Glaucoma is an eye disorder in which internal eye pressure (Intraocular pressure-IOP) is very high. In this condition, eye has too much aqueous humor pressure either because of over production of fluid or of improper draining. This leads to damage of optic nerve results in Vision loss. This nerve acts like an electric cable with over a million wires. It is responsible for carrying images from the eye to the brain.
According to World Health Organization, Glaucoma is the second leading cause of blindness (behind cataracts).

GLAUCOMA SYMPTOMS:
Glaucoma, known as “silent thief of sight” as it causes no pain and shows no symptoms in early stages and quietly causes vision loss. As no symptoms occur, the best way to diagnose this form of glaucoma is by periodic eye examination. Onset of any of symptoms like blurred vision, severe eye pain, red eyes, headache, nausea and vomiting is the warning alarm for eyes.

GLAUCOMA CAUSE:
A clear fluid flows in and out of the space at the front of the eye, nourishing nearby tissues. Glaucoma causes the fluid to pass through too slowly or to stop draining altogether. As the fluid builds up, the pressure inside the eye increases, causing damage to the optic nerve and vision loss.

RISK FACTORS:
Age: Glaucoma is more common among older people. People above 40 are 6 times more likely to get glaucoma.
Family History: The most common type of glaucoma, primary open angle glaucoma, is hereditary. Family history of glaucoma increases the risk of glaucoma four to nine times.
Indiscriminate use of Steroids: Studies indicate Steroids increase intraocular pressure. These could be in the form of Oral medications, Steroid Inhalers and Steroid Eye Drops used for long periods of time.
Injury to Eye: Injury to the eye may cause secondary open angle glaucoma. This type of glaucoma can occur immediately after the injury or years later.

CARE, NUTRITION AND SUPPLEMENTS:
Glaucoma is controlled and treated if detected in early stages. Early detection of Glaucoma save the patient form vision loss and eye damage. Glaucoma is control with Medicines (Oral and eye-drops) and Laser Surgery.

Other than Medicines and Surgery, following care, nutrition and supplements are required to keep eye healthy and free from eye problems:

1. Exercise: Regular physical activity can lower intra ocular pressure by a little bit.

2. Food & Diet: Carrots, Spinach, Green leafy vegetables, citrus fruits, blueberries, cherries, tomatoes, whole milk, egg, lean meat and seafood should be taken to keep eye healthy and full of vision. And should limit the intake of caffeine, alcohol and smoking.

3. Nutritional Supplements: There are few supplements known to improve the clinical condition of Glaucoma.

A. Alpha Lipoic Acid (ALA): Alpha Lipoic Acid (ALA) is very powerful antioxidant and this antioxidant property is helpful in improving eye conditions like glaucoma, cataract and diabetic retinopathy. Clinical studies shows that, regular intake of 150 mg of Alpha Lipoic acid improves visual acuity and colour perception by 45- 47% in glaucoma patients. ALA shows strong neuroprotective properties which significantly prevent ischemic optic nerve damage and improves fluid discharge.

Ref.: Filina AA, et al. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 1995; 111:6-8.

B. Omega-3 Fatty Acids: Studies show direct association between Omega 3 fatty acid and eye health. Omega 3 fatty acid is helpful in inflammatory and intraocular pressure (IOP) conditions. It is studied that with the regular consumption of Omega 3 fatty acid leads to decrease in IOP with age by increasing the aqueous outflow in glaucoma patients. Omega 3 fatty acid helps to decrease the eye inflammation by reducing the production of inflammatory cellular signaling molecules.

Ref.: 1. Cellini M, Rossi A & Moretti M. The use of polyunsaturated fatty acids in ocular hypertension. Acta ophtalmol Scand 1999;77 (suppl. 229):54-55
2. Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing aqueous outflow. Invest Ophthalmol Vis Sci. 2007.

CoQ10: Every day, you chew a supplement that contains 60mg of coenzyme Q10, or CoQ10, an antioxidant that helps maintain the soft tissues in your body-including your gums. Some early research suggests that taking CoQ10 can even help shrink the pockets caused by gum disease.

Calcium: Calcium, a mineral found in your jawbone. If you don’t get enough calcium, your jaw weakens, loosening your teeth. Men and women from ages 19 to 49 need 1,000mg of calcium, daily, while those over 50, require 1,200mg. A cup of milk or yogurt packs about 300mg and an ounce of most cheeses has around 200mg.

Vitamin D: To absorb calcium, your body needs vitamin D. According to the WHO recommendation, a full third of Indians don’t get enough. You must follow the recommendation and get at least 400IU daily. Milk has about 100IU per cup and a 3-ounce serving of fattier fish, like salmon or mackerel, contains about 300IU. If you don’t drink milk or eat fish, you could probably use a supplement of 400 IU daily.

