of particles are required.

6. Antigens are coated on adsorbent particles where the particle size is important for uniform dose calculation.

PARTICLE SIZE AND SIZE DISTRIBUTION

A powder sample is characterized by three things: (a) shape of the particles, (b) size of the particles and (c) size distribution of the particles. If the shape of a particle is perfectly spherical it is easy to express it by its diameter; but if it is not spherical then it becomes very difficult to express in diameter. Most of the pharmaceutical particles are not perfectly spherical.

If all the particles have same diameter then the powder sample is called a monodisperse system, but if all the particles are not of equal sizes then that powder sample is called polydisperse system. Most of the pharmaceutical powders and dispersion are polydisperse systems.

Average particle size

Suppose a powder sample is examined under microscope and the diameter of the particles are measured individually. The average diameter can be expressed in various ways. Edmundson has derived a general eqution for the average particle size (d_mean):

where n = number of particles in a certain size range

d = diameter of those particles

p = 1 stands for length, p = 2 stands for surface area and p = 3 stands for volume of the particle

If p > 0 (i.e. p is positive) then d_mean is arithmetic mean

If p = 0 then d_mean is geometric mean

If p <>mean is harmonic mean

f = frequency index [f has values of 0, 1, 2, 3 then the frequency distribution is expressed in number (0), length (1), surface (2) and volume or weight (3) of the particles, respectively.]

Let us take the following example:

Diameter (mm) (d)	Number (n)	nd	nd2	nd3	nd4
0.75 1.25 1.75 2.25 2.75 3.25 3.75	2 10 22 54 17 8 5	1.50 12.50 38.50 121.50 46.75 26.00 18.75	1.13 15.63 67.38 273.38 128.56 84.50 70.31	0.85 19.54 117.92 615.11 353.54 274.63 263.66	0.64 24.43 206.36 1384.00 972.24 892.55 988.73
	= 118	= 265.50	= 640.89	= 1645.25	= 4468.95

Statistical diameters:

	p	f	Type of mean	Size parameter	Frequency	Mean Diameter	Value of data obtained from the table	Comments
	1	0	Arithmetic	Length	Number	Length-Number mean, dln.	2.25	Rarely found in pharmaceutical powders
	2	0	Arithmetic	Surface	Number	Surface-number mean, dsn.	2.33	Refers to particles having average surface area.
	3	0	Arithmetic	Volume	Number	Volume-number mean, dvn.	2.41	Refers to particles having average weight
	2	1	Arithmetic	Surface	Length	Surface-length mean, dsl.2.41	2.41	No practical significance
	3	2	Arithmetic	Volume	Surface	Volume-Surface mean, dvs.	2.57	Inversely related to specific surface area* Important pharmaceutically

* Specific surface area =

Particle size distribution

When the number or weight of particles lying within a certain size range is plotted against the size range or mean particle size, a graph is obtained, that is called as frequency distribution curve.

Estimation of flow properties of a powder:

Two indicators of flow properties are there (i) Angle of repose (f) and (ii) Flow rate

Angle of repose

This is the maximum angle possible between the surface of a heap of powder and the horizontal plane.

It is an indicator of the frictional and cohesive forces in a loose powder.

Method-1:	Method-2	Method-3
Powder is released slowly through a funnel on a horizontal round surface. A heap will form. When the particles will glide over the heap the addition was stopped and the height (h) was measured. The diameter (D) of the round surface was known previously. Angle of repose, f =	A hollow cylinder is half-filled with the powder. One end of the cylinder is sealed with a transparent plate. The inside surface of the cylinder is lined with sand paper to reduce the slip of powder. The cylinder is rotated about its horizontal axis, until the powder surface cascades. The value of f is measured with a protractor.	A rectangular box is lined with sand paper. The box is filled with powder and tilted slowly until the powder begins to slide. The angle, f, is measured as the angle of repose.

Flow rate measurement:

The flow rate of granules (less cohesive materials) may be assessed by passing the powder through a circular orifice fitted in the base of a cylindrical container. The powder is taken in the container and released through the orifice on the pan of a balance. The weight of powder or granules falling per unit of time is recorded.

To improve the flow properties of granules a type of powders are used, they are called glidants. Examples of glidants are talc, corn starch etc.