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Drug-Enteral Tube Feeding Interaction

posted Nov 24, 2009, 1:05 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Considerations for Drug-Enteral Tube Feeding Interaction

Continuous enteral feedings has been used extensively in critically ill patients, these patients are often administered medications through their feeding tubes out of necessity. As not all oral medications may be compatible with enteral nutrition, complications associated with administration of medications through feeding tubes may arise. Moreover, improper management of these interactions may lead to therapeutic failure or adversely affect the patients.

In the discussions below, we will highlight some drug - enteral tube feeding interactions which have been found to be clinically important.

Interaction with Quinolones

The oral bioavailability of ciprofloxacin (using crushed tablets) was reduced by 28% when given to 13 normal subjects with Ensure.[1] Other enteral feeds (Jevity®, Osmolite®, Pulmocare® and Sustacal®) similarly reduce the bioavailability and maximum serum levels of ciprofloxacin by about one third.[2] Although no treatment failures have yet been reported, the impact on ciprofloxacin levels by enteral feeds to such a magnitude is still expected to be clinically important.[3] On the other hand, the interaction with other quinolones are of little clinical importance.[3]

It is believed that chelation reactions between the quinolone molecules and the divalent cations (such as calcium, aluminum, magnesium and iron) resulting in the formation of non-absorbable quinolone-cation complexes alone cannot fully explain this interaction. Some of the macronutrients, especially the protein content, also have a significant role in reducing the oral bioavailability of ciprofloxacin.[4,5]

When necessary, enteral feed may be stopped for 1 hour before and 2 hours after dose, alternatively a higher dose of the affected drug may be considered. It has also been suggested that sterile water should be used to dissolve the crushed tablets of ciprofloxacin since chelation with ions in tap water may occur.[6]

Interaction with Phenytoin

This drug-nutrient interaction is well documented. Most studies and case reports that used the continuous enteral feeding approach with phenytoin administered via the nasogastric tube or jejunostomy consistently found a reduction in serum phenytoin concentrations and required dose adjustments, regardless of the type of enteral feeding formulas used.[4,7]

A patient on phenytoin being fed with Fortison® through a nasogastric tube was observed to have a reduction of about 76% in phenytoin serum level.[8] Another study in 20 patients and 5 healthy subjects also found about a 70% reduction in phenytoin absorption when they are fed with Isocal® through nasogastric tube at a rate of 100 to 125mL/hr.[9]

The mechanism of this interaction is not entirely clear, however, it was reported that phenytoin could bind to Calcium caseinates and protein hydrolysates in the enteral feedings which reduced its absorption.[5,7] Phenytoin could also bind to the feeding tubing which further reduces its absorption.[3]

Therefore it is recommended that phenytoin is given as a single daily dose and enteral feed should be stopped 2 hours before dose and restart 2 hours after in order to minimise interaction. Phenytoin suspension should also be diluted with at least equal parts of water, and enteral tube be flushed with plenty of water before and after administration.[6]

Interaction with Warfarin

It has always been assumed that the decrease in the anticoagulant effect of warfarin is mainly caused by increased vitamin K absorption from the enteral formulas (such as Ensure®, Ensure-Plus®, Isocal® and Osmolite®, etc).[3] It has been found, however, that Warfarin also binds to the soy proteins or proteinaceous caseinate salts in the formulas.[4,7]

Based on limited evidence available, the dose of warfarin required for enteral feeds may differ from that used when the patient is on a normal oral diet. The INRs should be closely monitor when dose adjustment is required.[7]

Discussion

Drugs may interact directly or indirectly with enteral feeds. Some indicators[6,10] which may prompt medical staff to check for possible interaction include:

  • drugs with a narrow therapeutic index
  • drugs which interact with food, vitamins or electrolyte, or need to be given on an empty stomach
  • when multiple drugs in liquid form especially at high volumes are to be given concomitantly with enteral feeds

In addition, the tube size and placement site may also affect drug administration. Measures should always be taken to avoid blockage of the tube.[6]

Appropriate timing of medication in relation to feeds may help minimise the interactions. If enteral feeding is given continuously and the medication required are also to be given by the oral route, the feed should generally be withheld for at least 1 hour before and after drug administration. If it is not feasible to withhold enteral feeding, drug plasma levels and patients clinical progress should be closely monitored, and consideration should be given to increase the oral dosage.[6]