Vitamin C: There’s one more super-important nutrient for your teeth: Vitamin C. It’s a building block for collagen, which helps keep your teeth attached to your gums. A study in the Journal of Periodontology found that men and women who consumed less than 60mg of vitamin C daily were 150 percent more likely to have gum disease than people who took in at least 180mg. Fruit and veggies are the major sources of vitamin C (One orange alone has 60mg). You get enough C in your diet, but if you don’t, consider taking a supplement.

Omega-3 fatty acids: Studies shows that “People with low intake (of DHA) had an approximately 1.5 times higher incidence rate ratio of periodontal disease progression”. Regular intake of Omega-3 supplements is helpful in the treatment of periodontal disease and other gum diseases. Its anti-inflammatory effects effectively reduce the chances of gum inflammation, weak gum and teeth.

Probiotics & Prebiotics: Probiotics are potential therapy for maintaining oral health. It is used to reduce dental caries and periodontal diseases. Probiotics significantly maintains healthy balance of the bacteria flora in the mouth. Microbial growth promotes serious tooth decay and bad breath. Daily intake of probiotics in early childhood may result in less dental carries. Probiotics suppress the odor-producing bacteria, resulting in a decrease in the foul smelling gases arising in the mouth. It also helps to reduce the gum inflammation and plague formation caused by microbial growth. Prebiotics give the probiotics to exert their influence by aiding and boosting immunity.

Tip: AVOID FIZZY SUPPLEMENTS

Don’t buy the chewable Vitamin-C tablets or any kind of supplement that fizzes when you dissolve it in water. Chewable and fizzy vitamins lower the pH in your mouth and erode your tooth enamel big time. In fact, a recent study from the University of Helsinki found that fizzy supplements, including those containing calcium, caused teeth to lose minerals. The worst offenders were the fizzy vitamin-C supplements-they corroded the teeth so much that the layer below the enamel was exposed.

A healthy smile can help you look years younger. Just think about your diet, and weigh your need for six favorite supplements.

Mifepristone is a synthetic  19-nor steroid compound with a bulky p-(dimethylamino)phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.

It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency  contraceptive.

In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist).

Mifepristone is also a powerful glucocorticoid receptor antagonist and a weak androgen receptor antagonist  and has occasionally been used in refractory Cushing’s Syndrome (due to ectopic/ neoplastic ACTH/Cortisol secretion).

Mifepristone’s relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol; its relative binding affinity at the androgen receptor is less than one third that of testosterone. It does not bind to the estrogen receptor or the mineralocorticoid receptor.

PHARMACOLOGY

Pharmacodynamics

The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites.Mifepristone inhibits the activity of endogenous or exogenous progesterone leading to  termination of pregnancy .

Doses of 1 mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women. During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins.

Mifepristone also exhibits  antiglucocorticoid and weak antiandrogenic activity. Doses of 4.5 mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol.

Pharmacokinetics

Absorption

Following oral administration mifepristone is rapidly absorbed, with a peak  plasma concentration  occurring approximately 90 minutes after ingestion.

Distribution

Mifepristone is 98% bound to plasma proteins, albumin and alpha 1 -acid glycoprotein. Binding to the latter protein is saturable, and the drug displays nonlinear kinetics with respect to plasma concentration and clearance.

Following a distribution phase, elimination of mifepristone is slow at first (50% eliminated between 12 and 72 hours) and then becomes more rapid with a terminal elimination half-life of 18 hours.

Metabolism

Metabolism of mifepristone is primarily via pathways involving N-demethylation and terminal hydroxylation of the 17-propynyl chain.                                                                                                                                                                      CYP450 3A4 is primarily responsible for the metabolism. The three major metabolites identified in humans are:

(1) N- monodemethylated metabolite most widely found in plasma,

(2) Results  from the loss of two methyl groups from the 4-dimethylaminophenyl in position 11ß  and

(3) Results from terminal hydroxylation of the 17-propynyl chain.

Excretion

83% of the drug is excreted  by the faeces and 9% by the urine. Serum levels are undetectable

Indications

1. Medical termination of intrauterine pregnancies of up to 49 days gestation

2. Softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination

3. Labor induction in fetal death in utero.

4. Regular long-term use as an oral contraceptive

5.To treat Endogenous Cushing’s syndrome –Recently FDA approved

Undesirable effects

Women typically experience abdominal pain, including uterine cramping and vaginal bleeding or spotting.

Other commonly reported side effects are nausea, vomiting and diarrhoea. Pelvic pain, fainting, headache, dizziness ,fever and asthenia occurred rarely.

