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1. Furosemide (INN) or 6rusemide (former BAN) is a loop diuretic used in the treatment of congestive heart
failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also
been used to prevent thoroughbred and standardbred race horses from bleeding through the nose during races.

Along with some other diuretics, Furosemide is also included on the World Anti-Doping Agency's banned drug
list due to its alleged use as a masking agent for other drugs.

Mechanism o6 action

Main article: Loop diuretic

Like other loop diuretics, furosemide acts by inhibiting the Na-K-2Cl symporter in the thick ascending limb of
the loop of Henle. The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase
or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative as well as positive
free water clearance.

Due to the large NaCl absorptive capacity of the Loop of Henle, diuresis is not limited by development of
acidosis, as it is with the carbonic anhydrase inhibitors.

By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-
positive potential that derives from K + recycling. This electrical potential normally drives divalent cation
reabsorbtion in the loop, and by reducing this potential loop diuretics cause an increase in Mg2+ and Ca2+
excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since Ca2+ is actively
reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia.

Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors. [1][2][3] Furosemide

has been reported to reversibly antagonize GABA-evoked currents of Į6ȕ2Ȗ2 receptors at µ0 concentrations, but
not Į1ȕ2Ȗ2 receptors.[1][3] During development, the Į6ȕ2Ȗ2 receptor increases in expression in cerebellar granule
neurons, corresponding to increased sensitivity to furosemide. [2]

Πinica use in humans

Furosemide, as a loop diuretic, is principally used in the following indications (Aventis, 1998):

J Adema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome
J Hypertension
J Adjunct in cerebral/pulmonary edema where rapid diuresis is required (IV injection)

It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration
[4]
.

Although disputed,[5] it is considered ototoxic: â
 

 




 



 
â[6]

The tendency, as for all loop diuretics, to cause low potassium levels ( hypokalemia) has given rise to
combination products, either with potassium itself (e.g. Lasix-K) or with the potassium sparing diuretic of
amiloride (Co-amilofruse).

Use in research

Furosemide has been used in research on the inner-ear. It's known to decrease temporarily the response to sound
by reducing the mobility of the basilar membrane of the cochlea and by reducing the transduction that normally
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results from the bending of stereocilia on hair cells. (demonstrated in 1991 by Mario Ruggero and Nola Rich
from the University of Minnesota)

èrecautions, side-e66ects, and administration

Furosemide is injected either intramuscularly (IM) or intravenously (IV), usually 0.5-1.0 mg/kg 2x/day,
although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte
imbalance, including loss of potassium, calcium, sodium, and magnesium. It is especially important to prevent
potassium loss. Axcessive use of Furosemide will most li kely lead to a metabolic alkalosis due to hypochloremia
and hypokalemia. The drug should therefore not be used in horses that are dehydrated or experiencing kidney
failure. It should be used with caution in horses with liver problems or electrolyte abnormalitie s. Overdose may
lead to dehydration, change in drinking patterns and urination, seizures, GI problems, kidney damage, lethargy,
collapse, and coma.

Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of
electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim
sulfa (causes decreased platelet count). It may also cause interactions with anesthesics, so its use should be
related to the veterinarian if the animal is going into surgery, and it decreases the kidney's ability to excrete
aspirin, so dosages will need to be adjusted if combined with that drug

Furosemide may cause digoxin toxicity due to hypokalemia.

The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the
placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia
dysfunction (Cushings).

Furosemide is detectable in urine 36±72 hours following injection. Its use is prohibited by most equestrian
organizations.

Drug Interactions

Furosemide has potential interactions with the following medications: [7]

J Aminoglycoside antibiotics such as Gentamicin

J Aspirin and other salicylates
J Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide)
J Indomethacin
J Lithium
J Synergistic effects with other antihypertensives (e.g. Doxazosin)
J Sucralfate

u. Essentia e 6orte- is a preparation of essential phospholipids. Assentiale normalizes the metabolism of lipids
and proteins, improves the detoxification function of the liver, restores the cellular structure of the liver and
retards the producing of conjunctive tissue. Assentiale medications are indicated for the treatment of fatty
degeneration of the liver, hepatitis (including toxic hepatitis, liver damage caused by medicines or alcohol
abuse), cirrhosis of the liver, disturbances in liver function associated with different illnesses.