Reference:

  1. Mullers B.A. et al. Effect of enteral feeding with Ensure on oral bioavailabilities of ofloxacin and ciprofloxagin. Antimicrob Agents Chemo. (1994) 38, 2101-5.
  2. Noer BL et al. The effect of enteral feedings on ciprofloxacin Pharmacotherapy (1990) 10, 254.
  3. Ivan H Stockley. Stockley's Drug Interactions 6th edition 2002. Pharmaceutical Press.
  4. Chan, Ling Tak - Neander. Drug-nutrient interaction in clinical nutrition. Curr Opin Clin Nutr. Metab Care, May 2002; Vol 5(3); P.327-332.
  5. Hennessy, Daniel D. Recovery of Phenytoin from feeding formulas and protein mixtures. Am J Health Syst Pharm, Sept 2003; Vol 60(18); P.1850-2.
  6. Thomson F.C. et al. Managing drug therapy in patients receiving enteral and parenteral nutrition. Hosp. Pharm, June 2000; Vol 7; No.6 P.158-164.
  7. Dickerson, Roland N. Medication Administration Considerations for Patients Receiving Enteral Tube Feedings. Hosp-Plan, Jan. 2004; Vol 39(1); P.84-89.
  8. Summers V.M. et al. Nasogastric feeding and phenytoin interaction. Pharm J. (1989) 243, 181.
  9. Bauer L.A. Interference of oral phenytoin absorption by continous nasogastric feedings. Neurology (1982) 32, 570-2.
  10. Engle, Kelly K. et al. Techniques for administering oral medications to critical care patients receiving continuous enteral nutrition. Am J Health Syst Pharm, Jul. 1999; Vol 56(14); P.1441 - 4.

Ezetimibe

posted Nov 24, 2009, 1:03 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Ezetimibe: a new agent for the treatment of hypercholesterolaemia

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the principal agents for managing hyperlipidaemia. They act by inhibiting cholesterol production in the liver leading to a reduction in low-density lipoprotein (LDL) cholesterol and triglyceride levels, increasing high-density lipoprotein (HDL) cholesterol levels slightly and thus help to decrease the risk of coronary heart disease. Despite their established efficacy, not all patients achieve the recommended LDL cholesterol goals. Inadequate dosing due to adverse effects with high-dose, increased potential for intolerance and drug interactions with combinations of other available agents like bile acid sequestrants, fibric acid derivatives and nicotinic acid are all possible contributing factors. In addition, available statins have only modest effects on HDL. Thus, new lipid-lowering agents are needed for better clinical efficacy.

Mechanism of Action and Interactions

Ezetimibe (Ezetrol) is the first of a new class of antihyperlipidaemic agents, the selective cholesterol-absorption inhibitors. It acts by inhibiting the absorption of dietary and biliary cholesterol at the brush border of the small intestine without affecting the absorption of bile acids, fatty acids, fat soluble vitamins or triglycerides. Through inhibition of cholesterol absorption, Ezetimibe also reduce plant sterol absorption. The drug is rapidly absorbed, extensively conjugated to glucuronide in the intestine, and excreted primarily in the stool. Ezetimibe and /or its glucuronide circulate enterohepatically delivering the agent back to the intestine repeatedly. Therefore, systemic exposure is much reduced.

Ezetimibe is recommended for the treatment of Primary Hypercholesterolaemia, either in combination with statins or as monotherapy (if statins are not tolerated). It is also used for the treatment of Homozygous Familial Hypercholesterolaemia in conjunction with statins and as adjunctive therapy to diet in the treatment of Homozygous Sitosterolaemia (Phytosterolaemia). Familial Hypercholesterolaemia is caused by a mutation in the gene which codes for the receptors for LDL cholesterol. This result in absent or defective LDL receptors responsible for the clearance of LDL, and consequently in increased levels of plasma LDL. The homozygous form of the disorder results in very high concentration of cholesterol in the blood. These patients have a lower response rate to available pharmacological therapies than patients with the heterozygous form of the disease. Sitosterolaemia (Phytosterolaemia) is another genetic disorder which can cause hypercholesterolaemia through increased absorption of cholesterol and plant sterols from the gut.