Serious bacterial infection, bleeding, ectopic pregnancies that have ruptured and death  including another death from sepsis were recently reported

Drug Interactions 

Although specific drug or food interactions with mifepristone have not been studied, on the basis of drug`s metabolism by CYP 3A4, it is possible that

-Ketoconazole, Itraconazole, Erythromycin, and grapefruit juice may inhibit mifepristone  metabolism (increasing serum levels of it).

-Rifampin, Dexamethasone, , and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine)   may induce mifepristone metabolism (lowering serum levels of mifepristone).

-Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anaesthesia.

 Contraindications

Contraindicated in patients with any one of the following conditions:

-Confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass

- IUD in place

-Chronic adrenal failure

-History of allergy to mifepristone

-Haemorrhagic disorders

-Inherited porphyria

-Anticoagulant or long-term corticosteroid therapy

Ascorbic acid enhances absorption of iron. Ascorbic acid reduces ferric iron to ferrous iron which remains soluble even at neutral pH.

Ascorbate is a reducing agent and prevents Oxidation. Thus maintains Iron in highly soluble ferrous form.

Ferrous form is absorbed thrice as much as ferric form of iron.

Ferrous ascorbate has the advantage of providing both ferrous ion and ascorbate in the same compound.

There is no dissociation of Ferrous ascorbate on entering GI Tract due to the stable chelate of Iron with Ascorbate.

Also there is no action of food inhibitors as the complex does not dissociate.

There is  greater absorption of iron in vivo from ferrous ascorbate [Fe(HL)2] as compared with ferrous sulfate.

This is due to

a)Retardation or prevention of Ferrous oxidation by ascorbate and

b)The existence of Ferrous as a chelate with ascorbate.

The available literature demonstrates  that Ferrous ascorbate  { Fe(HL)2 } dissociates in aqueous solution into a monomeric cationic species Fe(HL)1+, Fe2+ and HL-.

The HL anion acts as a monodentate.

The low stability constant KFe(HL)1, about 20 l.mol-1 at mu = 0 and 25 degrees C, results in the conclusion that Fe(HL)2 is almost completely dissociated into Fe2+ and HL- at about pH = 5.

So complex formation does not contribute significantly to the increased iron absorption. Between pH = 6 and pH = 8 a solubility enhancing effect of ascorbate is observed which may be of relevance for the iron absorption from ferrous ascorbate.

Hence the stability of complex Ferrous Ascorbate contributes to the increased Iron Absorption.                                                                                                

Research shows that omega-3 fatty acids reduce inflammation and may help lower risk of chronic diseases such as heart disease, cancer, and arthritis. Omega-3 fatty acids are highly concentrated in the brain and appear to be important for cognitive (brain memory and performance) and behavioral function. In fact, infants who do not get enough omega-3 fatty acids from their mothers during pregnancy are at risk for developing vision and nerve problems. Symptoms of omega-3 fatty acid deficiency include fatigue, poor memory, dry skin, heart problems, mood swings or depression, and poor circulation.

It is important to have the proper ratio of omega-3 and omega-6 (another essential fatty acid) in the diet. Omega-3 fatty acids help reduce inflammation, and most omega-6 fatty acids tend to promote inflammation. The typical American diet tends to contain 14 – 25 times more omega-6 fatty acids than omega-3 fatty acids, which many nutritionally oriented physicians consider to be way too high on the omega-6 side.

DIETARY SOURCES:

Fish, plant, and nut oils are the primary dietary source of omega-3 fatty acids.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in cold water fish such as salmon, mackerel, halibut, sardines, tuna, and herring.

ALA is found in flaxseeds, flaxseed oil, canola (rapeseed) oil, soybeans, soybean oil, pumpkin seeds, pumpkin seed oil, purslane, perilla seed oil, walnuts, and walnut oil.

The health effects of omega-3 fatty acids come mostly from EPA and DHA. ALA from flax and other vegetarian sources needs to be converted in the body to EPA and DHA.

INDICATIONS:

Clinical evidence is strongest for heart disease and problems that contribute to heart disease, but omega-3 fatty acids may also be used for:

High blood pressure

Several clinical studies suggest that diets rich in omega-3 fatty acids lower blood pressure in people with hypertension. An analysis of 17 clinical studies using fish oil supplements found that taking 3 or more grams of fish oil daily may reduce blood pressure in people with untreated hypertension. Doses this high, however, should only be taken under the direction of a physician.