èharmaceutica action

Phospholipids are essential structural components of all cellular membranes. Assential phospholipids (substance
APL) - are the complex substances of natural origin (ethers of cholinephosphoric acid (phosphatidylcholine) and
unsaturated fatty acids (linoleic, linolenic, olein)). Assentiale medications possess the membranotropic
properties, metabolic and hepatoprotective action; regulates lipid and carbohydrate metabolism. Assential
phospholipids increase functional status of the liver.
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While the disturbance of the liver metabolism essential phospholipids ensure the entering the high energy
phospholipids, which are ideally combined with the endogenous phospholipids. Under the Assentialle
phospholipids influence clinical and biochemical liver indexes are improved.

Combination of Assentiale with cordiamin ( nikethamide) and vitamin A (50 mg/kg for 35 days) considerably
activates the mono-oxigenase, glucoro- and glutathione transferase systems of the liver: and as a result the free-
radical processes became less intense [1].

The spectrum of essential phospholipids' activity in chronic degenerative liver diseases can be described in the
following properties:

J recovery and maintaining the consistency of the hepatocytes;

J activation of the phospholipid-depending ferments;
J improvement in the lipids metabolism caused by accelerated synthesis of lipoproteins in the liver;
J activation of synthesis RNA and as a result the normalization of the proteins metabolism ;
J increased synthesis of glycogen in the liver;
J improvement in the detoxification function of the liver;
J the conversion of neutral fats and cholesterol into the easily metabolizing forms;
J decreased the fatty infiltration of the hepatocytes.

Œommon use

Assentiale is used to treat the following diseases:

J Hepatitis(acute and chronic), toxic hepatitis, medicinal and alcoholic hepatitis, poisonings. Hepatic
steatosis of different aetiology(in 53.6 % of patients the effect of six-month treatment with Assentiale
forte was very good (improvement of all investigated parameters) [2]

diabetes(the data suggests that Assentiale protects and improves liver function in diabetic subjects with non
alcoholic fatty liver[3] [3] ) and chronic infections);

J Disturbance in liver function in somatic diseases;

J Hepatic cirrhosis;
J Necrosis of the liver cells, liver failure, liver coma;
J Pre- and Post- surgical treatment, especially in hepatobiliary area;
J Hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia;
J Diseases of the cardiovascular system: coronary heart disease, stable stenocardia [4], post-infarction
condition, disturbance of the cerebral and peripheral circulation, Hypertension, thrombembolia
prophylaxis, atherosclerosis, diabetic angiopathy, thrombembolia prophylaxis and fat
embolism(solution for injection);
J Digestive system diseases (chronic pancreatitis, gastric and duodenum ulcer;
J 6or Toxicosis of pregnancy(edema, proteinuria ɢ and blood pressure disorders);
J Radiation sickness (radiation syndrome);
J Psoriasis, atomic dermatitis, eczema;
J Pyelonephritis [5]
J Prophylaxis of micromegaly.

d ai abi ity

Assentiale medications are manufactured under 4 trade names:

ASSANTIALA- solution for intravenous injections in vials 5 ml. Assentiale contains essential
phospholipids(APL substance) 250 mg, Pyridoxine chidrochloride 2,5 mg (Vitamin B 6), Cyanocobolamine
0,1 mg (Vitamin B 12), Sodium Pantothenate 1.5 mg, Nicotinamide 25 mg
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ASSANTIALA FORTA N- Capsules N30 or N100. One capsule contains essential phospholipids (APL
substance) 300 mg.

ASSANTIALA N. -solution for intravenous injection in vials 5 ml. Assentale N contains essential
phospholipids(APL substance) 250 mg.

ASSANTIALA FORTA ± capsules N50. Assentiale forte contains essential phospholipids(APL substance)
300 mg, Thiamine mono nitrate(Vitamin B 1)6 mg, Riboflavine(Vitamiin B 2) 6 mg, Pyridoxine chidrochloride
6 mg(Vitamin B6), Cyanocobolamine 0.06 mg (Vitamin B 12), Nicotinamide 30 mg, Tocopherole acetate
6 mg(Vitamin A).