Clinical Efficacy

In a multi-centre, randomized, double-blind, placebo-controlled trial involving 892 patients with Primary Hypercholesterolaemia, a 12-week course of monotherapy with Ezetimibe reduces concentration of LDL cholesterol by approximately 17% compared with an increase of 0.4% in the placebo group. The mean percentage increase in HDL cholesterol was 1.3% with Ezetimibe versus a decrease of 1.6% with placebo.

As patients with hypercholesterolaemia are often treated with an HMG-CoA reductase inhibitor, Ezetimibe has been studied in combination with these statins. In a study of 50 patients with Homozygous Familial Hypercholesterolaemia, 12 weeks of treatment with Ezetimibe and either Atorvastatin or Simvastatin had greater efficacy than statin therapy alone. Combined treatment reduced LDL cholesterol by 20.7% while high-dose (80mg/day) statin therapy reduced it by 6.7%. In a double-blind, multi-centre trial, an 8 week course of adding Ezetimibe to the treatment regimen of 37 patients with Homozygous Sitosterolaemia lowered their sitosterol concentration by 21% and their campesterol concentration by 24%.

Dosage and Precautions

The recommended dose of Ezetimibe is 10mg once daily. No dosage adjustments are required in geriatrics or in patients with renal impairment. It can be administered at any time of the day, with or without food. The drug was shown to be generally well tolerated. Adverse reactions are usually mild and transient. The overall incidence of side effects reported was similar to that reported with placebo. Although 5% of patients treated with Ezetimibe complain of myalgia, there are currently no reports of rhabdomyolysis. Other adverse effects include abdominal pain, arthralgia, back pain, cough, diarrhoea, fatigue, headache and sinusitis. Due to its minimal systemic absorption, drug interactions are few. However, caution is needed when prescribing Ezetimibe to patients who are being treated with a bile acid binding resin such as cholestyramine. These drugs interact resulting in reduced concentration of Ezetimibe. If such combination is used, Ezetimibe should be given two hours before or four hours after the bile acid sequestrants. Combined therapy with fibrates is not recommended because the safety and efficacy of the co-administration has not been established. When Ezetimibe is combined with a statin patient's liver enzyme should be checked. In patients with altered liver function, this combination is contraindicated.

Summary

Ezetimibe is a new cholesterol absorption inhibitor shown to be a safe and effective addition to the current LDL cholesterol lowering regimen. It is most useful in those patients who cannot tolerate statin or are at risk of statin interaction. The co-administration of statins (inhibiting cholesterol synthesis) and Ezetimibe (inhibiting cholesterol absorption) offers a new therapeutic option for patients with severe hypercholesterolaemia or patients who do not reach the defined treatment goals under therapy with statins alone.

References:

  1. Micromedex
  2. Australian Prescriber 2003; 26: 147-148
  3. Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002; 62(16): 2333-2347
  4. Dujovne CA, Ettinger MP, McNeer JF,Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP, for the Ezetimibe Study Group. Efficacy and safety of a potent new elective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolaemia. Am J Cardiol 2002; 90:1092-1097
  5. Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolaemia. Circulation 2002; 105:101-7

Tadalafil

posted Nov 24, 2009, 1:01 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Erectile dysfunction, the inability to achieve and maintain an erection adequate for satisfactory sexual performance, has been reported to affect as many as 150 million men worldwide (1). Local treatments for erectile dysfunction include vacuum erection devices, penile prostheses and intracavernosal therapy. These treatment options may often limit patient satisfaction because of their invasiveness, unappealing technique or side effects (2). A more user friendly form of therapy for patients with erectile dysfunction is an orally active treatment. Sildenafil (Viagra) was the first oral agent to be launched in recent years. Its success was followed by the introduction of other new drugs into the market, including tadalafil (Cialis) and vardenafil (Levitra).

Mechanism of Action

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by a PDE5-inhibitor such as tadalafil enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation (3).