Heart disease

The role of omega-3 fatty acids in cardiovascular disease is well established. One of the best ways to help prevent heart disease is to eat a diet low in saturated fat and to eat foods that are rich in monounsaturated and polyunsaturated fats (including omega-3 fatty acids). Clinical evidence suggests that EPA and DHA (eicosapentaenoic acid and docosahexaenoic acid, the 2 omega-3 fatty acids found in fish oil) help reduce risk factors for heart disease, including high cholesterol and high blood pressure. Fish oil has been shown to lower levels of triglycerides (fats in the blood), and to lower the risk of death, heart attack, stroke, and abnormal heart rhythms in people who have already had a heart attack. Fish oil also appears to help prevent and treat atherosclerosis (hardening of the arteries) by slowing the development of plaque and blood clots, which can clog arteries.

High cholesterol

People who follow a Mediterranean style diet tend to have higher HDL or “good” cholesterol levels, which help promote heart health. Inuit Eskimos, who get high amounts of omega-3 fatty acids from eating fatty fish, also tend to have increased HDL cholesterol and decreased triglycerides (fats in the blood). Several studies have shown that fish oil supplements reduce triglyceride levels. Finally, walnuts (which are rich in alpha linolenic acid or ANA, which converts to omega-3s in the body) have been reported to lower total cholesterol and triglycerides in people with high cholesterol levels.

Diabetes

People with diabetes often have high triglyceride and low HDL levels. Omega-3 fatty acids from fish oil can help lower triglycerides and apoproteins (markers of diabetes), and raise HDL, so eating foods or taking fish oil supplements may help people with diabetes. Another type of omega-3 fatty acid, ALA (from flaxseed, for example) may not have the same benefit as fish oil. Some people with diabetes can’ t efficiently convert ANA to a form of omega-3 fatty acids that the body can use. Also, some people with type 2 diabetes may have slight increases in fasting blood sugar when taking fish oil, so talk to your doctor to see if fish oil is right for you.

Rheumatoid arthritis

Most clinical studies examining omega-3 fatty acid supplements for arthritis have focused on rheumatoid arthritis (RA), an autoimmune disease that causes inflammation in the joints. A number of small studies have found that fish oil helps reduce symptoms of RA, including joint pain and morning stiffness. One study suggests that people with RA who take fish oil may be able to lower their dose of non-steroidal anti-inflammatory drugs (NSAIDs). However, unlike prescription medications, fish oil does not appear to slow progression of RA, only to treat the symptoms. Joint damage still occurs.

Laboratory studies suggest that diets rich in omega-3 fatty acids (and low in the inflammatory omega-6 fatty acids) may help people with osteoarthritis, although more study is needed. New Zealand green lipped mussel (Perna canaliculus), another potential source of omega-3 fatty acids, has been reported to reduce joint stiffness and pain, increase grip strength, and improve walking pace in a small group of people with osteoarthritis. For some people, symptoms got worse before they improved.

An analysis of 17 randomized, controlled clinical trials looked at the pain relieving effects of omega-3 fatty acid supplements in people with RA or joint pain caused by inflammatory bowel disease (IBS) and painful menstruation (dysmenorrhea). The results suggest that omega-3 fatty acids, along with conventional therapies such as NSAIDs, may help relieve joint pain associated with these conditions.

Systemic lupus erythematosus (SLE)

Several small studies suggest that EPA may help reduce symptoms of lupus, an autoimmune condition characterized by fatigue and joint pain.

Osteoporosis

Some studies suggest that omega-3 fatty acids may help increase levels of calcium in the body and improve bone strength, although not all results were positive. Some studies also suggest that people who don’ t get enough of some essential fatty acids (particularly EPA and gamma-linolenic acid [GLA], an omega-6 fatty acid) are more likely to have bone loss than those with normal levels of these fatty acids. In a study of women over 65 with osteoporosis, those who took EPA and GLA supplements had less bone loss over 3 years than those who took placebo. Many of these women also experienced an increase in bone density.

Depression

Studies have found mixed results as to whether taking omega-3 fatty acids can help depression symptoms. Several studies have found that people who took omega-3 fatty acids in addition to prescription antidepressants had a greater improvement in symptoms than those who took antidepressants alone. Other studies show that omega-3 fatty acid intake helps protect against postpartom depression, among other benefits. However, other studies have found no benefit.

Schizophrenia

Preliminary clinical evidence suggests that people with schizophrenia may have an improvement in symptoms when given omega-3 fatty acids. However, a recent well designed study concluded that EPA supplements are no better than placebo in improving symptoms of this condition.

Attention deficit/hyperactivity disorder (ADHD)

Children with attention deficit/hyperactivity disorder (ADHD) may have low levels of certain essential fatty acids (including EPA and DHA). In a clinical study of nearly 100 boys, those with lower levels of omega-3 fatty acids had more learning and behavioral problems (such as temper tantrums and sleep disturbances) than boys with normal omega-3 fatty acid levels.