Œontradiction and cautions

Do not use Assentiale in hypersensitivity or allergy to any ingredients of the preparation. The application of
Assentiale in newborn children is not safe. During pregnancy women are recommended to consult their health
care provider prior to taking Assentiale.

Side e66ects

In very rare cases it can cause :abdominal pain, nausea, diarrhea and allergic reaction(skin rash).

Recommendation storage

Capsules should be stored at temperature not more than 20°C. Vials should be stored at 2° - 8°C

3.Thiamine or thiamin or itamin B1 (pronounced /š± š.Èmšn/ Y
ö), and named as the "thio-
vitamine" ("sulfur-containing vitamin") is a water-soluble vitamin of the B complex. First named 
 for the
detrimental neurological effects of its lack in the diet, it was eventually assigned the generic descriptor name
vitamin B 1. Its phosphate derivatives are involved in many cellular processes. The best-characterized form is
thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. In yeast, TPP is also
required in the first step of alcoholic fermentation.

All living organisms use thiamine in their biochemistry, but it is synthesized in bacteria, fungi, and plants.
Animals must obtain it from their diet, and, thus, for th em it is a vitamin. Insufficient intake in birds produces a
characteristic polyneuritis, and in mammals results in a disease called beriberi affecting the peripheral nervous
system (polyneuritis) and/or the cardiovascular system, with fatal outcome if not cured by thiamine
administration. [1] In less severe deficiency, nonspecific signs include malaise, weight loss, irritability and
confusion.[2]

There is still much work devoted to elucidating the exact mechanisms by which thiamine deficiency leads to the
specific symptoms observed (see below). New thiamine phosphate derivatives have recently been discovered, [3]
emphasizing the complexity of thiamine metabolism and the need for more research in the field.

4. èroprano o (INN) is a non-selective beta blocker mainly used in the treatment of hypertension. It was the
first successful beta blocker developed. Propranolol is available in generic form as propranolol hydrochloride, as
well as an AstraZeneca and Wyeth product under the trade names Inderal, Inderal LA, Avlocardyl (also
available in prolonged absorption form named "Avlocardyl Retard"), Deralin, Dociton, Inderalici, InnoPran XL,
Sumial, Anaprilinum (depending on marketplace and release rate), Bedranol SR (Sandoz).

Propranolol is one of the banned substances in the Olympics, presumably for its use in controlling stage fright
and tremors. It was taken by Kim Jong Su, a North Korean pistol shooter who won two medals at the 2008
Olympic Games. He was the first Olympic shooter to be disqualified for drug use. [1]


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£istory and de e opment

Scottish scientist James W. Black successfully developed propranolol in the late 1950s. In 1988, he was
awarded the Nobel Prize in Medicine for this discovery. Propranolol was derived from the early ȕ-adrenergic
antagonists dichloroisoprenaline and pronethalol. The key structural modification, which was carried through to
essentially all subsequent beta blockers, was the insertion of a methoxy bridge into the arylethanolamine
structure of pronethalol thus greatly increasing the potency of the compound. This also apparently eliminated
the carcinogenicity found with pronethalol in animal models.

Newer, more selective beta-blockers (such as nebivolol) are now used in the treatment of hypertension.

Indications

Propranolol is indicated for the management of various conditions including:

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While once first-line treatment for hypertension, the role for beta-blockers was downgraded in June 2006 in the
United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and
evidence is increasing that the most frequently used beta-blockers at usual doses carry an unacceptable risk of
provoking type 2 diabetes.[8]

Propranolol is also used to lower portal vein pressure in portal hypertension and prevent esophageal variceal
bleeding.

66- abe and in estigationa use

Propranolol is often used by musicians and other performers to prevent stage fright. It has been taken by
surgeons to reduce their own innate hand tremors during surgery.[9]

Propranolol is currently being investigated as a potential treatment for post-traumatic stress disorder. [10][11][12]
Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory
consolidation. Studies have shown that individuals given propranolol immediately after a traumatic experience
show less severe symptoms of PTSD compared to their respective control groups that did not receive the drug
(Vaiva et al., 2003). However, results remain inconclusive as to the success o f propranolol in treatment of
PTSD.