Dosage and Administration

The recommended starting dose of tadalafil is 10mg. taken prior to sexual activity. The dose may be increased to 20mg or decreased to 5mg depending upon individual efficacy and tolerability. The maximum recommended dosing frequency is once daily. Dosage adjustment is only required in patients with severe renal insufficiency (creatinine clearance < 30ml/min). For patients with severe hepatic insufficiency, the use of taladafil is not recommended. For patients taking concomitant potent inhibitor of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 10mg, not to exceed once every 72 hours. Dosage adjustments are not required in patients greater than 65 years of age. Unlike sildenafil, the rate and extent of absorption of tadalafil are not influenced by food.

Contraindications and Precautions

Tadalafil is contraindicated in patients who are taking any form of organic nitrate. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Tadalafil is also contraindicated in patients for whom sexual intercourse is inadvisable due to unstable cardiovascular disease, for example: patients with myocardial infarction within the last 90 days, patients with unstable angina or angina occurring during sexual intercourse, patients with New York Heart Association Class 2 or greater heart failure in the last 6 months, patients with uncontrolled arrhythmias, hypotension (< 90/50 mmHg), or uncontrolled hypertension, patients with a stroke within the last 6 months.

Adverse effects most commonly reported are headache and dyspepsia. There may also be dizziness, flushing, nasal congestion, back pain and myalgia. The selectivity of tadalafil against PDE6 (found in retina) is insignificant, therefore visual side effects should be minimal (3).

Summary

The efficacy of tadalafil has been well proven in double-blind, placebo-controlled studies which demonstrated significant improvement in erectile function (4,5). These were in terms rigidity of erection, ability to penetrate, ability to maintain an erection during intercourse and percentage of intercourses with successful completion. Efficacy were uniformly reported for patients with mild, moderate or severe erectile dysfunction, and also in men with diabetes (5)

Tadalafil has been found to be effective from as early 16 minutes up to 36 hours following dosing. The claim is that this removes the time pressure for sexual performance and allow for a more natural, physiological response.

Tadalafil, sildenafil and vardenafil have all been proven effective against placebo. Direct comparison of these drugs will be required to clarify comparative efficacy and safety. At present, the choice between tadalafil, sildenafil and vardenafil is largely one of patient preference.

References

  1. Brock, B.B, McMahon, C.G., et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. The Journal of Urology. 2002;168:1332-1336
  2. Hellstrom W.J.G., Gittelman M., et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. Journal of Andrology. 2002;23:763-771
  3. Cialis product information, Eli Lilly and Company
  4. Porst H, Padma-Nathan H, Giuliano F et al: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 2003; 62:121-126.
  5. Saenz de Tejada I, Anglin G, Knight JR et al: Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002; 25(12):2159-2164.

Herb-drug interactions

posted Nov 24, 2009, 12:59 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

A fatal mix concocted by intent and inattention: Herb-drug Interactions

It is widely acknowledged that many herbal medicines offer the prospect of novel and effective alternative drug therapy. It is disconcerting, however, that many herbal retailers may be guilty of selling herbal medicines without much more than a desperate hope that the herb will be safe.

Given the increasing popularity of herbal medicines, pharmacists must take herbal medicines seriously. The government legislators must pressure herbal manufacturers to provide efficacy studies to show that these drugs do work, and how, rather than just what the herbs are "good for".

If quality information on the pharmacology, pharmacokinetics and most importantly clinical efficacy and safety profile of herbal medicines are available, we could confidently advise our patients who are often taking multiple drugs.

Part of the attractiveness of herbal medicine to the general public is a somewhat naïve perception that these drugs are free of side effects and can be combined with other medicines without fear of interaction. These perceptions are often based on old lines like, "They have been in use for thousands of years", "they are natural", or "well, I have never heard of any side effects". Unfortunately, often these unscientific and superficial beliefs are reinforced by herbal retailers. In fact, many case reports of adverse outcomes with herbal remedies are well documented in medical literature or aired in the media.

A drug interaction is said to result when the effects of one drug are changed by the presence of another drug, food, drink or some environmental substance. Herbal-drug interactions have resulted in serious events, including seizure, stroke, heart attack, liver failure and death. Attention has even been drawn to the potential for herbal medicines to adversely affect fertility, the viability of a pregnancy and the growing foetus.

A recently published survey from the US showed that more that half the patients presenting to an emergency department were using some kind of complementary medicines, which often affected their emergency care.

A table of interactions is shown on the following page.