However, studies examining whether omega-3 fatty acids help improve symptoms of ADHD have found mixed results. A few studies have found that omega-3 fatty acids helped improve behavioral symptoms, but most were not well designed. One study that looked at DHA in addition to stimulant therapy (standard therapy for ADHD) found no effect. More research is needed, but eating foods that are high in omega-3 fatty acids is a reasonable approach for someone with ADHD.

Cognitive decline

A number of studies show that reduced intake of omega-3 fatty acids is associated with increased risk of age related cognitive decline or dementia, including Alzheimer’s disease. Scientists believe the omega-3 fatty acid DHA is protective against Alzheimer’s disease and dementia.

Skin disorders

In one clinical study, 13 people with sun sensitivity known as photo dermatitis showed less sensitivity to UV rays after taking fish oil supplements. However, topical sunscreens are much better at protecting the skin from damaging effects of the sun than omega-3 fatty acids. In another study of 40 people with psoriasis, those who took EPA with their prescription medications did better than those treated with the medications alone. However, a larger study of people with psoriasis found no benefit from fish oil.

Inflammatory bowel disease (IBD)

Results are mixed as to whether omega-3 fatty acids can help reduce symptoms of Crohn’ s disease and ulcerative colitis, the 2 types of IBD. Some studies suggest that omega-3 fatty acids may help when added to medication, such as sulfasalazine (a standard medication for IBD). Others find no effect. More studies are needed. Fish oil supplements can cause side effects that are similar to symptoms of IBD (such as flatulence, belching, bloating, and diarrhea).

Asthma

Studies examining omega-3 fatty acids for asthma are mixed. In one small, well designed clinical study of 29 children with asthma, those who took fish oil supplements rich in EPA and DHA for 10 months reduced their symptoms compared to children who took placebo. However, most studies have shown no effect.

Macular Degeneration

A questionnaire given to more than 3,000 people over the age of 49 found that those who ate more fish were less likely to have macular degeneration (a serious age related eye condition that can progress to blindness) than those who ate less fish. Similarly, a clinical study comparing 350 people with macular degeneration to 500 without the eye disease found that those with a healthy dietary balance of omega-3 and omega-6 fatty acids and more fish in their diets were less likely to have macular degeneration.

Menstrual pain

In one study of 42 women, they had less menstrual pain when they took fish oil supplements than when they took placebo.

Colon cancer

Eating foods rich in omega-3 fatty acids seems to reduce the risk of colorectal cancer. For example, Eskimos, who tend to have a high fat diet, but eat significant amounts of fish rich in omega-3 fatty acids, have a low rate of colorectal cancer. Animal studies and laboratory studies have found that omega-3 fatty acids prevent worsening of colon cancer. Preliminary studies suggest that taking fish oil daily may help slow the progression of colon cancer in people with early stages of the disease.

Breast cancer

Although not all experts agree, women who eat foods rich in omega-3 fatty acids over many years may be less likely to develop breast cancer. More research is needed to understand the effect that omega-3 fatty acids may have on the prevention of breast cancer.

Prostate cancer

Population based studies of groups of men suggest that a low fat diet including omega-3 fatty acids from fish or fish oil help prevent the development of prostate cancer.

POSSIBLE INTERACTIONS:

Blood thinning medications – Omega-3 fatty acids may increase the effects of blood thinning medications, including aspirin, warfarin , and clopedigrel.

Diabetes medications – Taking omega-3 fatty acid supplements may increase fasting blood sugar levels. Use with caution if taking medications to lower blood sugar, such as glipizide, glyburide, Metformin or insulin.

Cyclosporine – Cyclosporine is a medication given to people with organ transplants. Taking omega-3 fatty acids during cyclosporine therapy may reduce toxic side effects, such as high blood pressure and kidney damage, associated with this medication.

Etretinate and topical steroids – Adding omega-3 fatty acids (specifically EPA) to the drug therapy etretinate and topical corticosteroids may improve symptoms of psoriasis.

Cholesterol-lowering medications – Following dietary guidelines, including increasing the amount of omega-3 fatty acids in your diet and reducing the omega-6 to omega-3 ratio, may help a group of cholesterol lowering medications known as statins (Atorvastatin,Lovastatin,Simvastatin) to work more effectively.

Nonsteroidal anti-inflammatory drugs (NSAIDs) – In an animal study, treatment with omega-3 fatty acids reduced the risk of ulcers from nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include ibuprofen and naproxen. More research is needed to see whether omega-3 fatty acids would have the same effects in people.

Although some foods, such as milk and orange juice, are fortified with vitamin D, studies have shown that many individuals still consume low amounts of this nutrient or have insufficient vitamin D serum levels. This may in part be related to changing dietary patterns in this United States, such as low consumption of milk and foods rich in vitamin D (eg, salmon, eel, tuna, and mackerel). Since most biologically active vitamin D comes from skin exposure to sunlight, the increased widespread use of broad-spectrum, high sun-protection-factor sunscreens in recent years may also contribute to the rise in vitamin D deficiency.

