DRUGDEX® Evaluations

GLYCERIN 0.0   Overview1)  Classa)  This drug is a member of the following class(es):AntiglaucomaCardiovascular AgentDiuretic, OsmoticGastrointestinal AgentLaxative, HyperosmoticLaxative, Stool SoftenerLubricant, OcularProtectant, DentalProtectant, Dermatological2)  Contraindicationsa)  Hypersensitivity to any component in the preparationb)  Well-established anuriac)  Severe dehydrationd)  Frank or impending acute pulmonary edemae)  Severe cardiac decompensation 

 1.0   Dosing Information

Drug Properties

Storage and Stability

Adult Dosage

Pediatric Dosage

 1.1   Drug PropertiesA)  Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index)B)  SynonymsGlycerinGlycerineGlycerolC)  Physicochemical Properties1)  Molecular Weighta)  92.09 

 1.2   Storage and StabilityA)  Extemporaneous Formulation - Intravenous route1)  An intravenous (IV) injection of glycerin is not commercially available. An IV preparation can be prepared by adding 100 grams (g) glycerin and 45.5 g anhydrous dextrose to 1 liter water (yields 10% glycerin and 5% dextrose solution). Sodium chloride is then added to make a solution of 10% glycerin, 5% dextrose and 0.45 to 0.9% sodium chloride (Frank et al, 1981).2)  MD Anderson Hospital utilized glycerin USP and dextrose 5% water to prepare a 10% v/v solution containing 0.125 grams/milliliter (g/mL). A volume of 100 mL of glycerine was added to 900 mL of sterile dextrose solution. The solution was then autoclaved according to liquid sterilization guidelines at 250 F for 29 minutes in the Authovac model B autoclave. An expiration date of 30 days was put on the bottle, at which time it was autoclaved again. The solution was filtered by a 0.45 micron filter to remove any extraneous particulate matter that might have been present in the glycerin (Bedikian et al, 1980).3)  Small volumes of anhydrous glycerin for trigeminal cistern injection may be sterilized using dry heat autoclave or slow careful filtration through a 0.45 micron Millipore(R) filter (Pers Comm, 1983a; Pers Comm, 1983b).4)  Glycerin may be sterilized by maintaining a temperature of 150 degrees for 1 hour (Reynolds, 1989). 

 1.3   Adult Dosage

Normal Dosage

Dosage in Hepatic Insufficiency

1.3.1   Normal Dosage

Ophthalmic route

Rectal route

Cerebral edema

Neoplasm of central nervous system

Occlusive stroke

Primary angle-closure glaucoma

Raised intracranial pressure

Raised intraocular pressure

1.3.1.A   Ophthalmic route1)  Hypertonic agents, such as glycerin, are effective for short- or long-term treatment of epithelial edema by reducing corneal edema and improving visual acuity. The long-term use of ocular glycerin is not well tolerated and instillation is painful. Glycerin may also be used prior to ophthalmoscopy or gonioscopy when the cornea is too edematous to permit a diagnosis. To facilitate diagnosis, 1 to 3 drops of glycerin should be instilled ocularly prior to examination. A local anesthetic should be instilled prior to the instillation of glycerin (AMA Department of Drugs, 1990b). 

1.3.1.B   Rectal route1)  The recommended adult dose for glycerin suppositories to promote fecal evacuation is 3 grams (AMA Department of Drugs, 1990b); suppositories should be retained for 15 minutes (Olin, 1991).2)  If liquid glycerin is administered rectally, gently insert stem with steady pressure with the tip pointing toward the navel and squeeze the unit until almost all the liquid has been delivered; a small amount of liquid will remain. The unit should then be withdrawn (Olin, 1991). 

1.3.1.C   Cerebral edema1)  Initially, glycerin 25 to 50 grams orally or 0.5 to 1 gram/kilogram (g/kg) intravenously (over 30 minutes) should be administered (Troup et al, 1971; Frank et al, 1981b). Subsequent doses of 0.25 to 0.5 g/kg orally every 4 to 6 hours may be administered (Frank et al, 1981b). 

1.3.1.D   Neoplasm of central nervous system1)  Preoperative doses of glycerin 1.5 to 2 grams/kilogram (g/kg) via a nasogastric tube given 30 minutes prior to dura incision produces a significant reduction in brain volume, lasting several hours. Intravenous doses of 1 g/kg (over 30 minutes) are equally effective (Frank et al, 1981b).2)  For prolonged control of elevated intracranial pressure, glycerin doses of 1 gram/kilogram every 6 hours orally or intravenously for the first several days are recommended (Frank et al, 1981b). 

1.3.1.E   Occlusive stroke1)  Recommended doses are glycerin 1.5 grams/kilogram/day orally (6 divided doses) or 1.2 grams/kilogram/day intravenously (in 5% dextrose and saline) (Katzman et al, 1977). 

1.3.1.F   Primary angle-closure glaucomaSee Drug Consult reference: DRUG THERAPY OF GLAUCOMA 

1.3.1.G   Raised intracranial pressure1)  The glycerin dose should be titrated to achieve the desired intracranial pressure reduction; 0.75 to 1.75 grams/kilogram were administered every 2 hours to maintain an intracranial pressure of less than or equal to 15 mmHg. The dose was given by continuous intravenous infusion, with half the dose given over the first 30 minutes and the remainder over the next 1.5 hours (Nahata et al, 1981a). 

1.3.1.H   Raised intraocular pressure1)  The usual recommended oral dose of glycerin 50% to reduce intraocular pressure is 2 to 3 milliliters/kilogram (approximately 120 to 180 mL per patient) administered 1 to 1.5 hours prior to surgery (Prod Info Osmoglyn(R), 1994a).2)  The recommended dose is 1 to 1.5 grams/kilogram orally as a 50% to 75% solution (Gilman et al, 1990)(AMA Department of Drugs, 1990b; Frank et al, 1981b). Glycerin may be administered more than once daily, if required. Palatability may be improved by adding lemon juice or instant coffee to unflavored preparation or pouring the solution over crushed ice and drinking the solution through a straw. Patients should not drink additional water (AMA Department of Drugs, 1990b). The total daily dose of glycerin should not exceed 120 grams (Gilman et al, 1990). 1.3.1.I   INTRAVENOUS RATE OF ADMINISTRATION1)  Intravascular hemolysis is associated with the high infusion rates of glycerin (greater than 500 mL of 10% solutions over 4 hours) that are required to minimize cerebral edema related to strokes. Clinically significant hemolysis may be avoided by observing an infusion rate below 125 mL/hour (Kumana et al, 1991).1.3.1.J   MAXIMUM DOSE1)  The maximum daily dose of glycerin is 120 grams (Gilman et al, 1990).1.3.1.K   TRIGEMINAL CISTERN INJECTION

1)  Glycerin 0.2 to 0.4 milliliter administered via a trigeminal cistern injection was beneficial in relieving paroxysmal facial pain in numerous conditions unresponsive to previous therapy. The injections were beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster headache, and atypical facial pain (Waltz et al, 1985). 

1.3.3   Dosage in Hepatic InsufficiencyA)  The clearance of glycerin as determined in available human studies is usually lower than normal liver blood flow, indicating the drug may not undergo a significant first-pass effect (Frank et al, 1981b).  

 1.4   Pediatric Dosage

Normal Dosage

Dosage in Hepatic Insufficiency

1.4.1   Normal Dosage

Oral route

Rectal route

Raised intracranial pressure

1.4.1.A   Oral route1)  The dose of glycerin in children to reduce intraocular pressure and vitreous volume prior to surgery is 1 to 1.5 grams/kilogram given as a 50% or 75% solution (AMA Department of Drugs, 1990b).2)  At Columbus Children's Hospital, 50% oral solutions are prepared by mixing with orange juice or lemon juice to decrease nausea and improve palatability (Frank et al, 1981b). 

1.4.1.B   Rectal route1)  The recommended dose for children younger than 6 years of age of glycerin suppositories to promote fecal evacuation is 1 to 1.5 grams (AMA Department of Drugs, 1990b); suppositories should be retained for 15 minutes (Olin, 1991). 

1.4.1.C   Raised intracranial pressure1)  Relatively high intravenous doses of glycerin 0.2 to 1 gram/kilogram/hour which produce plasma concentrations of 1 to 3 milligrams/milliliter (10 to 30 milliosmoles/milliliter) are required to control intracranial hypertension in children with cerebral edema. Glycerin serum concentrations may be estimated from serum osmolality (Pitlick et al, 1982).  

1.4.3   Dosage in Hepatic InsufficiencyA)  Glycerin clearance was not related to hepatic function in a series of patients with Reye's syndrome. Total body clearance of glycerin ranged from 1.99 to 5.1 milliliters/kilogram/minute (Nahata et al, 1981a). This is consistent with the mean clearance of glycerin, 2.17 milliliters/kilogram/minute, in patients with normal liver function. It is speculated that since the drug is metabolized largely by the liver (80%) and liver function is disturbed in patients with Reye's syndrome, the clearance of glycerin may be higher in other diseases with normal liver function (Frank et al, 1981b).B)  The clearance of glycerin as determined in available human studies is usually lower than normal liver blood flow, indicating the drug may not undergo a significant first-pass effect (Frank et al, 1981b).   

 2.0   Pharmacokinetics

Onset and Duration

ADME

 2.1   Onset and DurationA)  Onset1)  Initial Responsea)  Intracranial pressure reduction, intravenous: 10 to 30 minutes (Frank et al, 1981a).1)  GLYCERIN has a slower onset of action than UREA or MANNITOL administered intravenously (AMA Department of Drugs, 1990).b)  Intracranial pressure reduction, oral: 10 to 30 minutes (Frank et al, 1981a).c)  Intraocular pressure reduction, intravenous: 10 to 30 minutes (Frank et al, 1981a).1)  GLYCERIN has a slower onset of action than UREA or MANNITOL administered intravenously (AMA Department of Drugs, 1990).

d)  Intraocular pressure reduction, oral: 10 to 30 minutes (Frank et al, 1981.e)  Fecal evacuation, rectal: 15 to 30 minutes (AMA Department of Drugs, 1990).2)  Peak Responsea)  Intraocular pressure reduction, oral: 1 hour (Gilman et al, 1990)(AMA Department of Drugs, 1990; Friedman et al, 1980)B)  Duration1)  Single Dosea)  Intracranial pressure reduction, oral: 2 to 4 hours (Frank et al, 1981a).1)  Intracranial pressure reduction usually persists for 2 to 4 hours following a 1-g/kg oral or intravenous dose (Frank et al, 1981a).b)  Intraocular pressure reduction, oral: 5 hours (AMA Department of Drugs, 1990); (Gilman et al, 1990).1)  The reduction of intraocular pressure and vitreous volume diminishes 5 hours following oral administration of GLYCERIN (AMA Department of Drugs, 1990); (Gilman et al, 1990). 

 2.3   ADME

Absorption

Distribution

Metabolism

Excretion

Elimination Half-life

2.3.1   AbsorptionA)  Bioavailability1)  Oral, syrup: well absorbed (Reynolds, 1991); (Gilman et al, 1990)a)  Following oral administration, GLYCERIN is well absorbed and rapidly metabolized (Reynolds, 1991); (Gilman et al, 1990) 

2.3.2   DistributionA)  Distribution Sites1)  OTHER DISTRIBUTION SITESa)  EXTRACELLULAR SPACE (Frank et al, 1981a).1)  GLYCERIN distribution is reported to correspond to the extracellular space (50% to 65% of total body weight) (Frank et al, 1981a). 