Reported cases of inappropriate labelling of a recreational herbal product highlighted the importance of quality control. Quality control problems in herbal medicines are a failure of Good Manufacturing Practice (GMP). The contributing factors include misidentification, lack of standardization, contamination, substitution, adulteration, incorrect dosage, inappropriate labelling and finally, inappropriate advertising. These could be the results of operator error or a deliberate act.

The purpose of GMP is to minimize such events. Examples of deliberate acts may include the incorporation of heavy metals and orthodox drugs into the formulation without informing the consumer by adequate labelling. For example, it has been noted that the heavy metal contents of some imported traditional Chinese medicines can reach alarming levels, such as 20,000 times the allowable level of mercury and 1,000 times the acceptable level of arsenic. Deliberate contamination with sometimes superseded Western orthodox drugs can be a problem, especially in their potential to compromise patient's existing condition. Classic examples have included undeclared phenylbutazone, know to cause agranulocytosis.

References:

  1. Moses, G. Herb-drug Interactions. Australian Pharmacists Vol. 19 No. 4 2003. 215-216.
  2. Bury RW, Fullifaw RO, Barraclough D, et al. Problem with herbal medicines. Med. J Aust 1987; 146:324-325
  3. Ries CA, Sahud MA. Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 1975; 231(4):352-355.

Exemestane

posted Nov 24, 2009, 12:57 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Exemestane - the Preferred Adjuvant Hormonal Therapy in Metastatic Breast Cancer after Tamoxifen?

Introduction

Exemestane (EXE) is a steroidal irreversible aromatase inhibitor blocking the conversion of androgens to estrogens in peripheral tissues. It is currently indicated in the treatment of oestrogen-receptor positive advanced breast cancer in women with natural or induced post-menopausal status whose disease has progressed following anti-oestrogen therapy.

In contrast to nonsteroidal aromatase inhibitors (NS-AI), especially the 3rd generation aromatase inhibitors (such as anastrozole and letrozole) which bind reversibly to the cytochrome P450 (heme) moiety of the aromatase enzyme, EXE acts as false substrate that binds irreversibly to the substrate binding site of the enzyme. Both groups are well tolerated and exert similar efficacy with an over 90% reduction in circulating levels of estrogen.[1] However, the difference is EXE causes profound and prolonged reduction in aromatase levels, while NS-AI leads to aromatase up-regulation, thus possibly resulting in an earlier emergence of a resistant cell population [2]. In addition, EXE should theoretically exert a more effective global or some intra-tumoral aromatase inhibition because its metabolite, 17-hydroxyEXE has weak androgenic activity.

Clinical Trial Review: Exemestane vs Tamoxifen

Coombes et al. [3] conducted a double-blinded, randomized international trial to test whether switching to EXE after 2-3 years of tamoxifen therapy was more effective than continuing tamoxifen therapy for up to 5 years as recommended in the standard treatment. The study involved over 4500 patients and they were followed up for a median of 30.6 months. The EXE group showed a 32% statistically significant reduction in risk which corresponded to an absolute benefit in terms of disease-free survival of 4.7% at three years of randomization. The survival free of distant disease was better in the EXE group but the overall survival was not significantly different.

EXE was associated with a higher incidence of arthralgia and diarrhea than tamoxifen, but gynecologic symptoms (such as vaginal bleeding) and thromboembolic events were recorded more frequently in the tamoxifen group.

The trial panel recommended switching after 2-3 years after the start of tamoxifen treatment to EXE because of the following reasons. First of all, breast cancer frequently becomes resistant to tamoxifen within 5 years of continued treatment. Laboratory studies indicate the change in drug-receptor interaction of tamoxifen is caused by the up-regulation of tyrosine kinase receptors (especially the HER2 & epidermal growth-factor receptors) and downstream protein kinase. This change not only increases the expression of agonistic activity of tamoxifen but also increases the sensitivity of breast cancers to estradiol. Secondly, the serious side effects of tamoxifen, including thromboembolism and uterine carcinoma, can occur after prolonged use. Thirdly, tamoxifen can decrease bone resorption and thus, pretreatment with tamoxifen might lessen the effect of osteopenia caused by EXE.