Several guidelines have been issued by national organizations that recommend varying amounts of vitamin D intake. Perhaps the most current, authoritative consensus report has been issued by the Institute of Medicine. This guideline recommends a daily dietary allowance of vitamin D of 600-800 IU/day for most patients. However, increased amounts are necessary for treating insufficiency and deficiency. Although much attention has been given to vitamin D intake, most consensus statements do not delineate the differences between the 2 major oral formulations: vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol).

Vitamin D is produced cutaneously and converted to active metabolites in the liver and kidney. On exposure to ultraviolet irradiation, provitamin D₃ (7-dehydrocholesterol) in the skin is converted to previtamin D₃, which is then isomerized to more stable vitamin D₃ via a thermally induced transformation. Vitamin D₃, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D. This is the major circulating form of vitamin D that is assayed to detect deficiency. 25-hydroxyvitamin D is hydroxylated again in the kidney to form 1,25-dihydroxyvitamin D₃, the major biologically active form of vitamin D, also known as calcitriol.Thus, in the setting of severe renal impairment, formulations of calcitriol are preferred over ergocalciferol and cholecalciferol because the terminal hydroxylation occurs in the kidney.

Regarding the manufacturing of oral vitamin D formulations, ergocalciferol is made from ultraviolet irradiation of ergosterol in yeast. Cholecalciferol is made from irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol. Traditionally, oral formulations of vitamin D₂ and D₃ have long been regarded as equivalent in their clinical activity. However, studies indicate that ergocalciferol (vitamin D₂) is much less potent and has a shorter duration of action than cholecalciferol.

Historically, ergocalciferol has been used instead of cholecalciferol for severe vitamin D deficiency. This is out of convention, or perhaps because high-dose ergocalciferol is more widely available in doses of up to 50,000 IU per softgel capsule from multiple manufacturers. Although this dose of cholecalciferol is available from at least 1 manufacturer, it is often challenging to find in retail outlets. Based on this author’s experience, and verified by others, it is often difficult to raise 25-hydroxyvitamin D levels with ergocalciferol in patients with severe vitamin D deficiency.

Armas and colleaguesadministered single oral doses of 50,000 IU of the respective vitamin D preparations to 20 healthy male volunteers, and followed the time course of 25-hydroxyvitamin D levels over a period of 28 days. A pharmacokinetic analysis was also done. Both ergocalciferol and cholecalciferol produced similar initial increases in serum levels of 25-hydroxyvitamin D over the first 3 days, indicating equivalent absorption. However, levels continued to increase with cholecalciferol and peaked at day 14, whereas levels decreased rapidly with ergocalciferol and were no different from baseline at day 14. The investigators concluded that ergocalciferol potency is less than 30% of that of cholecalciferol and that it has a markedly shorter duration of action.

This study is consistent with other single, high-dose studies that indicate the mean time to peak concentration of ergocalciferol to be about 3 days compared with 14 days for cholecalciferol. A review by Houghton and Viethestimated that cholecalciferol is more than 3 times as effective as ergocalciferol in elevating 25-hydroxyvitamin D and maintaining those levels for a longer time. These authors also note that cholecalciferol metabolites have superior affinity for vitamin D-binding proteins in plasma, relative to ergocalciferol.

In conclusion, ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃) are not bioequivalent and should not be considered interchangeable. Although few head-to-head trials exist, based on pharmacokinetic studies and limited clinical evidence, cholecalciferol is preferred over ergocalciferol. Because of its shorter half-life and decreased potency, this is especially relevant in the setting of severe deficiency, where high-dose ergocalciferol is often only given once weekly. Health professionals should encourage use of cholecalciferol over ergocalciferol in all patients without severe renal failure, either as a general supplement or as a treatment for vitamin D deficiency.

What form of vitamin D is recommended in chronic kidney disease?

Vitamin D is produced endogenously in the skin and converted to active metabolites in the liver and kidney. Upon exposure to ultraviolet irradiation, provitamin D3 (7-dehydrocholesterol) in the skin is converted to previtamin D3, which is then isomerized to vitamin D3 (cholecalciferol). Vitamin D3, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D (25-OH VD). This is the major circulating form of vitamin D that is assayed to detect deficiency.

A subsequent hydroxylation of 25-OH VD occurs in the kidney to form 1,25-dihydroxyvitamin D, the major biologically active form of vitamin D, also known as calcitriol.Thus, in the setting of severe chronic kidney disease (CKD), formulations of calcitriol may be preferred over vitamin D2 and D3 to treat deficiency because the terminal hydroxylation occurs in the kidney.