2.3.3   MetabolismA)  Metabolism Sites and Kinetics1)  LIVER, 80% (Reynolds, 1991; Frank et al, 1981a)a)  Metabolism is dependent on GLYCERIN kinase. Following phosphorylation, approximately 70% to 90% is oxidized by glycerin-3-phosphate dehydrogenase to dihydroxyacetone phosphate. This enters the Embden-Meyerhof pathway at the level of glyceraldehyde-3-phosphate. The remainder combines with free fatty acids to form triglycerides (Frank et al, 1981a).2)  KIDNEY, 10% to 20% (Reynolds, 1991; Frank et al, 1981a)a)  Metabolism is dependent on GLYCERIN kinase. Following phosphorylation, approximately 70% to 90% is oxidized by glycerin-3-phosphate dehydrogenase to dihydroxyacetone phosphate. This enters the Embden-Meyerhof pathway at the level of glyceraldehyde-3-phosphate. The remainder combines with free fatty acids to form triglycerides (Frank et al, 1981a). 

2.3.4   ExcretionA)  Kidney1)  GLYCERIN is filtered and in concentrations up to 0.15 mg/mL, undergoes complete renal tubular reabsorption. In higher concentrations, however, GLYCERIN begins to appear in the urine and induces an osmotic diuresis (Swanson & Thompson, 1969; Frank et al, 1981a). 

2.3.5   Elimination Half-lifeA)  Parent Compound1)  Elimination half-life: 30 to 45 minutes (Frank et al, 1981a).   

 3.0   Cautions

Contraindications

Precautions

Adverse Reactions

Teratogenicity/Effects in Pregnancy/Breastfeeding

Drug Interactions

 3.1   ContraindicationsA)  Hypersensitivity to any component in the preparationB)  Well-established anuriaC)  Severe dehydrationD)  Frank or impending acute pulmonary edemaE)  Severe cardiac decompensation 

 3.2   PrecautionsA)  Administer with caution to patients with cardiac, renal, or hepatic diseaseB)  DiabetesC)  Hemolytic anemiaD)  Altered hydration may lead to pulmonary edema and/or congestive heart failure 

 3.3   Adverse Reactions

Cardiovascular Effects

Endocrine/Metabolic Effects

Gastrointestinal Effects

Hematologic Effects

Hepatic Effects

Neurologic Effects

Ophthalmic Effects

Otic Effects

Renal Effects

Other

3.3.1   Cardiovascular Effects

3.3.1.A   Cardiovascular finding1)  HYPERTENSION developed in 1 patient following the use of oral glycerin (50% solution) (D'Alena & Ferguson, 1966).2)  Cardiac ARRHYTHMIAS have been reported with the administration of glycerin (Reynolds, 1991).  

3.3.3   Endocrine/Metabolic Effects

3.3.3.A   Hyperglycemia1)  Glycerin can produce hyperglycemia (Gilman et al, 1990)(Frank et al, 1981; Freund, 1968) and HYPEROSMOLARITY, which is usually clinically significant only in patients with diabetes or a prediabetic condition (Freund, 1968; Frank et al, 1981). HYPEROSMOLAR NONKETOTIC HYPERGLYCEMIA has rarely developed following oral administration (Reynolds, 1991; AMA Department of Drugs, 1990a; Sears, 1976; Oakley & Ellis, 1976), and deaths have occurred. The most susceptible patients are maturity-onset, elderly diabetics with acute or chronic diseases that predispose them to fluid depletion; oral glycerin should be avoided in these patients. If glycerin is used in patients who are predisposed, measures should be taken to prevent hyperosmolar nonketotic hyperglycemia and dehydration (Reynolds, 1991).2)  NONKETOTIC HYPEROSMOLAR HYPERGLYCEMIA was reported in 2 patients following use of glycerin via nasogastric (NG) tube for cerebral edema. A 63-year-old maturity-onset diabetic female received 60 grams glycerin 4 times daily via NG tube for 3 days. Laboratory data revealed serum glucose of 950 mg%, osmolarity 322 mOsm/L, central venous pressure (CVP) less than 1 cm H2O, blood urea nitrogen (BUN) 25 mg%, sodium 137 mEq/L and 4+ glycosuria. The patient also developed hypotension (70/50 mmHg). Glycerin was discontinued, and insulin, dextrose, saline and bicarbonate were administered. Levarterenol was administered to treat hypotension; however, the patient died secondary to refractory hypotension and ventricular fibrillation. The second patient, a 66-year-old, non-diabetic male, received 90 g glycerin 4 times daily via NG tube for 15 days. Laboratory data at that time revealed osmolarity of 364 mOsm/L, glucose 850 mg%, CVP less than 1 cm H2O, BUN 60 mg%, serum sodium 159 mEq/L and 4+ glycosuria. This patient was treated similarly to the other, but died due to cerebral edema (Sears, 1976).3)  Hyperosmolar NONKETOTIC COMA was described in a 29-year-old male diabetic following oral administration of glycerin (50%) 120 mL twice daily for 1 day for treatment of acute neovascular glaucoma. The patient developed increasing lethargy, anorexia, nausea and vomiting during a 24-hour period. Chronic renal failure developed. Serum osmolality was 366 mOsm/kg, cerebrospinal fluid glucose 532 mg%, and blood glucose 1129 mg%. Blood pH after 1 day of therapy was 6.98. Urinalysis revealed specific gravity of 1.020, 3+ proteinuria and 4+ glucosuria. Electrocardiogram revealed left ventricular hypertrophy, and occult blood was detected in stools. The

patient was given 8.3 L of intravenous hypotonic saline, albumin and pack cells. A total of 600 units of regular insulin and 6 ampules of sodium bicarbonate were administered, successfully increasing blood glucose and pH. The patient eventually recovered from KETOACIDOSIS, but remained in chronic renal failure. The authors suggest that the primary goal of treatment of these cases is reversible dehydration by employing hypotonic solutions (Oakley & Ellis, 1976).  

3.3.4   Gastrointestinal Effects

3.3.4.A   Gastrointestinal tract finding1)  NAUSEA and VOMITING have been reported following oral administration of glycerin (Reynolds, 1991; AMA Department of Drugs, 1990a; Krupin et al, 1970; Charan & Sarda, 1967; Leone & Callahan, 1967; Buckell & Walsh, 1964); DIARRHEA occurs less frequently (Reynolds, 1991; AMA Department of Drugs, 1990a).2)  Increased THIRST may develop following the administration of glycerin (Reynolds, 1991).  

3.3.5   Hematologic Effects

3.3.5.A   Hematology finding1)  INTRAVASCULAR HEMOLYSIS and hemoglobinuria may result from glycerin administration (Reynolds, 1991; Cantore et al, 1965; Mickell et al, 1977; Nahata et al, 1981; Gilsanz et al, 1975; Hagnevik et al, 1974); (Welch, 1974). Hemolysis appears to be related to the rate of administration of glycerin as well as the tonicity of the solution. Available data would suggest that hemolysis can be minimized if intravenous glycerin 5% to 10% is administered in 5% dextrose with normal saline, at rates equal to or less than 6 mg/kg/minute (Frank et al, 1981).2)  Intravascular hemolysis is associated with the high infusion rates of glycerin (greater than 500 mL of 10% solutions over 4 hours) that are required to minimize cerebral edema related to strokes. Clinically significant hemolysis may be avoided by observing an infusion rate below 125 mL/hour. The addition of a small amount of fructose to glycerin solutions has also been proposed as a method of minimizing hemolysis (Kumana et al, 1991).  

3.3.6   Hepatic Effects

3.3.6.A   Hepatotoxicity1)  Transient HEPATOMEGALY may occur during glycerin therapy secondary to glycogen storage; however, this is reversible (Frank et al, 1981).  

3.3.9   Neurologic Effects

3.3.9.A   Central nervous system finding1)  HEADACHE has been reported following oral glycerin administration (Reynolds, 1991; AMA Department of Drugs, 1990a; Buckell & Walsh, 1964; Leone & Callahan, 1967; Krupin et al, 1970); DIZZINESS and MENTAL CONFUSION may also develop (Reynolds, 1991). CONFUSION and AMNESIA may occur in elderly patients (AMA Department of Drugs, 1990a).  

3.3.10   Ophthalmic Effects

3.3.10.A   Eye / vision finding1)  The topical application of glycerin can damage the endothelial cells of the cornea. Caution should be used when applying glycerin to the cornea (Reynolds, 1991).  

3.3.11   Otic Effects

3.3.11.A   Ototoxicity1)  Temporary HEARING LOSS occurred in a 42-year-old male following a glycerin test with salt loading (Bodo et al, 1984). Transient hearing loss also developed following the ingestion of glycerin for a test for Meniere's disease (Reynolds, 1991).  

3.3.13   Renal Effects

3.3.13.A   Nephrotoxicity1)  RENAL TOXICITY and failure has occurred secondary to glycerin administration secondary to hemolysis and hemoglobinuria (Reynolds, 1991; Hagnevik et al, 1974; Gilsanz et al, 1975). Other evidence indicates that renal toxicity, not associated with myoglobin, is related to a type of renal toxin that might be produced (Frank et al, 1981). A decrease in renal tubular flow rate secondary to glycerin may precipitate renal failure, and renal damage might be prevented by increasing glomerular flow rates with intravenous mannitol or sodium ascorbate (Frank et al, 1981).2)  Acute RENAL FAILURE was reported in a 69-year-old male following the administration of 40% glycerin (1.5 g/minute) by intravenous infusion over 10 minutes. Immediately following infusion, the patient developed chills, cyanosis, trembling, mild hypertension, mental confusion, and disorientation. Oligo-anuria developed with serum creatinine levels reaching 5 mg%. Hemolysis and HEMOGLOBINURIA were present. GLYCOSURIA and ALKALURIA persisted for 1 month, suggesting a renal tubular lesion. The patient was treated with mannitol, sodium bicarbonate and normal saline, resulting in recovery (Novarini et al, 1979).3)  RENOCEREBRAL OXALOSIS was reported in a patient given 50 g of 10% glycerin solution (in 0.9% sodium chloride) over 20

minutes (Krausz et al, 1977).  

3.3.16   Other

3.3.16.A   Abuse of laxatives1)  Typical symptoms of laxative abuse include abdominal pain, weakness, fatigue, thirst, vomiting, edema, bone pain (due to osteomalacia), fluid and electrolyte imbalance, hypoalbuminemia (due to protein-losing gastroenteropathy), and syndromes that mimic colitis (Longe & DiPiro, 1992). If the bowel has not been permanently damaged, it may require several months to retrain the bowel without the assistance of laxatives (Curry, 1993).   

 3.4   Teratogenicity/Effects in Pregnancy/BreastfeedingA)  Teratogenicity/Effects in Pregnancy1)  U.S. Food and Drug Administration's Pregnancy Category: Category C (Prod Info Osmoglyn(R), 1994) (All Trimesters)a)  Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.See Drug Consult reference: PREGNANCY RISK CATEGORIES2)  Crosses Placenta: Unknown3)  Clinical Managementa)  Use of glycerin as a hyperosmotic agent is not recommended during pregnancy due to concern that intravascular influx of fluid will lead to escape of intravascular fluid into the lungs and brain (Cunningham et al, 1993). Ophthalmic use of glycerin probably does not constitute any risk to the fetus.4)  Literature Reportsa)  There have been no epidemiological studies or case reports concerning the use of glycerin in pregnant women.B)  Breastfeeding1)  Thomson Lactation Rating: Infant risk cannot be ruled out.a)  Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.2)  Clinical Managementa)  No reports describing the use of glycerin during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known if glycerin affects the quantity and composition of breastmilk. Until more data is available, use caution when considering glycerin in lactating women.3)  Literature Reportsa)  No reports describing the use of glycerin during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. 