Propranolol in combination with etodolac is currently being investigated in a Phase 3 trial of 400 colorectal
cancer patients as a potential treatment for prevention of colorectal cancer recurrence. [13] The aim of this study is
to assess the use of perioperative medical intervention using a combination of a propranolol and etodolac in
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order to attenuate the surgically induced immunosuppression and other physiological perturbations, aiming to
reduce the rate of tumor recurrence and distant metastatic disease.

Recent evidence (June 2008) suggests that propranolol can be used to treat severe infantile hemangiomas
(IHs). [14] This treatment has proven superior to corticosteroids, as propranolol has fewer side effects and is more
effective when treating IHs.

Propranolol was investigated for possible effects on resting energy expenditure and muscle catabolism in
patients with severe burns. [15] In children with burns, treatment with propranolol during hospitalization
attenuated hypermetabolism and reversed muscle wasting.

Propranolol along with a number of other membrane-acting drugs have been investigated for possible effects on
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 and so the treatment of malaria. In vitro positive effects until recently had not been
matched by useful in vivo anti-parasite activity against è , [16] or è 


.[17] However a
single study from 2006 has suggested that propranolol may reduce the dosages required for existing drugs to be
effective against è  
 by 5- to 10-fold, suggesting a role for combination therapies. [18]

èrecautions and contraindications

Propranolol should be used with caution in patients with: [19]

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Propranolol is contraindicated in patients with: [19]

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dd erse e66ects

Adverse drug reactions (ADRs) associated with propranolol therapy are similar to other lipophilic beta blockers
(

).

èregnancy and actation

Propranolol, like other beta blockers, is classified as Pregnancy category C in the United States and ADAC
Category C in Australia. Beta-blocking agents in general reduce perfusion of the placenta which may lead to
adverse outcomes for the neonate, including pulmonary or cardiac complications, or premature birth. The
newborn may experience additional adverse effects such as hypoglycemia and bradycardia.[]

Most beta-blocking agents appear in the milk of lactating women. This is especially the case for a lipophilic
drug like propranolol. Breastfeeding is not recommended in patients receiving propranolol therapy.[]

èharmacokinetics
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Propranolol is rapidly and completely absorbed, with peak plasma levels achieved approximately 1±3 hours
after ingestion. Co-administration with food appears to enhance bioavailability. Despite complete absorption,
propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment will
therefore increase its bioavailability. The main metabolite 4 -hydroxypropranolol, with a longer half-life (5.2±7.5
hours) than the parent compound (3±4 hours), is also pharmacologically active.

Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a
single oral dose is longer than the half-life and may be up to 12 hours, if the single dose is high enough (e.g.,
80 mg). Affective plasma concentrations are between 10±100 ng/mL.

Toxic levels are associated with plasma concentrations above 2000 ng/ml.

Mechanism o6 action

Propranolol is a non-selective beta blocker, that is, it blocks the action of epinephrine and norepinephrine on
both ȕ1- and ȕ2 -adrenergic receptors. It has little intrinsic sympathomimetic activity (ISA) but has strong
membrane stabilizing activity (only at high blood concentrations, e.g. overdosage). Research has also shown
that propranolol has inhibitory effects on the norepinephrine transporter and/or stimulates norepinephrine
release (present experiments have shown that the concentration of norepinephrine is increased in the synapse but
do not have the ability to discern which effect is taking place). [20] Since propranolol blocks ȕ-adrenoceptors, the
increase in synaptic norepinephrine only results in Į-adrenergic activation, with the Į1-adrenoceptor being
particularly important for effects observed in animal models. Therefore, some have suggested that it be looked
upon as an indirect Į1 agonist as well as a ȕ antagonist. Probably owing to the effect at the Į1 -adrenoceptor, the
racemate and the individual enantiomers of propranolol have been shown to substitute for cocaine in rats, with
the most potent enantiomer being S-(±)-propranolol. Both enantiomers of the drug have a local anesthetic
(topical) effect. In addition, some evidence suggests that propranolol may function as a partial agonist at one or
more serotonin receptors (possibly 5-HT1B).

Interactions

Beta blockers, including propranolol, have an additive effect with other drugs which decrease blood pressure, or
which decrease cardiac contractility or conductivity. Clinically-significant interactions particularly occur
with:[19]

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Dosage

The usual maintenance dose ranges for oral propranolol therapy vary by indication:

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Intravenous (IV) propranolol may be used in acute arrhythmia or thyrotoxic crisis