Paridaens et al. [4] conducted an open-label and randomized trial to compare EXE versus tamoxifen as first-line hormonal therapy for postmenopausal women with metastatic breast cancer. This study involved over 380 patients and the median progression-free survival for patients taking EXE was 10.9 months while those taking tamoxifen was 6.7 months. Both complete and partial response rate were also higher in the EXE group (complete response: 7.4% vs 2.6%; partial response 36.8% vs 26.6%).

Clinical Trial Review: Exemestane vs other NS-AIs

Lonning et al. [1] conducted an open-label trial to evaluate the efficacy and toxicity of EXE in postmenopausal women with metastatic breast cancer who has progressive disease after 8 or more weeks of treatment with a NS-AI (including aminoglutethimide, anastrozole, letrozole and vorozole). The patient was first receiving 25mg of EXE once daily and would be given 100mg upon development of progressive disease. The study sample size was over 240 patients with a median duration of treatment of 37 weeks and 58 patients received a dose escalation to 100mg daily.

EXE produced objective responses in 6.6% of treated patients, including 8.1% and 4.8% of patients after failure of treatment with aminoglutethimide and other NS-AIs. No additional clinical benefit was observed in patients with an increasing dose of EXE to 100mg. Furthermore, both doses of EXE are well tolerated by patients with nausea, fatigue and hot flushes as the three most frequently complained side effects.

Fernie et al. [5] also had similar findings in a study to investigate the efficacy of EXE in postmenopausal women with metastatic breast cancer after failure of multiple hormonal therapies, including NS-AI. The study involved 96 patients and 4.2% had objective response and 34.4% had stable disease for at least 24 weeks.

Conclusions

The current standard treatment for hormone-receptor positive breast cancer as recommended by the American Society of Clinical Oncology is tamoxifen for up to 5 years [6]. In patients failing tamoxifen therapy, a high dose progestogen therapy such as megestrol acetate used to be the second-line option for these patients until the arrival of the aromatase inhibitors.

Considerable evidence now demonstrates that aromatase inhibition [7, 8] is superior, in terms of both efficacy and tolerability to megestrol acetate in postmenopausal women with tamoxifen-resistant advanced breast cancer and metastatic breast cancer. There is additionally some early evidence that EXE is superior to the NS-AI [1]. The long-term consequence of estrogen deprivation in postmenopausal women presently remains unclear. Particular concern should be paid on bone and cardiovascular health. Nevertheless, EXE appears a promising preferred option in treating advanced, metastatic breast cancer in natural- or induced-postmenopausal women failing tamoxifen treatment [9].

References

  1. Lonning PE Bajetta E, Murray R, et al. Activity of EXE in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. Journal of Clinical Oncology 2000, Vol 18, No.11:2234-2244
  2. Paridaens R, Dirix L, Lohrisch C, et al. Mature results of a randomized phase II multicenter study of EXE versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annuals of Oncology 2003. 14:1391-1398
  3. Coombes RC, Hall E, Gibson L, et al. A randomized trial of EXE after 2-3 years of tamoxifen therapy in postmenopausal women with primary breast cancer. The New England Journal of Medicine 2004. Vol 350, No. 11:1081-1092
  4. Paridaens R, Therasse P, Dirix L, et al. First results of a randomized phase III trial comparing EXE versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. European Journal of Cancer Supplement 2003:Vol 2, No 3:126
  5. Fernie NL, Zekri JM, Leonard RCF, et al. EXE in metastatic breast cancer; effective therapy after 3rd generation aromatase inhibitor failure. Poster Session IV of San Antonio 2003
  6. Winer EP, et al. American Society of Clinical Oncology Technology Assessment Working Group Update: Use of aromatase inhibitors in the adjuvant setting. J. Clin. Oncol. 2003:21:2597-2599
  7. Buzdar AU, Jonat W, Howell A, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from tow mature phase III trials. Cancer1998;83:1142-1152
  8. Dombernowsky P, Smith I, Falkson G, et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer; double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 1998;16:453-461
  9. Piccart-Gebhart MJ. New stars in the sky of treatment for early breast cancer. Editorial in the New England Journal of Medicine 2004. Vol 350, No. 11:1140-1142

An Overview of Glutamine

posted Nov 24, 2009, 12:55 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Introduction

Traditionally, glutamine has been considered as a non-essential amino acid. It is included in the list of "immunonutrients" that are required only when individuals are at risk of major infection. However, many recent laboratory and clinical data suggest that on top of the immunomodulating property, the multiple anabolic and host protective effects of glutamine may fuel the argument that glutamine may become an "essential" amino acid under certain clinical conditions.