 3.5   Drug Interactions

3.5.1   Drug-Drug Combinations

Arsenic Trioxide

Licorice

3.5.1.A   Arsenic Trioxide1)  Interaction Effect: increased risk of QT prolongation2)  Summary: Caution should be used when prescribing drugs known to induce hypokalemia or hypomagnesemia, such as diuretics, as they may precipitate QT prolongation (Prod Info TRISENOX(R) IV injection, 2006).3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Arsenic trioxide should be administered with extreme caution to patients who may be at risk for development of prolonged QT syndrome (e.g. hypokalemia or hypomagnesemia) (Prod Info TRISENOX(R) IV injection, 2006).7)  Probable Mechanism: induction of hypokalemia or hypomagnesemia 

3.5.1.B   Licorice1)  Interaction Effect: increased risk of hypokalemia and/or reduced effectiveness of the diuretic2)  Summary: Cases have been reported in which patients experienced hypokalemia and hypertension with concomitant use of licorice and diuretics (Harada et al, 2002a; deKlerk et al, 1997a; Folkerson et al, 1996; Farese et al, 1991a). Symptoms of congestive heart failure and hypokalemia occurred in a patient taking licorice, furosemide, and digoxin (Harada et al, 2002a). Hypokalemic paralysis has resulted from licorice use; concomitant diuretic use increased the risk (Hussain, 2003; Lin et al, 2003; Shintani et al, 1992a; Corsi et al, 1983). Licorice alone has been reported to be the likely cause of hypokalemia, hypertension, and cardiac arrhythmia (Dellow et al, 1999a; Eriksson et al, 1999; Kageyama et al, 1997; Bernardi et al, 1994; Blachley & Knochel, 1980; Wash & Bernard, 1975). The glycyrrhetinic acid component of licorice is metabolized to 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which inhibits 11-beta-hydroxysteroid dehydrogenase and reduces cortisol breakdown, resulting in a hypermineralocorticoid effect (Kato et al, 1995; Walker & Edwards, 1994).3)  Severity: moderate4)  Onset: delayed5)  Substantiation: probable6)  Clinical Management: Avoid concurrent use of licorice and diuretics.

7)  Probable Mechanism: pseudoaldosteronism from licorice ingestion resulting in hypokalemia8)  Literature Reportsa)  An 84-year-old male developed hypokalemia and symptoms of congestive heart failure after 7 days of concurrent use of a licorice-containing Chinese herbal laxative with digoxin and furosemide. The patient complained of fatigue, appetite loss, and lower extremity edema. Pulse rate was 30 beats per minute, potassium was 2.9 milliequivalents/Liter (mEq/L), and digoxin level 2.9 nanograms/milliliter (ng/mL). Chest radiograph revealed an enlarged cardiac silhouette and lung congestion. Partial arterial oxygen pressure and saturation was low, carbon dioxide pressure was high. Plasma renin activity was 0.3 ng/mL/hour (normal 0.3 to 2.9 ng/mL/hour) and aldosterone was 3.8 nanograms/deciliter (ng/dL) (normal 3.6 to 24 ng/dL). Digoxin and the herbal laxative were stopped; after 18 days, the patient's pulse increased to 60 beats per minute and symptoms of congestive heart failure were relieved. Potassium increased to 4.3 mEq/L, renin activity was 1 ng/mL/hour, aldosterone was 12 ng/dL, and digoxin level was 0.6 ng/mL (Harada et al, 2002). b)  Fifty-nine cases of glycyrrhizin-induced hypokalemic myopathy (GIHM) were reviewed. The combined use of licorice and hypotensive diuretic agents increased the risk of GIHM in the majority of cases. Of 56 cases which were reported, serum potassium was 1.98 milliequivalents/liter (mEq/L). Average blood aldosterone in 30 patients was normal, though 15 of those patients had below-normal values. Plasma renin activity averaged 0.17 nanograms/milliliter/hour (ng/mL/hour) (normal: 0.8-4.4 ng/mL/hour) in 27 patients. Complete cure was attained in 57 of the 59 cases of GIHM when licorice ingestion was discontinued and potassium supplementation given (Shintani et al, 1992). c)  A 49-year-old female presented with persistent hypertension and hypokalemia (2.6 mmol/L; normal 3.3 to 4.8 mmol/L) following consumption of licorice. Blood pressure was found to be volume-sensitive and plasma renin activity and plasma aldosterone were low. The patient's hypokalemia was unresponsive to amiloride but normalized with spironolactone. Prior to discontinuing her regular licorice intake, her blood pressure control was unsatisfactory on a combination of furosemide 120 mg daily, felodipine 2.5 mg daily, monoxidine 0.2 mg daily, spironolactone 75 mg daily, and doxazosin 4 mg daily. The patient then admitted to consuming 30 to 40 Pontefract cakes, a licorice-based sweet, per week (approximately 0.25 kilograms). After discontinuing the Pontefract cakes, blood pressure fell steadily allowing progressive withdrawal of antihypertensive treatment (Dellow et al, 1999). d)  A 21-year-old female developed headache and hypertension (190/120 mmHg), associated with licorice consumption (100 grams daily) along with an oral contraceptive. She was advised to discontinue eating licorice. Blood pressure remained elevated with treatment combining atenolol, lisinopril, hydrochlorothiazide, and amlodipine. Drug treatment was discontinued, and 2 weeks later blood pressure was 180/110 mmHg, potassium 2.6 mmol/L (normal 3.8 to 5.0 mmol/L), bicarbonate 35.9 mmol/L (normal 23 to 29 mmol/L). Plasma aldosterone was 160 picomoles/liter (pmol/L) (normal 320 to 2000 pmol/L). The patient then admitted to replacing her licorice intake with two packets of Stimerolol Sugar Free(R) chewing gum per day. This chewing gum contains 585 mg licorice in each 15 gram packet, which equals 8% to 12% glycyrrhizinic acid. Her glycyrrhizinic acid intake was calculated to be 120 mg daily. Within 3 weeks of discontinuing the gum, her blood pressure and potassium level normalized (deKlerk et al, 1997). e)  A 35-year-old woman taking an oral contraceptive and chlorothiazide experienced hypokalemia (2.2 mmol/L). Her blood pressure was 140/80 mmHg. Chlorothiazide was stopped and potassium chloride 600 mg three times daily was started. After one week, potassium remained abnormal at 2.0 mmol/L, after 2 weeks it decreased further to 1.5 mmol/L. Intravenous potassium supplementation was started. Although she denied licorice use, it was discovered that she used BenBits Cool Mint(R) chewing gum (Leaf, United Kingdom), 3 packets daily. This product contained 160 mg licorice in each 16 gram packet, of which 10% was glycyrrhizinic acid. After 2 days of intravenous potassium and 15 days of oral potassium, and within 3 weeks of discontinuing the chewing gum, edema disappeared, blood pressure decreased to 110/80 mmHg and potassium increased to 4.2 mmol/L. The authors attributed the hypokalemia to the licorice intake (deKlerk et al, 1997). f)  A 38-year-old male was hospitalized with respiratory and kidney failure due to complications of somnolence, flaccid paralysis of the extremities, arterial hypertension, edema and severe hypokalemia. He had been ingesting 200 grams of licorice daily for 10 weeks together with a thiazide diuretic for 2 weeks (Folkersen et al, 1996). g)  A 70-year-old male developed hypokalemia (1.9 millimoles/Liter (mmol/L)) and rhabdomyolysis while treated with a thiazide diuretic. Blood pressure and potassium were normalized following treatment with spironolactone, potassium chloride, and verapamil. It was discovered that he had been eating 60 to 100 grams of licorice candies daily for 4 to 5 years, containing 0.3% glycyrrhizic acid. Licorice ingestion was discontinued, then spironolactone and potassium were discontinued. Rechallenge with licorice (300 mg glycyrrhetinic acid) per day resulted in subnormal potassium (3.4 mmol/L), blood pressure 154/72 mmHg, and increased body weight by 4.9 kg. Licorice caused plasma renin activity to fall from 2.4 nanograms/Liter/second (ng/L/second) (normal 0.14 to 1.8 mg/L/second) to 0.2 mg/L/second after the week of licorice. Following the study, verapamil was continued while the patient abstained from licorice. Blood pressure and potassium remained normal (Farese et al, 1991).     

 4.0   Clinical Applications

Monitoring Parameters

Patient Instructions

Place In Therapy

Mechanism of Action / Pharmacology

Therapeutic Uses

Comparative Efficacy / Evaluation With Other Therapies

 4.1   Monitoring ParametersA)  Therapeutic1)  Reduction in intraocular or intracranial pressure.B)  Toxic1)  Renal function tests (renal toxicity)2)  Serum osmolality (hyperosmolality)

3)  Blood glucose levels (hyperglycemia)4)  Urinalysis (hemoglobinuria)5)  CBC 

 4.2   Patient InstructionsA)  Glycerin (Rectal)Glycerin

Treats occasional constipation by making bowel movements regular. This medicine is a laxative.

When This Medicine Should Not Be Used:You should not use this medicine if you have had an allergic reaction to glycerin. You should not use this medicine if you have rectal bleeding.

How to Use This Medicine:SuppositoryYour doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your doctor tells you to.This medicine comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.Never take rectal suppositories by mouth.Wash your hands with soap and water before and after using this medicine. Remove the foil or wrapper from the suppository before inserting it.Lie on your left side with your left leg straight or slightly bent, and your right knee bent upward. Gently push the pointed end of the suppository into the rectum about 1 inch.Keep lying down for about 15 minutes to keep the suppository from coming out before it melts. Then, wash your hands again.This medicine should cause you to have a bowel movement within 15 minutes to 1 hour.

If a Dose is Missed:If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up for a missed dose.

How to Store and Dispose of This Medicine:Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. You may store the suppositories in the refrigerator, but do not freeze them.Ask your pharmacist, doctor, or health caregiver about the best way to dispose of the used medicine applicator(s), containers, and any leftover medicine after you have finished your treatment. You will also need to throw away old medicine after the expiration date has passed.Keep all medicine away from children and never share your medicine with anyone.

Drugs and Foods to Avoid:Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.Make sure your doctor knows if you have been using any other laxative for more than 1 week prior to using this medicine.

Warnings While Using This Medicine:Make sure your doctor knows if you are pregnant or breast feeding.Make sure your doctor knows if you have stomach pain, nausea, vomiting, or if you have had a sudden change in bowel habits lasting longer than 2 weeks.If you do not have a bowel movement after using this medicine, stop using it and talk to your doctor.If your symptoms do not improve or if they get worse, call your doctor.This medicine should not be used for longer than one week.

Possible Side Effects While Using This Medicine:Call your doctor right away if you notice any of these side effects:Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing.Bleeding from your rectum.

If you notice these less serious side effects, talk with your doctor:Irritation or burning pain in your rectal area.

If you notice other side effects that you think are caused by this medicine, tell your doctor. 

 4.3   Place In TherapyA)  Glycerin is an osmotic diuretic which is effective in reducing elevated intracranial pressure associated with stroke, cerebral infarction, Reye's syndrome, and tumors of the central nervous system. The drug is also effective in treating cerebral edema resulting from head injuries.B)  In ophthalmology, glycerin is used for short-term reduction of intraocular pressure and vitreous volume. Glycerin is usually used in patients not responding to miotics and carbonic anhydrous inhibitors. Orally administered glycerin is considered safer than intravenous mannitol or urea; however, the onset of action of glycerin is slower and intraocular pressure returns to pretreatment levels sooner.C)  When compared with mannitol, glycerin offers the advantages of oral administration, less diuresis and electrolyte loss, and less rebound cerebral overhydration (Frank et al, 1981). These advantages warrant formulary inclusion of glycerin. 