In the setting of CKD it is important to estimate glomerular filtration rate (GFR) and to determine serum 25-OH VD, calcium, phosphorous, and intact PTH levels when choosing the most optimal regimen. Supplementation of vitamin D plays a major role in the prevention of secondary hyperparathyroidism in patients with CKD. According to clinical practice guidelines from the National Kidney Foundation, the preferred form of supplementation is guided by serum 25-OH VD levels, stage of kidney failure, and presence or absence of secondary hyperparathyroidism. Before and during supplementation, both serum calcium and phosphorous levels should be drawn every 3 months. If levels of these minerals rise, vitamin D supplementation may need to be withheld or the dosage modified.

In the presence of secondary hyperparathyroidism, which usually begins in stage 3 or 4 of CKD (GFR 30-59 mL/min and 15-29 mL/min, respectively), the preferred agent for supplementation is an activated vitamin D sterol (eg, calcitriol or paricalcitol). Supplementation should begin when serum levels of 25-OH VD fall below 30 ng/mL. The vitamin D sterol dose depends on the serum levels of 25-OH VD, PTH, calcium, and phosphorus. Likewise, in stage 5 of CKD (GFR < 15 mL/min and patients treated with hemodialysis or peritoneal dialysis), an activated vitamin D sterol is also preferred in lieu of vitamin D2 or D3.

However, in the absence of secondary hyperparathyroidism, as is often the case in patients with GFR > 60 mL/min or only mild renal impairment, either oral vitamin D2 or D3 can be used. Studies indicate that vitamin D2 (ergocalciferol) is much less potent and has a shorter duration of action than D3 (cholecalciferol) and that vitamin D3 more effectively raises 25-OH VD levels. Thus, cholecalciferol is preferred in patients with normal or mild renal impairment (GFR > 60 mL/min) with a normal intact PTH level.

The dihydroxy bile acid, ursodeoxycholic acid (UDCA), has been in widespread clinical use in the Western world since the mid 1980s, when it was initially used for gallstone dissolution [1,2] and subsequently for the treatment of chronic cholestatic liver diseases. Many clinical trials of UDCA in a variety of cholestatic disorders established biochemical and clinical improvements, and most importantly showed a significant prolongation of transplant-free survival after four years of treatment with UDCA in patients with primary biliary cirrhosis. Despite its clinical efficacy, the precise mechanism(s) by which UDCA improves liver function during cholestasis is still a matter of debate. It was initially considered that the choleretic effect of UDCA, coupled with its ability to cause a marked shift in the composition of the bile acid pool towards hydrophilicity, accounted for its mechanism of action. In recent years, however, it has become evident that UDCA and its conjugated derivatives are capable of exerting direct effects at the cellular, subcellular, and molecular levels by stabilising cell membranes, affecting signal transduction pathways, and regulating immune responses. In addition, we have shown that UDCA plays a unique role in modulating the apoptotic threshold in both hepatic and non-hepatic cells. The purpose of this article is to examine the mechanism(s) by which UDCA prevents apoptotic cell death associated with cholestasis. In addition, we will also review a potentially novel and, heretofore, unrecognised role of UDCA as a therapeutic agent in the treatment of non-liver diseases associated with increased levels of apoptosis as a pathogenesis of the disorder.

Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Hence, febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid.

For treatment of hyperuricemia in patients with gout, febuxostat is recommended at 40 mg or 80 mg once daily. No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal and hepatic impairment

A combination of two beta-lactam antibiotics,amoxicillin and dicloxacillin, and lactobacillus. They exert their bactericidal action by inhibition of cell wall synthesis. Amoxicillin is active against a wide range of Grampositive and Gram-negative pathogens, and dicloxacillin acts against penicillinase,producing Gram-positive pathogens. Lactobacillus is an aerobic, Gram-positive,ubiquitous inhabitant of the human oral cavity, the vagina and the gastrointestinal tract. It inhibits the colonization of pathogenic bacteria on the intestinal epithelium.

This inhibitory process, known as “competitive exclusion”, can be expanded by the competition between the pathogens and the lactobacilli for the adherence sites of the intestinal mucosa, and by the inhibitory substance.

PHARMACOLOGY

Pharmacodynamics

Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of the biosynthesis of cell wall mucopeptide. Amoxycillin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:

Aerobic Gram-positive microorganisms

Enterococcus faecalis

Staphylococcus spp.* (beta-lactamase-negative strains only)

Streptococcus pneumoniae

Streptococcus spp. (alpha- and beta-hemolytic strains only)

* Staphylococci that are susceptible to amoxicillin, but resistant to methicillin/oxacillin

should be considered as resistant to amoxicillin.