Functions of glutamine

Glutamine is the most abundant free amino acid in the body, some 60% of the free intracellular amino acids in skeletal muscle. The synthesis of glutamine is regulated by glucocorticoids. During stress conditions, the efflux of glutamine from skeletal muscle serves as an important carrier of nitrogen to the splanchnic area and immune system. As a donor of nitrogen, glutamine acts as a precursor for the synthesis of purines, pyrimidines, amino sugars and antioxidant glutathione, it is therefore essential for cell proliferation. Increasing evidence also suggests that glutamine represents an essential substrate, metabolic fuel and energy source for the functions of many organ systems, including maintenance of muscle, preservation of GI tract integrity, acid-base balance, and promotion of the immune system. 1-5

Glutamine deficiency

During stress conditions, such as prolonged starvation, major injury, burns or infections, trauma-induced alterations in inter-organ glutamine flow (from skeletal muscle to gut, kidney, and immune cells) occurs. When the demand for this nutrient outstrips endogenous production, a state of glutamine deficiency is attained. 4,5

Illustrative example of Glutamine balance in postoperative trauma (calculations based on a 70-kg patient): 5

Intestinal glutamine utilization10-14 g/d
Kidney glutamine uptake4 g/d
Immune cells uptake2-4 g/d
Glutamine efflux from muscle8-10 g/d
Balance-6 to -14 g/d

Hypothesis has been made that such deficiency of glutamine could compromise recovery and result in prolonged illness and an increase in late mortality. Over the last two decades, many clinical studies suggest that improved outcome may be possible when such deficiency is reversed by the provision of exogenous glutamine in an appropriate concentration and by an appropriate route. However, debates continue over whether or not glutamine becomes an essential nutrient during illness and should be included with conventional parenteral nutrition support as a replacement of a deficiency. 2,4,5

Free glutamine and glutamine-containing dipeptides

Free glutamine used as a nutrient substrate is limited by its unfavorable chemical properties. This is also the main drawback on the inclusion of glutamine in conventional parenteral nutrition formulation. The limited solubility (36g/L at 20 degrees Celsius) demands that glutamine concentration must not exceed 1-2% to avoid precipitation. Therefore, in order to provide an adequate amount of glutamine, the large volume required may impose a heavy fluid burden to critically ill patient.5

Secondly, the progressive breakdown of glutamine, especially during sterilization procedures and prolonged storage make free glutamine very difficult to deliver. In one clinical trial, a 2.5% solution of L-glutamine was produced by a hospital sterile production pharmacy, sterilized by filtration and stored for up to 14 days at 4 degrees Celsius.1

A solution to overcome the second point is to make use of glutamine-containing dipeptides. Dipeptides ala-gln and gly-gln with a glutamine residue at the C-terminal position show high solubility in water (568g/L and 154g/L, respectively). They are sufficiently stable during heat sterilization and prolonged storage. These properties qualify dipeptides as suitable constituents of liquid nutritional preparations. Studies also showed that these synthetic peptides are rapidly cleared from plasma after parenteral administration, without accumulation in tissues or lost in urine. Considerable hydrolase activity in extra-/intracellular tissue compartments ensures a quantitative peptide hydrolysis, with liberated amino acids being available for protein synthesis and/or generation of energy. 5

Effects of glutamine dipeptides supplemented parenteral nutrition

In one clinical trial, twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24g nitrogen/kg/day) and isoenergetic (29 kcal/kg/day) TPN over 5 days. Control received 1.5g of amino acids/kg/day, and the test group received 1.2g of amino acids and 0.3g of L-alanyl-L-glutamine (Ala-Gln)/kg/day. Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acid. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. No side effects or complaints were noted. Patients receiving Gln-dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 + 3.6g vs. -23 + 2.6 g nitrogen), improved lymphocytes recovery on day 6 (2.41 + 0.27 vs. 1.52 + 0.17 lymphocytes/mL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 + 4.89 vs. 5.03 + 3.11 ng/ml), compared to the control group. Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. 2