 4.4   Mechanism of Action / PharmacologyA)  MECHANISM OF ACTION1)  Glycerin (glycerol) is a potent hypertonic agent primarily used in the treatment of elevated intracranial pressure. The drug rapidly lowers both intraocular and intracranial pressure within 30 minutes following oral or intravenous dose. The absolute increase in serum

osmolality required to result in significant cerebral and intraocular dehydration is not clear (Frank et al, 1981a).2)  The main effect of glycerin results from its osmotic dehydrating effects, although other mechanisms have been postulated for its effect in lowering intracranial pressure. This includes an increase in blood flow to ischemic areas, decreases in serum free fatty acids and increases in synthesis of glycerides in the brain. These effects might be beneficial in the treatment of intracranial hypertension since free fatty acids are capable of producing coma, elevating in intracranial pressure, cerebral edema, and mitochondrial swelling in experimental animals. Free fatty acids are also increased in Reye's syndrome (Frank et al, 1981a).3)  Similarly, glycerin produces its ocular hypotensive effects secondary to increases in hyperosmolality of the blood (McCurdy et al, 1966), although evidence indicates that other mechanisms may be involved (Friedman et al, 1980) such as a reduction in aqueous humor (AMA Department of Drugs, 1990). Oral administration of glycerin in 42 cataract patients resulted in significant ocular hypotension 30 minutes post-administration (maximal effects at 60 minutes). However, peak increases in serum osmolarity occurred much later (90 to 120 minutes). Thus, other mechanisms are most likely involved in the ocular hypotensive effects of glycerin.4)  Due to its osmotic effect, glycerin softens, lubricates, and facilitates the elimination of inspissated feces. Additionally, this agent may stimulate rectal contractions (Gilman et al, 1990)(AMA Department of Drugs, 1990).B)  REVIEW ARTICLES1)  Aa)  comprehensive review of glycerin metabolism and documentation supportive of glycerin as a potential energy substrate is available which includes a discussion of the toxicity and adverse effects of glycerin administration (Tao et al, 1983).2)  A review on the pharmacokinetics, adverse effects, and therapeutic use of glycerin is available (Frank et al, 1981a).3)  A comprehensive review of the use of glycerin in the treatment of ischemic brain edema (Winter et al, 1995). 

 4.5   Therapeutic Uses

Bacterial meningitis; Adjunct

Cerebral edema

Cogan's syndrome

Constipation

Ménière's disease; Diagnosis

Meningoencephalitis - Viral meningitis

Neoplasm of central nervous system

Obesity

Occlusive stroke

Pain in face

Primary angle-closure glaucoma

Raised intracranial pressure

Raised intraocular pressure

Reye's syndrome

Trigeminal neuralgia

4.5.A   Bacterial meningitis; Adjunct1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Pediatric, Evidence favors efficacyRecommendation: Pediatric, Class IIbStrength of Evidence: Pediatric, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:In a prospective, multicenter, randomized, double-blind, double-dummy clinical trial in children aged 2 months through 16 years with bacterial meningitis (n=654), adjuvant treatment with oral glycerol (85% solution), alone or in combination with intravenous dexamethasone, led to improved outcomes of severe neurological sequelae and/or death compared to adjuvant dexamethasone alone or placebo (Peltola et al, 2007)3)  Pediatric:a)  Adjuvant therapy with oral glycerol, either alone or in combination with intravenous (IV) dexamethasone, improved severe neurological sequelae and/or death compared to dexamethasone alone or placebo in a prospective, multicenter, randomized, double-blind, double-dummy clinical trial in children aged 2 months through 16 years with bacterial meningitis. Meningitis was defined by the

following: a cerebrospinal fluid (CSF) culture positive for meningitis-causing bacteria, characteristic CSF findings, and positive blood culture results or a CSF sample with a positive latex agglutination test results, and signs/symptoms compatible with bacterial meningitis. Patients pretreated with antimicrobials were included in the study provided therapy comprised of oral or no greater than 1 parenteral dose administration. All patients received IV ceftriaxone 80 to 100 milligrams per kilogram (mg/kg) once daily for 7 to 10 days. Patients were randomly assigned to one of the following 4 arms: IV dexamethasone (n=166), IV dexamethasone and oral glycerol (n=159), oral glycerol (n=166), and placebo (n=163). Both dexamethasone and glycerol (85% solution) were administered 15 minutes prior to the ceftriaxone dose, and were dosed as 0.15 mg/kg and 1.5 grams/kilogram (1.5 milliliters/kilogram), respectively, every 6 hours for 48 hours. Nasogastric tubes were routinely used in study patients. In the event of vomiting within 30 minutes, the glycerol dose was repeated. Neurological, developmental, and hearing sequelae assessments occurred at hospital discharge; patients with deficits were scheduled for a follow-up visit 1-2 months later. The primary endpoints were death, severe neurological sequelae, and profound hearing loss (determined by brain stem evoked response audiometry or traditional audiometry). Severe neurological sequelae, which included blindness, quadriparesis or quadriplegia, hydrocephalus (requiring a shunt), or severe psychomotor retardation, was combined with death as a composite endpoint. Assessments were performed primarily at hospital discharge. Overall, 37% of patients received prior antibiotic therapy. At hospital discharge, 13% (n=86/654) of patients died, 8% (n=44/556) had severe neurological sequelae, and 8% (n=43/534) had profound hearing loss. An intent-to-treat analysis revealed that the incidence of severe neurological sequelae was significantly reduced in patients receiving glycerol alone (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.13-0.76; p vs placebo=0.01) or in combination with dexamethasone (OR, 0.39; 95% CI, 0.17-0.93; p=0.033) compared to dexamethasone alone (OR, 0.48; 95% CI, 0.21-1.07; p=0.72). Similarly, for the composite endpoint of death and severe neurological sequelae, significant reductions occurred in the glycerol-only and dexamethasone-glycerol groups (OR, 0.44; 95% CI, 0.25-0.76; p=0.003 and OR, 0.55; 95% CI, 0.32-0.93; p=0.027, respectively) compared to the dexamethasone-only group (OR, 0.65; 95% CI, 0.39-1.09; p=0.1). None of the adjunctive treatments (dexamethasone, glycerol, or the combination) significantly affected death or profound hearing loss. Pretreatment with antimicrobials, including their timing of administration with respect to study initiation, did not affect the results. The primary endpoint results are shown in the table. A post-hoc analysis of patients with Haemophilus influenzae type b meningitis (n=181) revealed that dexamethasone treatment prevented profound hearing loss (OR, 0.27; 95% CI, 0.09-0.77; p=0.014); however, the statistical significance was lost when receipt of pretreatment antimicrobials was taken into account. Of the 484 patients where a causative agent was identified, 222 were H. influenzae type b, 132 were S. pneumoniae, and 110 were N. meningitidis. Among adverse events, visible blood in stool occurred in 5% (n=6/111), 5% (n=5/101), 1% (n=1/113), and 2% (n=2/99) of patients in the dexamethasone-only, dexamethasone-glycerol, glycerol-only, and placebo groups, respectively. Vomiting and diarrhea were not more common in the glycerol-only group. There were no severe adverse drug events in any of the groups (Peltola et al, 2007).Outcome DXM and placebo (n; %) DXM and glycerol (n; %) Glycerol and placebo (n; %) Placebo (n; %)Death 23/166 (14%) 20/159 (13%) 17/166 (10%) 26/163 (16%)Severe neurological sequelae 10/139 (7%) 8/134 (6%) 7/147 (5%) 19/136 (14%)Severe neurological sequelae or death 33/162 (20%) 27/153 (18%) 24/164 (15%) 46/163 (28%)Profound hearing loss 10/135 (7%) 9/132 (7%) 12/136 (9%) 12/131 (9%)Key: DXM = dexamethasone; n = number of patients; * = determined by chi square test between 4 groups (for heterogeneity)

 

4.5.B   Cerebral edema1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence favors efficacyRecommendation: Adult, Class IIbStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Effective in the treatment of CEREBRAL EDEMA secondary to central nervous system or CNS TRAUMA3)  Adult:a)  GLYCERIN, administered intravenously or orally, has been effective in the treatment of CEREBRAL EDEMA secondary to central nervous system or CNS TRAUMA (Buckell & Walsh, 1964a; Bovet et al, 1961; Troup et al, 1971). Oral doses of 25 to 50 grams or intravenous doses of 0.5 to 1 gram/kilogram (g/kg) over 30 minutes are effective in acute situations. In severe cases, 1 g/kg every 2 hours by constant intravenous infusion is effective. For prolonged therapy, 0.25 to 0.5 g/kg every 4 to 6 hours has been successful (Frank et al, 1981b).b)  Effective results were reported in intracranial hypertension due to HEAD INJURIES with GLYCERIN 75 milliliters orally 1 to 3 times daily diluted in water or fruit juice. Nausea was the only side effect reported (Buckell & Walsh, 1964a).c)  Effective lowering of intracranial pressure in BRAIN INJURY patients was reported within one hour following oral doses of 25 to 50 grams (Troup et al, 1971).d)  Administration of GLYCERIN was helpful in preventing the development of cerebral edema in some patients receiving brain irradiation for metastatic brain neoplasms. Symptoms associated with increased intracranial pressure (headache, nausea, vomiting, blurred vision) were graded prior irradiation therapy in all 44 patients entering the trial. Additionally, neurological signs were recorded prior GLYCERIN treatment and reevaluated during the treatment period at least 2 times a week. Irrespective of tumor size or progression of the disease, all patients received whole-brain irradiation (3000 to 4500 rads). Patients were given oral GLYCERIN (Osmoglin (R)) over 20 to 30 minutes every 6 hours (1.2 to 2 grams/Kilogram body weight) throughout the period of brain irradiation and for 14 days thereafter. Patients in critical condition unable to take oral GLYCERIN received a 10% intravenous solution in dextrose 5%. The 12 patients beginning treatment without symptoms, remained stable without clinical deterioration; improvement in symptoms was evident in over 90% of those presenting with headache, nausea, and vomiting. Although more than half of the patients with confusion, paralysis, paresis and papilledema improved, 11 of the 32 patients presenting with symptoms failed to respond adequately and were changed from GLYCERIN to dexamethasone therapy (Bedikian et al, 1980a). 

4.5.C   Cogan's syndrome1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category CSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:

Possibly effective in one case report3)  Adult:a)  A 25-year-old female with Cogan's syndrome treated with oral glycerin 100 grams/day for 4 days and 100 milligrams every 8 hours for 2 further days received concomitant therapy with TRIAMCINOLONE, MECLIZINE, NIACIN and CHLOROQUINE. Marked improvement in hearing after each dose of GLYCERIN was observed and audiograms improved. The authors suspect the drug may reduce hydrops in the cochlea by acting as a hyperosmolar agent. Further studies are required to evaluate efficacy (Beckman & Trotsky, 1970). 