Aerobic Gram-negative microorganisms

Escherichia coli (beta-lactamase-negative strains only)

Haemophilus influenzae (beta-lactamase-negative strains only)

Neisseria gonorrhoeae (beta-lactamase-negative strains only)

Proteus mirabilis (beta-lactamase-negative strains only)

Helicobacter

Helicobacter pylori

Lactobacillus acidophilus therapy in the prevention and adjuvant therapy of certain infectious diseases, especially gastrointestinal disorders in children and adults, is advocated in many parts of the world. The recent emphasis on supplementation with lactobacilli is largely attributed to information obtained regarding their beneficial effects in preventing or minimizing the severity of antibiotic-associated diarrheal

episodes. Most probiotics have been designated as generally recognized as safe

(GRAS).

Pharmacokinetics

Amoxicillin

Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin has been partially investigated. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid (except when the meninges are inflamed). The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged

in the urine; its excretion can be delayed by concurrent administration of probenecid.

In blood serum, amoxicillin is approximately 20% protein-bound. Orally administered doses of 250 mg and 500 mg amoxicillin capsules result in average peak blood levels, 1 to 2 hours after administration, in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.

Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1 gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6–8 hours.

Dicloxacillin

The isoxazolyl penicillins (dicloxacillin, oxacillin, and cloxacillin) are more acidresistant and may be administered orally. Absorption after oral administration is rapid but incomplete: peak blood levels are achieved in 1–1.5 hours. In one study, after ingestion of a single 500 mg oral dose, peak serum concentrations range from 10–17 mg/mL for dicloxacillin. Oral absorption of dicloxacillin is delayed when the drug is administered after meals. It is distributed throughout the body, with the highest concentrations present in the kidneys and the liver. CSF penetration is low. It also crosses the placenta and enters into breast milk. Protein binding is 97.9 ± 0.6.

The elimination half-life is 0.7 hours, which is slightly prolonged in case of renal impairment. Non-renal elimination includes hepatic inactivation and excretion in the bile. Time to peak serum is 0.5-–2 hours. It is excreted in the feces and the urine (56–70%) as unchanged drug.

INDICATIONS

Indicated for the treatment of the following:

• Respiratory Tract Infections

Tonsillar abscess, otitis media, suppurative sinus infection, acute chronic bronchitis, bronchiectasis, bronchopneumonia, pleurisy, empyema, lung abscess, emphysema, bronchiolitis.

• Urinary Tract Infections

Acute and chronic pyelonephritis, cystitis, urethritis.

• Skin and Soft Tissue Infections

Recurrent boils, carbuncles, impetigo, cellulitis and other infected dermatoses.

• Bone Infections

Osteomyelitis and septic arthritis.

• Serious Infections

Septicemia, bacterial endocarditis, brain abscess and bacterial meningitis.

DOSAGE AND ADMINISTRATION

The dosage differs, depending on the type, site and severity of infections. The usual dosage is one capsule, three to four times daily.

In patients with severe renal impairment, the dosage should be modified by increasing the intervals between doses. With a creatinine clearance between 10 and 50 mL/min, the dosing interval can be up to 12 hours. If the clearance is less than 10 mL/min, the interval can be 16 hours.

CONTRAINDICATIONS

History of allergic reaction to any of the penicillins

WARNINGS AND PRECAUTIONS

Serious and, occasionally, fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin

hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy, a detailed inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs,

It should be discontinued and appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids and airway management, including intubation, should also be initiated as indicated.

Drug Interactions

Probenecid: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin

 Oral contraceptives: In common with other antibiotics, amoxicillin may affect the gut flora, leading to lower estrogen re-absorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Bacteriostatic drugs: Drugs such as chloramphenicol, erythromycin and tetracycline may reduce the bactericidal action of amoxicillin and cloxacillin.

Renal Impairment

Please see DOSAGE AND ADMINISTRATION.

Pregnancy

Can be given during pregnancy. However, the drug should be used with caution.

Lactation

The drug can be safely given to nursing mothers; to the baby, there is some risk of sensitization, skin rash and diarrhea.

Pediatric Use

Because of an incompletely developed renal function in neonates and young infants, the elimination of the drug may be delayed.

UNDESIRABLE EFFECTS

As with all penicillins, the side effects are generally those related to allergic response.

OVERDOSAGE

Symptoms of penicillin overdose include neuromuscular hypersensitivity (eg. agitation, hallucinations, asterixis, encephalopathy, confusion, and seizures).

Electrolyte imbalance may occur if the preparation contains potassium or sodium salts, especially in renal failure. Hemodialysis may aid in the removal of the drug from blood; otherwise, treatment is supportive or symptom-directed.