4.5.D   ConstipationFDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, yesEfficacy: Adult, Effective; Pediatric, EffectiveRecommendation: Adult, Class IIa; Pediatric, Class IIaStrength of Evidence: Adult, Category B; Pediatric, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Aids in fecal evacuation and are also used to soften and lubricate feces3)  Adult:a)  The use of glycerin suppositories rectally aids in fecal evacuation by stimulating rectal contraction via its hyperosmotic and irritant actions. Glycerin suppositories are also used to soften and lubricate inspissated feces, in bowel retraining programs, and to re-establish normal bowel function in patients who are laxative dependent (AMA Department of Drugs, 1990b).4)  Pediatric:a)  The use of glycerin suppositories rectally aids in fecal evacuation by stimulating rectal contraction via its hyperosmotic and irritant actions. Glycerin suppositories are also used to soften and lubricate inspissated feces, in bowel retraining programs, and to re-establish normal bowel function in patients who are laxative dependent (AMA Department of Drugs, 1990b). 

4.5.E   Ménière's disease; Diagnosis1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Limited value in the diagnosis of Meniere's disease, but has been used previously3)  Adult:a)  The glycerin test has been helpful in the selection process of suitable patients for endolymphatic sac operations. Hearing tests were performed on 60 patients before, 2.5 hours after, and 5 hours after the administration of glycerin 1.5 grams/kilogram. A positive test occurred if both an improvement in pure tone average (PTA), 15 db or more improvement in PTA for frequencies of 500, 1000, and 2000 Hz, and speech discrimination occurred (10% or greater). As determined by caloric response and vestibular examination, a positive response to the glycerin test (27 of 60 patients) failed to correlate with the stage of Meniere's disease (Karjalainen et al, 1984). 

4.5.F   Meningoencephalitis - Viral meningitis1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category CSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Lowered intracranial pressure in a 19-year-old with VIRAL MENINGOENCEPHALITIS3)  Adult:a)  Effective lowering of intracranial pressure was reported in a 19-year-old with VIRAL MENINGOENCEPHALITIS. GLYCERIN was administered orally in doses of 70 milliliters every 6 hours (a 50% solution in 0.15 molar sodium chloride) for a period of 3 weeks. Occasional vomiting was the only side effect (Newkirk et al, 1972). 

4.5.G   Neoplasm of central nervous system1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence favors efficacyRecommendation: Adult, Class IIbStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Oral and intravenous GLYCERIN have been effective in the treatment of intracranial hypertension secondary to CNS TUMORS or SPACE OCCUPYING LESIONS3)  Adult:a)  Both oral and intravenous GLYCERIN have been effective in the treatment of intracranial hypertension secondary to CNS TUMORS or SPACE OCCUPYING LESIONS (Frank et al, 1981b); (Cantori et al, 1965). Good results have been reported with doses of 0.5 to 2 grams/kilogram (g/kg) (30% to 50% oral solutions), usually initiated with 1 gram/kilogram followed by 0.5 g/kg every 3 hours (Frank et al, 1981b).b)  The recommended dose for patients with central nervous system tumors, space occupying lesions, and during NEUROSURGICAL PROCEDURES is a one-time preoperative dose of 1.5 to 2 grams/kilogram (g/kg) via nasogastric tube, one-half hour prior to dura incision. Alternatively, doses of 1 g/kg orally or intravenously every 6 hours for the first several days may produce more prolonged control of elevated intracranial pressure (Frank et al, 1981b).

c)  Administration of GLYCERIN was helpful in preventing the development of cerebral edema in some patients receiving brain irradiation for metastatic brain neoplasms. Symptoms associated with increased intracranial pressure (headache, nausea, vomiting, blurred vision) were graded prior irradiation therapy in all 44 patients entering the trial. Additionally, neurological signs were recorded prior GLYCERIN treatment and reevaluated during the treatment period at least 2 times a week. Irrespective of tumor size or progression of the disease, all patients received whole-brain irradiation (3000 to 4500 rads). Patients were given oral GLYCERIN (Osmoglin (R)) over 20 to 30 minutes every 6 hours (1.2 to 2 grams/Kilogram body weight) throughout the period of brain irradiation and for 14 days thereafter. Patients in critical condition unable to take oral GLYCERIN received a 10% solution in dextrose 5% intravenously. The 12 patients beginning treatment without symptoms remained stable without clinical deterioration; improvement in symptoms was evident in over 90% of those presenting with headache, nausea, and vomiting. Although more than half of the patients with confusion, paralysis, paresis and papilledema improved, 11 of the 32 patients presenting with symptoms failed to respond adequately and were changed from GLYCERIN to DEXAMETHASONE therapy (Bedikian et al, 1980a). 

4.5.H   Obesity1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Ineffective in suppressing hunger or reducing weight3)  Adult:a)  Several studies have suggested a role of GLYCERIN in the treatment of obesity by regulation of adipose tissue mass. GLYCERIN was compared to placebo in 8 obese patients in a controlled study. GLYCERIN 80, 160, or 360 milligrams/kilogram was administered three times daily in fruit juice for 8 weeks. No significant changes in body weight or appetite occurred with GLYCERIN on any dose compared to placebo. No differences in serum glucose, creatinine, blood urea nitrogen or serum electrolytes were observed (Greenway et al, 1981).b)  GLYCERIN 100 grams in 200 milliliters water was ineffective in suppressing hunger or reducing weight when provided as a daily supplement to obese patients on 1000-kcal/day diets (Leibel et al, 1980). 

4.5.I   Occlusive stroke1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Improved global performance and motor and sensory functions in patients with mild-to-moderate disabilityNo effect on reducing mortality in 26 patients with ischemic cerebral infarction with mild-to-severe disability3)  Adult:a)  Many reports have described the efficacy of glycerin in controlling elevated intracranial pressure in patients with STROKE (Meyer et al, 1971; Meyer et al, 1971a; Fawer et al, 1978; Fawer et al, 1977; Mathew et al, 1972; Massey & Brannon, 1977); (Frithz & Warner, 1975). However, despite the efficacy of glycerin in reducing brain edema in stroke, there is no evidence to indicate that glycerin will improve the long-term outlook for these patients (Katzman et al, 1977). Glycerin has effectively improved global performance and motor and sensory functions in patients with mild-to-moderate disability, but had no effect on reducing mortality in 26 patients with ischemic cerebral infarction with mild-to-severe disability (Fawer et al, 1977). These data suggest that patients with severe deficits will not respond at all to glycerin infusions. Patients in this study received 10% glycerin in 5% dextrose in normal saline (25 grams glycerin twice daily for 6 days).b)  In a double-blind, placebo-controlled study involving 61 patients, both glycerin and the combination of glycerin plus dextran were ineffective in the treatment of acute stroke. Patients were assigned to placebo, intravenous glycerin 10% 500 milliliters (mL) over 4 hours, or glycerin in the same doses plus dextran 50 grams or dextrose 25 grams (Rheomacrodex(R)) 500 mL intravenously over 3 hours. Patients received the regimens for 7 days following hospital admission (initiated 24 to 32 hours following the appearance of the first stroke symptoms). Neurologic scores according to a modified Matthew scale demonstrated no effect of either regimen on acute ischemic stroke. In addition, 98% of patients receiving glycerin developed signs of hemolysis. It was felt that neither glycerin or dextran have any value in the treatment of acute stroke (Frei et al, 1987). 

4.5.J   Pain in face1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category CSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster headache, and atypical facial pain3)  Adult:a)  GLYCERIN 0.2 to 0.4 milliliter administered via trigeminal cistern injection relieved paroxysmal facial pain in numerous conditions unresponsive to previous therapy. GLYCERIN was beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster headache, and atypical facial pain (Waltz et al, 1985). 

4.5.K   Primary angle-closure glaucomaSee Drug Consult reference: DRUG THERAPY OF GLAUCOMA 

4.5.L   Raised intracranial pressure

1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category CSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Oral GLYCERIN effectively lowered intracranial pressure associated with pseudotumor cerebri in several isolated reports3)  Adult:a)  Oral GLYCERIN, in several isolated reports, was effective in lowering intracranial pressure associated with pseudotumor cerebri BENIGN INTRACRANIAL HYPERTENSION (or ELEVATED INTRACRANIAL PRESSURE). The drug effectively decreased papilledema and headaches, and improved the blind spot. GLYCERIN doses of 0.25 to 1 gram/kilogram orally 3 to 6 times daily have been effective (Frank et al, 1981b). 

4.5.M   Raised intraocular pressure1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, EffectiveRecommendation: Adult, Class IIbStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Oral glycerin is used to reduce the intraocular pressure and vitreous volume prior to various ophthalmologic procedures3)  Adult:a)  Oral GLYCERIN is used to reduce the intraocular pressure and vitreous volume prior to various ophthalmologic procedures such as CATARACT EXTRACTION (AMA Department of Drugs, 1990b; Krupin et al, 1970a; Leone & Callahan, 1967a; Charan & Sarda, 1967a; Awasthi et al, 1967; Kornblueth et al, 1966), IRIDECTOMY, and sometimes for short-term treatment of GLAUCOMA or SECONDARY GLAUCOMAS. GLYCERIN may not be as effective in treating inflammatory secondary glaucomas since its action is dependent on an intact blood aqueous humor barrier. In acute-closure glaucoma, preoperative GLYCERIN reduces intraocular pressure and CORNEAL EDEMA rapidly. When the pressure is high, the iris sphincter may become ischemic and the miotic agent may not be effective until the pressure is reduced initially. In chronic glaucomas, GLYCERIN is used only for pre- and postoperative treatment (AMA Department of Drugs, 1990b; Frank et al, 1981b). GLYCERIN is used pre- and postoperatively in CONGENITAL GLAUCOMA, RETINAL DETACHMENT SURGERY, and KERATOPLASTY (AMA Department of Drugs, 1990b). Although GLYCERIN is considered safer than UREA or MANNITOL, GLYCERIN reduces intraocular pressure slower than the other agents (AMA Department of Drugs, 1990b; Trevor-Roper, 1964).b)  The effect of GLYCERIN on intraocular pressure (IOP) was evaluated in glaucomatous patients and normal subjects. Oral GLYCERIN in doses of 1 to 1.5 grams/kilogram (g/kg) for 10 to 25 days was effective in reducing IOP in 15 normal subjects and 32 patients with glaucoma (Consul & Kulshrestha, 1965). Additionally, an oral dose of 1.5 g/kg of a GLYCERIN 50% solution successfully reduced IOP in 14 patients with glaucoma (Drance, 1964).c)  Hypertonic agents, such as GLYCERIN, are effective for short- or long-term treatment of epithelial edema by reducing corneal edema and improving visual acuity. The long-term use of ocular GLYCERIN is not well tolerated and instillation is painful. GLYCERIN may also be used prior to ophthalmoscopy or gonioscopy when the cornea is too edematous to permit a diagnosis. A local anesthetic should be instilled prior to the instillation of GLYCERIN (AMA Department of Drugs, 1990b).d)  Significant reduction in intraocular pressure (IOP) was reported within 3 hours of administration of GLYCERIN in a 2-year-old boy who developed increased IOP secondary to EYE TRAUMA (a blow in the eye). The patient received 1 gram/kilogram orally for 2 days (Hill, 1964). 

4.5.N   Reye's syndrome1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Pediatric, Evidence is inconclusiveRecommendation: Pediatric, Class IIIStrength of Evidence: Pediatric, Category CSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Elevated intracranial pressure associated with Reye's syndrome has been effectively controlled with GLYCERIN3)  Pediatric:a)  The elevated intracranial pressure associated with Reye's syndrome has been effectively controlled with GLYCERIN in doses of 0.75 to 2 grams/kilogram intravenously every 2 hours (Mickell et al, 1977a; Nahata et al, 1981a; Frank et al, 1981b).b)  GLYCERIN effectively controlled intracranial hypertension in 9 patients with Reye's syndrome. GLYCERIN (10% solution in 5% dextrose with 0.45% sodium chloride) was administered by continuous intravenous (IV) infusion; doses of 0.75 to 1.75 grams/kilogram were administered every 2 hours. One-half of the total dose was administered during the first 30 minutes and the remainder over the next 1.5 hours. This was repeated every 2 hours, with the dose of GLYCERIN being adjusted to maintain an intracranial pressure of less than or equal to 15 mmHg. Serum concentrations of GLYCERIN ranged from 1.48 to 5.3 milligrams/milliliter and total body clearance from 1.99 to 5.1 milliliters/kilogram/minute. The authors suggest that due to substantial intersubject variability of GLYCERIN kinetics, that the drug be titrated IV to achieve the desired intracranial pressure. Patients did not develop rebound intracranial hypertension (Nahata et al, 1981a). 

4.5.O   Trigeminal neuralgia1)  OverviewFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence favors efficacyRecommendation: Adult, Class IIbStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:

Injection of GLYCERIN by the anterior percutaneous route into the trigeminal cistern was effective in alleviating pain in 86% of 75 patients with trigeminal neuralgia3)  Adult:a)  Peripheral GLYCERIN injection was successful in the treatment of 13 patients (17 nerves affected) suffering from idiopathic trigeminal neuralgia. The area of 12 nerves remained pain free for periods of 6 to 26 months, 2 nerves failed to respond to treatment whereas a decreased sensation was noticed in the area of 6 nerves. Although peripheral GLYCERIN injections compare well to results obtained from percutaneous retrogasserian GLYCERIN rhizotomy, the author felt that his preliminary results needed further clinical substantiation with longer follow-up periods (Stajcic, 1989).b)  GLYCERIN 0.2 to 0.4 milliliters via trigeminal cistern injection was reported beneficial in relieving paroxysmal facial pain in numerous conditions unresponsive to previous therapy. The injections were beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster headache and atypical facial pain (Waltz et al, 1985).c)  Percutaneous retrogasserian GLYCERIN injection (PRGI) appears to relieve trigeminal neuralgia in patients without changing facial sensation. This was demonstrated in 30 patients with TIC DOULOUREUX refractory to medical therapy. Small volumes (0.15 to 0.35 milliliter) of sterile GLYCERIN were precisely placed, by first insuring the anatomy of the trigeminal cistern using METRIZAMIDE. Nineteen of the 30 patients had no change in facial sensation following the injection. Although the long-term relief of tic douloureux following PRGI remains to be determined, preliminary results indicate that 23 patients have remained pain-free 5 to 12 months after the procedure (Lunsford, 1982).d)  Injection of GLYCERIN 0.2 to 0.4 milligram by the anterior percutaneous route into the trigeminal cistern was effective in alleviating pain in 86% of 75 patients with trigeminal neuralgia. Injection was visualized by the aid of METRIZAMIDE. GLYCERIN may act on demyelinated nerve fibers, which may be involved in the triggering mechanism of trigeminal neuralgia (Hakanson, 1981).  

 4.6   Comparative Efficacy / Evaluation With Other Therapies

Bisacodyl

Carbamide Peroxide

Dexamethasone

Dienestrol

Xylitol

4.6.A   Bisacodyl

4.6.A.1   Bowel carea)  In patients with upper motor neuron spinal cord lesions (n=15), total bowel care time was reduced by use of polyethylene glycol- based BISACODYL (PGB) suppositories compared with hydrogenated vegetable oil-based BISACODYL (HVB) suppositories. PGB suppositories compared with GLYCERINE-DOCUSATE MINI-ENEMAS (Theravac(R) SB mini-enemas) showed generally similar time requirements for bowel care. Total time for bowel care was 74.5 minutes, 43 minutes, and 37 minutes using HVB suppositories, PGB suppositories, and Theravac mini-enemas, respectively (p=0.01, PGB versus HVB; p less than 0.458, PGB vs Theravac). The step which showed the greatest variation in time requirements was time to flatus after application of the suppository or mini-enema (HBV, 32 minutes; PGB, 15 minutes; Theravac, 15 minutes; p less than 0.026, PGB vs HVB; p less than 0.983, PGB vs Theravac). Stool volume and the number of incontinence episodes were not significantly different between the 3 therapies. Factoring in nursing time, costs of the 3 treatments were $22.60-HVB; $13.39- PGB; and $12.19-Theravac. Bowel care was performed using a consistent protocol. HVB and PGB suppositories both contained 10 milligrams (mg) of bisacodyl. Theravac mini-enemas were polyethylene glycol-based and contained a 4-milliliter combination of glycerine 275 mg and docusate sodium 283 mg. Patients were randomized to treatment sequence; investigators, nurses, and patients were unaware of the type of suppository used in a bowel care session (House & Stiens, 1997).  

4.6.B   Carbamide Peroxide

4.6.B.1   Removal of ear waxa)  SUMMARY: Carbamide peroxide can facilitate earwax removal far better than glycerol but it is of variable efficacy compared to other cerumenolytics (Fahmy & Whitefield, 1982; Mehta, 1985).b)  A double-blind clinical trial comparing Exterol(R) (5% carbamide peroxide) and glycerol showed significant superiority of Exterol(R) over glycerol (Fahmy & Whitefield, 1982). All hard earwaxes treated with Exterol(R) were dispersed with ease and only 25% of the very hard ones entailed difficult syringing whereas only 75% of the hard earwaxes treated with glycerol were removed with ease and almost all 14 (88%) of the very hard ones entailed difficult syringing.  

4.6.C   Dexamethasone

4.6.C.1   Bacterial meningitis; Adjuncta)  Adjuvant therapy with oral glycerol, either alone or in combination with intravenous (IV) dexamethasone, improved severe neurological sequelae and/or death compared to dexamethasone alone or placebo in a prospective, multicenter, randomized, double-blind, double-dummy clinical trial in children aged 2 months through 16 years with bacterial meningitis. Meningitis was defined by the following: a cerebrospinal fluid (CSF) culture positive for meningitis-causing bacteria, characteristic CSF findings, and positive blood culture results or a CSF sample with a positive latex agglutination test results, and signs/symptoms compatible with bacterial meningitis. Patients pretreated with antimicrobials were included in the study provided therapy comprised of oral or no greater than 1 parenteral

dose administration. All patients received IV ceftriaxone 80 to 100 milligrams per kilogram (mg/kg) once daily for 7 to 10 days. Patients were randomly assigned to one of the following 4 arms: IV dexamethasone (n=166), IV dexamethasone and oral glycerol (n=159), oral glycerol (n=166), and placebo (n=163). Both dexamethasone and glycerol (85% solution) were administered 15 minutes prior to the ceftriaxone dose, and were dosed as 0.15 mg/kg and 1.5 grams/kilogram (1.5 milliliters/kilogram), respectively, every 6 hours for 48 hours. Nasogastric tubes were routinely used in study patients. In the event of vomiting within 30 minutes, the glycerol dose was repeated. Neurological, developmental, and hearing sequelae assessments occurred at hospital discharge; patients with deficits were scheduled for a follow-up visit 1-2 months later. The primary endpoints were death, severe neurological sequelae, and profound hearing loss (determined by brain stem evoked response audiometry or traditional audiometry). Severe neurological sequelae, which included blindness, quadriparesis or quadriplegia, hydrocephalus (requiring a shunt), or severe psychomotor retardation, was combined with death as a composite endpoint. Assessments were performed primarily at hospital discharge. Overall, 37% of patients received prior antibiotic therapy. At hospital discharge, 13% (n=86/654) of patients died, 8% (n=44/556) had severe neurological sequelae, and 8% (n=43/534) had profound hearing loss. An intent-to-treat analysis revealed that the incidence of severe neurological sequelae was significantly reduced in patients receiving glycerol alone (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.13-0.76; p vs placebo=0.01) or in combination with dexamethasone (OR, 0.39; 95% CI, 0.17-0.93; p=0.033) compared to dexamethasone alone (OR, 0.48; 95% CI, 0.21-1.07; p=0.72). Similarly, for the composite endpoint of death and severe neurological sequelae, significant reductions occurred in the glycerol-only and dexamethasone-glycerol groups (OR, 0.44; 95% CI, 0.25-0.76; p=0.003 and OR, 0.55; 95% CI, 0.32-0.93; p=0.027, respectively) compared to the dexamethasone-only group (OR, 0.65; 95% CI, 0.39-1.09; p=0.1). None of the adjunctive treatments (dexamethasone, glycerol, or the combination) significantly affected death or profound hearing loss. Pretreatment with antimicrobials, including their timing of administration with respect to study initiation, did not affect the results. The primary endpoint results are shown in the table. A post-hoc analysis of patients with Haemophilus influenzae type b meningitis (n=181) revealed that dexamethasone treatment prevented profound hearing loss (OR, 0.27; 95% CI, 0.09-0.77; p=0.014); however, the statistical significance was lost when receipt of pretreatment antimicrobials was taken into account. Of the 484 patients where a causative agent was identified, 222 were H. influenzae type b, 132 were S. pneumoniae, and 110 were N. meningitidis. Among adverse events, visible blood in stool occurred in 5% (n=6/111), 5% (n=5/101), 1% (n=1/113), and 2% (n=2/99) of patients in the dexamethasone-only, dexamethasone-glycerol, glycerol-only, and placebo groups, respectively. Vomiting and diarrhea were not more common in the glycerol-only group. There were no severe adverse drug events in any of the groups (Peltola et al, 2007).

Outcome DXM and placebo (n; %) DXM and glycerol (n; %) Glycerol and placebo (n; %) Placebo (n; %)

Death 23/166 (14%) 20/159 (13%) 17/166 (10%) 26/163 (16%)

Severe neurological sequelae 10/139 (7%) 8/134 (6%) 7/147 (5%) 19/136 (14%)

Severe neurological sequelae or death 33/162 (20%) 27/153 (18%) 24/164 (15%) 46/163 (28%)

Profound hearing loss 10/135 (7%) 9/132 (7%) 12/136 (9%) 12/131 (9%)

Key: DXM = dexamethasone; n = number of patients; * = determined by chi square test between 4 groups (for heterogeneity)

  

4.6.D   Dienestrol

4.6.D.1   Atrophy of vaginaa)  Dienestrol cream (0.01%) and a non-hormonal vaginal gel consisting of glycerin and mineral oil (Replens(R)) demonstrated essentially equivalent efficacy in a randomized, 3-month study of 39 postmenopausal women with symptoms of vaginal atrophy. Dienestrol 0.5 milligram was administered daily for 2 weeks, then 3 times weekly thereafter; the non-hormonal gel was administered 3 times weekly for the duration of the study. Vaginal dryness improved with both treatments as early as the first week, with a significant difference in favor of dienestrol from the first week on (p less than 0.0001 to 0.0024), and other symptoms including itching, irritation, and dyspareunia decreased for both groups, without marked intergroup differences. The non-hormonal gel may offer an adequate alternative to estrogen for treatment of vaginal dryness (Bygdeman & Swahn, 1996).  

4.6.E   Xylitol

4.6.E.1   Dental caries; Prophylaxisa)  The twice daily use of a dentifrice containing xylitol and glycerin for 3 months was associated with a significantly lower level of Streptococcus mutans in saliva compared to those individuals using a sorbitol-containing dentifrice. Streptococcus mutans are strongly associated with the development of dental caries. Whether the use of a xylitol/glycerin dentifrice actually minimizes the development of dental caries is unknown and further studies are required (Svanberg & Birkhed, 1991).    

 6.0   References1. AMA Department of Drugs: Drug Evaluations subscription, American Medical Association, Chicago, IL, 1990a.2. AMA Department of Drugs: Drug Evaluations subscription, American Medical Association, Chicago, IL, 1990b.

3. AMA Department of DrugsAMA Department of Drugs: Drug Evaluations subscription, American Medical Association, Chicago, IL, 1990.

4. Abel SR: Eye disorders In: Young LY & Koda-Kimble MA (Eds): Applied Therapeutics The Clinical Use of Drugs, 5th. Applied Therapeutics Inc, Vancouver, WA, 1992.

5. Alm A, Villumsen J, Tornquist P, et al: Intraocular pressure-reducing effect of PhXA41 in patients with increased eye pressure: a one-month study. Ophthalmology 1993; 100:1312-1317.

6. Alward WLM: Medical management of glaucoma. N Engl J Med 1998; 339:1298-1307.

7. Anon: FDC Reports: The Pink Sheet. December 11 1995; 57:8.

8. Anon: Latanoprost - the antiglaucoma drug of the decade?. Inpharma 1993; 911:8.

9. Awasthi P, Mathur SP, & Srivastava MP: Oral glycerol in cataract surgery. Br J Ophthalmol 1967; 51:130-131.

10. Balfour JA & Wilde MI: Dorzolamide: a review of its pharmacology and therapeutic potential in the management of glaucoma and ocular hypertension. Drugs Aging 1997; 10(5):384-403.

11. Beckman H & Trotsky MB: Cogan's syndrome treated with oral glycerin: report of a case. Arch Otolaryngol 1970; 91:179-182.

12. Bedikian AY, Valdivieso M, Heilbrun LK, et al: Glycerol: an alternative to dexamethasone for patients receiving brain irradiation for metastatic disease. South Med J 1980; 73:1210-1214.

13. Bedikian AY, Valdivieso M, Heilbrun LK, et al: Glycerol: an alternative to dexamethasone for patients receiving brain irradiation for metastatic disease. South Med J 1980a; 73:1210-1214.

14. Bernardi M, D'Intino PE, Trevisani F, et al: Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci 1994; 55(11):863-872.

15. Blachley JD & Knochel JP: Tobacco chewer's hypokalemia: licorice revisited. N Engl J Med 1980; 302(14):784-785.

16. Bodo G, Rozsa L, & Shea JJ: Temporary loss of hearing after salt loading in glycerol test. Am J Otol 1984; 5:16-19.

17. Bovet D, Cantore GP, & Guidetti B: Il glicerolol in neurochirugia, nova therapia dell ipertensione endocranica. Gas Int Med Chir 1961; 66:3021-3034.

18. Buckell M & Walsh L: Effect of glycerol by mouth on raised intracranial pressure in man. Lancet 1964; 2:1151-1152.

19. Buckell M & Walsh L: Effect of glycerol by mouth on raised intracranial pressure in man. Lancet 1964a; 2:1151-1152.

20. Burke McSpadden, RPh, Pharmacy Department, University of Colorado Health Sciences Center, Denver, CO

21. Bygdeman M & Swahn ML: Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 1996; 23(3):259-263.

22. Camras C, Alm A, Watson P, et al: Latanoprost, a prostaglandin analog, for glaucoma therapy. Ophthalmology 1996; 103:1916-1924.

23. Cantore GP, Guidetti B, & Virno M: Oral glycerol for reduction of intracranial pressure. J Neurosurg 1965; 21:278-283.

24. Charan H & Sarda RP: Glycerol in cataract surgery. Am J Ophthalmol 1967; 63:88-89.

25. Charan H & Sarda RP: Glycerol in cataract surgery. Am J Ophthalmol 1967a; 63:88-89.

26. Consul BN & Kulshrestha OP: Oral glycerol in glaucoma. Am J Ophthalmol 1965; 60:900-907.

27. Corsi FM, Galgani S, Gasparini C, et al: Acute hypokalemic myopathy due to chronic licorice ingestion: report of a case. Ital J Neurol Sci 1983; 4(4):493-497.

28. Cunliffe I: New drugs in glaucoma therapy. Hosp Med 2003; 64(3):156-60.

29. Cunningham FG, MacDonald PC, Leveno KF, et alCunningham FG, MacDonald PC, Leveno KF, et al (Eds): Williams Obstetrics, 19th. Appleton & Lange, Norwalk, CT, 1993.

30. D'Alena P & Ferguson W: Adverse effects after glycerol orally and mannitol parenterally. Arch Ophthalmol 1966; 75:201-203.

31. Dellow EL, Unwin RJ, & Honour JW: Pontefract cakes can be bad for you: refractory hypertension and liquorice excess. Nephrol Dial Transplant 1999; 14:218-220.

32. Dellow EL, Unwin RJ, & Honour JW: Pontefract cakes can be bad for you: refractory hypertension and liquorice excess. Nephrol Dial Transplant 1999a; 14:218-220.

33. Drance SM: Effect of oral glycerol on intraocular pressure in normal and glaucomatous eyes. Arch Ophthalmol 1964; 72:491-493.

34. Eriksson JW, Carlberg B, & Hillorn V: Life-threatening ventricular tachycardia due to liquorice-induced hypokalemia. J Int Med 1999; 245(3):307-310.

35. Everitt DE & Avorn J: Systemic effects of medications used to treat glaucoma. Ann Intern Med 1990; 112:120-125.

36. Fahmy S & Whitefield M: Multicentre clinical trial of Exterol(R) as a cerumenolytic. Br J Clin Pract 1982; 36:197-204.

37. Farese RV, Biglieri EG, Shackleton CHL, et al: Licorice-induced hypermineralocorticoidism. N Eng J Med 1991; 325(17):1223-1227.

38. Farese RV, Biglieri EG, Shackleton CHL, et al: Licorice-induced hypermineralocorticoidism. N Eng J Med 1991a; 325(17):1223-1227.

39. Fawer R, Justafre JC, Berger JP, et al: Intravenous glycerol in cerebral infarction. Schweiz Med Wochenschr 1977; 107:1867-1868.

40. Fawer R, Justafre JC, Berger JP, et al: Intravenous glycerol in cerebral infarction: a controlled 4-month trial. Stroke 1978; 9:484-486.

41. Folkersen L, Knudsen NA, & Teglbjaerg PS: Licorice. A basis for precautions one more time!. Ugeskr Laeger 1996; 158(51):7420-7421.

42. Folkerson L, Knudsen NA, & Teglbjaerg PS: Licorice. A basis for precautions one more time!. Ugeskr Laeger 1996; 158(51):7420-7421.

43. Frank MSB, Nahata MC, & Hilty MD: Glycerol: a review of its pharmacology, pharmacokinetics, adverse reactions and clinical use. Pharmacotherapy 1981; 1:147-160.

44. Frank MSB, Nahata MC, & Hilty MD: Glycerol: a review of its pharmacology, pharmacokinetics, adverse reactions and clinical use. Pharmacotherapy 1981a; 1:147-160.

45. Frank MSB, Nahata MC, & Hilty MD: Glycerol: a review of its pharmacology, pharmacokinetics, adverse reactions and clinical use. Pharmacotherapy 1981b; 1:147-160.

46. Frei A, Cottier C, Wunderlich P, et al: Glycerol and dextran combined in the therapy of acute stroke. A placebo-controlled, double-blind trial with a planned interim analysis. Stroke 1987; 18:373-379.

47. Freund G: The metabolic effects of glycerol administered to diabetic patients. Arch Intern Med 1968; 121:123-129.

48. Friedman Z, Neumann E, Merksamer E, et al: Ocular hypotensive effect of oral glycerol in relation to blood osmolarity, glucose and electrolytes. Metab Pediatr Ophthalmol 1980; 4:217-219.

49. Gilsanz U, Buencuero J, Revollar JL, et al: Controlled trial of glycerol vs dexamethasone in the treatment of cerebral oedema in acute cerebral infarction. Lancet 1975; 1:1049-1051.

50. Glyrol product information (CooperVision—US). Rev, 11/80.

51. Greenway FL, Heber D, & Bray GA: Failure of oral glycerol treatment to induce weight loss in obese humans. Curr Ther Res 1981; 29:849-852.

52. Gross RL & Pineyro A: Current use of ophthalmic beta blockers. J Glaucoma 1997; 6:188-191.

53. Hagnevik K, Lins LE, Gordon E, et al: Glycerol-induced haemolysis with haemoglobinuria and acute renal failure. Report of three cases. Lancet 1974; 1:75-77.

54. Hakanson S: Trigeminal neuralgia treated by the injection of glycerol into the trigeminal cistern. Neurosurgery 1981; 9:638-646.

55. Harada T, Ohtaki E, Misu K, et al: Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing Chinese herbal laxative. Cardiology 2002; 98(4):218.

56. Harada T, Ohtaki E, Misu K, et al: Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing Chinese herbal laxative. Cardiology 2002a; 98(4):218.

57. Hill K: Reduction of intraocular pressure by means of osmotic agents. J Maine Med Assoc 1964; 55:186-189.

58. Hommer A, Kapik B, Shams N, et al: Unoprostone as adjunctive therapy to timolol: a double masked randomised study versus brimonidine and dorzolamide. Br J Ophthalmol 2003; 87:592-598.

59. House JG & Stiens SA: Pharmacologically initiated defecation for persons with spinal cord injury: effectiveness of three agents. Arch Phys Med Rehabil 1997; 78:1062-1065.

60. Hoyng PFJ, Rulo A, Greve E, et al: The additive intraocular pressure-lowering effect of latanoprost in combined therapy with other ocular hypotensive agents. Surv Ophthalmol 1997; 41(suppl 2):S93-S98.

61. Hussain RM: The sweet cake that reaches parts other cakes can't!. Postgrad Med J 2003; 79:115-116.

62. Kageyama K, Watanobe H, Nishie M, et al: A case of pseudoaldosteronism induced by a mouth refresher containing licorice. Endocr J 1997; 44(4):631-632.

63. Karjalainen S, Karja J, & Nuutinen J: The limited value of the glycerol test in Meniere's disease. J Laryngol Otol 1984; 98:259-263.

64. Kato H, Kanaoka M, Yano S, et al: 3-Monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin Endocrinol Metab 1995; 80(6):1929-1933.

65. Katzman R, Clasen R, Klatzo I, et al: Report of Joint Committee for Stroke Resources. IV: Brain Edema in Stroke. Stroke 1977; 8:512-540.

66. Kjellgren D, Douglas G, Mikelberg FS, et al: The short-time effect of latanoprost on the intraocular pressure in normal pressure glaucoma. Acta Ophthalmol Scand 1995; 73:233-236.

67. Kolker AE & Becker B: Epinephrine maculopathy. Arch Ophthalmol 1968; 79:552-562.

68. Kornblueth W, Gombos G, & Traub B: The effect of osmotic agents employed before cataract extraction on the position of the vitreous following removal of the lens. Am J Ophthalmol 1966; 62:220-222.

69. Krausz T, Sellyei M, & Abranyi I: Renocerebral oxalosis after intravenous glycerol infusion. Lancet 1977; 2:89-90.

70. Krupin T, Kolker AE, & Becker B: A comparison of isosorbide and glycerol for cataract surgery. Am J Ophthalmol 1970; 69:737-740.

71. Krupin T, Kolker AE, & Becker B: A comparison of isosorbide and glycerol for cataract surgery. Am J Ophthalmol 1970a; 69:737-740.

72. Kumana CR, Yu YL, Chang CM, et al: Glycerol infusion rates warrant caution. Stroke 1991; 22:1608.

73. Leone CR & Callahan A: Restoration of the anterior chamber with glycerol 50% and mydriasis. Am J Ophthalmol 1967; 63:1686-1688.

74. Leone CR & Callahan A: Restoration of the anterior chamber with glycerol 50% and mydriasis. Am J Ophthalmol 1967a; 63:1686-1688.

75. Lesar TS: Comparison of ophthalmic B-blocking agents. Clin Pharm 1987; 6:451-463.

76. Lin SH, Yang SS, Chau T, et al: An unusual cause of hypokalemic paralysis: chronic licorice ingestion. Am J Med Sci 2003; 325(3):153-156.

77. Longe RL & DiPiro JT: Diarrhea and constipation In: DiPiro JT, Talbert RL, & Hayes PE (Eds): Pharmacotherapy: A Pathophysiologic Approach, 2nd. Elsevier Science Publishing Co, New York, NY, 1992, pp 566-578.

78. Massey EW & Brannon WL: Glycerol administration: alternative method and review. Mil Med 1977; 142:696-698.

79. Mathew NT, Rivera VM, Meyer FS, et al: Double-blind evaluation of glycerol therapy in acute cerebral infarction. Lancet 1972; 2:1327-1329.

80. McCurdy DK, Schneider B, & Scheie HG: Oral glycerol: the mechanism of intraocular hypotension. Am J Ophthalmol 1966; 61(5 part 2):1244-1249.

81. Mehta AK: An in vitro comparison of the disintegration of human ear wax by five cerumenolytics commonly used in general practice. Br J Clin Pract 1985; 39:200-203.

82. Meyer JS, Charney JZ, Rivera VM, et al: Treatment with glycerol of cerebral oedema due to acute cerebral infarction. Lancet 1971a; 2:993-997.

83. Meyer JS, Fukuuchi Y, Shimazu K, et al: Treatment of cerebral infarction with hyperosmolar agents (glycerol and mannitol). Circulation 1971; 44(suppl 2):96.

84. Mickell JJ, Reigel DH, Cook DR, et al: Intracranial pressure monitoring and normalization therapy in children. Pediatrics 1977; 59:606-613.

85. Mickell JJ, Reigel DH, Cook DR, et al: Intracranial pressure monitoring and normalization therapy in children. Pediatrics 1977a; 59:606-613.

86. Nahata MC, Kerzner B, McClung HJ, et al: Variations in glycerol kinetics in Reye's syndrome. Clin Pharmacol Ther 1981; 29:782-787.

87. Nahata MC, Kerzner B, McClung HJ, et al: Variations in glycerol kinetics in Reye's syndrome. Clin Pharmacol Ther 1981a; 29:782-787.

88. Newkirk TA, Tourtellotte WW, & Reinglass JL: Prolonged control of increased intracranial pressure with glycerin. Arch Neurol 1972; 27:95-96.

89. Nordlund JR, Pasquale LR, Robin AL, et al: The cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine. Arch Ophthalmol 1995; 113:77-83.

90. Novarini A, Coruzzi P, Montanari A, et al: Acute renal failure due to glycerol in man (letter). Nouv Presse Med 1979; 8:369.

91. Oakley DE & Ellis PP: Glycerol and hyperosmolar nonketotic coma. Am J Ophthalmol 1976; 81:469-472.

92. Olin B (Ed): Facts and Comparisons, Facts and Comparisons, Inc, St Louis, MO, 1991.

93. Osmoglyn product information (Alcon—US). Rev Rec 11/93., 6/88.

94. Panel consensus 1983.. ., .

95. Panelist comment.. ., 1991 revision cycle.

96. Peltola H, Roine I, Fernandez J, et al: Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2007; 45(10):1277-1286.

97. Personal Communication: Colgate-Palmolive, Inc (212-310-2000). New York, NY, 1983a.

98. Personal Communication: Dr L Dade Lunsford, Presbyterian University Hospital. Pittsburgh, PA, 1983b.

99. Pitlick WH, Pirikitakuhir P, Painter MJ, et al: Effects of glycerol and hyperosmolality on intracranial pressure. Clin Pharmacol Ther 1982; 31:466-471.

100. Product Information: Cosopt(R), dorzolamide hydrochloride-timolol maleate. Merck & Co, Inc, West Point, PA, USA, 1998.

101. Product Information: Iopidine(R) 0.5% Ophthalmic Solution, apraclonidine. Alcon Laboratories, Fort Worth, TX, USA, 1997a.

102. Product Information: Iopidine(R) Sterile Ophthalmic Solution, apraclonidine. Alcon Laboratories, Fort Worth, TX, USA, 1997.

103. Product Information: Osmoglyn(R), glycerin, Alcon Laboratories, Nutley, NJ, 1994. Osmoglyn(R), glycerin, Alcon Laboratories, Nutley, NJ, 1994a.

104. Product Information: Osmoglyn(R), glycerin. Alcon Laboratories, Nutley, NJ, 1994.

105. Product Information: TRISENOX(R) IV injection, arsenic trioxide IV injection. Cephalon,Inc, Frazer, PA, 2006.

106. Racz P, Ruzsonyi MR, Nagy ZT, et al: Maintained intraocular pressure reduction with once-a-day application of a new prostaglandin F2-alpha analogue (PhXA41): an in-hospital, placebo-controlled study. Arch Ophthalmol 1993; 111:657-661.

107. Reynolds JEF (ed): Martindale: The Extra Pharmacopoeia (electronic version). Micromedex, Inc. Denver, CO. 1991.

108. Reynolds JEF (ed): Martindale: The Extra Pharmacopoeia (electronic version). Micromedex, Inc. Denver, CO. 1991a.

109. Reynolds JEF: Martindales: The Extra Pharmacopoeia, 28th. The Pharmaceutical Press, London, England, 1989.

110. Robin AL, Ritch R, Shin DH, et al: Apraclonidine Maximum-Tolerated Therapy Study Group: Short-term efficacy of apraclonidine hydrochloride added to maximum-tolerated medical therapy for glaucoma. Am J Ophthalmol 1995; 120:423-432.

111. Robin AL: Argon laser trabeculoplasty medical therapy to prevent the intraocular pressure rise associated with argon laser trabeculoplasty. Ophthalmic Surg 1991; 22:31-37.

112. Sall KN, Greff LJ, Johnson-Pratt LR, et al: Dorzolamide/timolol combination versus concomitant administration of brimonidine and timolol: six-month comparison of efficacy and tolerability. Ophthalmology 2003; 110:615-624.

113. Schuman JS: Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular hypertension. Surv Ophthalmol 1996; 41(suppl 1):S27-S37.

114. Sears ES: Nonketotic hyperosmolar hyperglycemia during glycerol therapy for cerebral edema. Neurology 1976; 26:89-94.

115. Shintani S, Murase H, Tsukagoshi H, et al: Glycyrrhizin (Licorice)-induced hypokalemic myopathy. Eur Neurol 1992; 32(1):44-51.

116. Shintani S, Murase H, Tsukagoshi H, et al: Glycyrrhizin (Licorice)-induced hypokalemic myopathy. Eur Neurol 1992a; 32(1):44-51.

117. Soltau JB & Zimmerman TJ: Changing paradigms in the medical treatment of glaucoma. Surv Ophthal 2002; 47(Suppl 1):S2-S5.

118. Sorensen SJ & Abel SR: Comparison of the ocular beta-blockers. Ann Pharmacother 1996; 30:43-54.

119. Stajcic Z: Peripheral glycerol injections in the treatment of idiopathic trigeminal neuralgia. A preliminary study. Int J Oral Maxillofac Surg 1989; 18:255-257.

120. Stewart WC & Castelli WP: Systemic side effects of topical beta-blockers. Clin Cardiol 1996; 19:691-697.

121. Svanberg M & Birkhed D: Effect of dentifrices containing either xylitol and glycerol or sorbitol on mutans streptococci in saliva. Caries Res 1991; 25:449-453.

122. Swanson RE & Thompson RB: Renal tubular handling of glycerol and ethylene glycerol in the dog. Am J Physiol 1969; 217:553-562.

123. Tao RC, Kelley RE, Yoshimura NN, et al: Glycerol: its metabolism and use as an intravenous energy source. J Parenter Enteral Nutr 1983; 7:479-488.

124. Toris CB, Camras CB, & Yablonski ME: Effects of PhXA41, a new prostaglandin F2-alpha analog, on aqueous humor dynamics in human eyes. Ophthalmology 1993; 100:1297-1304.

125. Trevor-Roper PD: The use of oral glycerol in glaucoma (summary). Proc R Soc Med 1964; 57:37-38.

126. Troup H, Valtonen S, & Valpalahti M: Intraventricular pressure after administration of dehydrating agents to severely brain-injured patients. Acta Neurochir 1971; 24:89-95.

127. Vogel R, Tipping R, Kulaga SF, et al: Changing therapy from timolol to betaxolol: effect on intraocular pressure in selected patients with glaucoma. Arch Ophthalmol 1989; 107:1303-1307.

128. Wald SL & Laurin RL: Oral glycerol for the treatment of traumatic intracranial hypertension.. J Neurosurg 1982; 56:323-31.

129. Walker BR & Edwards CRW: Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin N Am 1994; 23:359-377.

130. Waltz TA, Dalessio DJ, & Ott KH: Trigeminal cistern glycerol injections for facial pain. Headache 1985; 25:354-357.

131. Wash LK & Bernard JD: Licorice-induced pseudoaldosteronism. Am J Hosp Pharm 1975; 32(1):73-74.

132. Weiner IM.: Diuretics and other agents employed in the mobilization of edema fluid. In: Gilman AG, Goodman LS, Rall TW, Nies AS, Taylor P, editors. The pharmacologic basis of therapeutics.. New York: Pergamon Press, 713-6., 1990.

133. Weiner IM: Diuretics and other agents employed in the mobilization of edema fluid. In: Gilman AG, Goodman LS, Rall TW, Nies AS, Taylor P, editors. The pharmacologic basis of therapeutics., 8. Pergamon Press, New York, 1990, pp 713-6.

134. Winter R, Nau R, & Hacke W: Behandlung des ischaemischen Hirninfarkts mit Glyzerin. Nervenartz 1995; 66:596-602.

135. Woster PS & Blanc KL: Management of elevated intracranial pressure.. Clin Pharm 1990; 9:762-72.

136. Wray SH: Disturbances of Vision and Ocular Movements In: Braunwald E, Isslebacher KJ, Petersdorf RG, et al (Eds): Harrison's Principles of Internal Medicine, 11th. McGraw-Hill Book Company, New York, NY, 1987.

137. Wyse TB, Talluto DM, Krupin T, et al: Topical prostaglandins for glaucoma therapy. J Glaucoma 1997; 6:180-187.

138. Ziai N, Dolan JW, Kacere RD, et al: The effects on aqueous dynamics of PhXA41, a new prostaglandin F2-alpha analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993; 111:1351-1358.

139. deKlerk G, Neiuwenhuis M, & Beutler J: Hypokalemia and hypertension associated with use of liquorice flavoured chewing gum. Br Med J 1997; 314(7082):731-32.

140. deKlerk G, Neiuwenhuis M, & Beutler J: Hypokalemia and hypertension associated with use of liquorice flavoured chewing gum. Br Med J 1997a; 314(7082):731-732.

 

Last Modified: October 21, 2010© 1974-2011 Thomson Reuters. All rights reserved.