Possible benefits of glutamine supplements suggested by clinical trials 1-5

 Observation
Muscular glutamine concentrationMaintained / Not influenced
Nitrogen balanceImproved
Trauma related intestinal atrophyAvoided
Protein synthesisIncreased
ImmunityImproved
Length of hospital stayReduced

Patient groups that may benefit from glutamine dipeptide therapy5

Severe catabolic illness

  • Burn/Trauma/Major operation
  • Acute/chronic infection
  • Bone marrow transplantation

Intestinal dysfunction

  • Inflammatory bowel disease
  • Infectious enteritis
  • Intestinal immaturity or necrotizing enterocolitis
  • Short bowel syndrome
  • Mucosal damage following chemotherapy, radiation or critical illness

Immunodeficiency syndromes

  • Immune system dysfunction associated with critical illness or bone marrow transplantation AIDS

Patients with advanced malignant disease

  • Glutamine-depleted patients suffering from cancer

Administration and dosage

Intravenous route is the most reliable administration method of glutamine dipeptides. Enteral formulations may not provide the requisite amounts of glutamine in blood and muscle, and also it can be an excellent culture medium for micro-organisms as well as carrying risks of easy contamination. They are suggested to be given immediately following catabolic insults, so as to provide timely support to the attenuated tissues with glutamine. The suggested usual dosage is 0.3 - 0.4g / kg / day, higher doses may be required in severely injured patients with, for example, multiple injuries, burns and sepsis5.

Reference

  1. Griffiths RD, Jones C, Palmer TEA. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997; 13:295-302
  2. Morlion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery - a randomized, double-blind, controlled study Ann. Surg. 1998: 227:302-308
  3. Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Nutrition 1998: 14:618-626
  4. Ziegler TR, Yonng LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann. Intern. Med. 1992; 116:821-828
  5. Beyond nutritional therapy - Glutamine Dipeptides - Scientific brochure by Fresenius Kabi

EVRA: The contraceptive transdermal patch

posted Nov 24, 2009, 12:52 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Introduction

Hormonal contraceptive agents are administered to the body through a variety of routes. The most common delivery methods are oral tablet, depot injection, implants and intrauterine device. EVRA, a contraceptive patch, that delivers an estrogen and a progestin via a transdermal route, has been launched in Hong Kong recently. It offers an additional choice to users and can enhance compliance by once weekly administration.

Description

EVRA is a combination transdermal contraceptive patch containing 6 mg norelgestromin (NGMN) and 600 mcg ethinyl estradiol (EE). The average daily dose absorbed into the systemic circulation is 150 mcg NGMN and 20 mcg EE.

Administration

A new patch is applied on the same day of each week for three consecutive weeks. The first patch is applied during the first 24 hours of the menstrual period. It also can begin on the first Sunday after a menstrual period starts. However, a non-hormonal contraception should be used for the first week of the cycle. The fourth week is patch-free. Withdrawal bleeding is expected to begin during this time. In no case should there be more than 7 consecutive patch-free days.

The patch may be applied to the upper torso (front and back, excluding the breasts), upper outer arm, abdomen or the buttocks. A different application area should be chosen when putting on each new patch. It should not be placed on skin that is red, irritated or cut, or on areas of the skin where make-up, lotions, creams, powders or other products are or will be applied.

Users can maintain their usual activities, including bathing and swimming while wearing the patch. However, if the patch comes loose, partially lifts off from the skin or falls off within 24 hours, it should be re-applied to the same place or replaced with a new patch immediately. No back-up contraception is needed and the patch change day will remain the same. If it has been more than 24 hours since the patch has come off, start a new four weeks cycle immediately by putting on a new patch. The day that the new patch is applied will be the patch change day. A non-hormonal contraception method should be used for the first week of the new cycle.

Mechanism of Action

The mechanism of action of the EVRA is the same as the combination oral contraceptives. The patch delivers hormones directly through the skin and into the bloodstream. The hormonal agents inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, these agents produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs.

Efficacy

A study has been performed in the United States and Canada with a total of 1417 healthy adult women of child-bearing potential participated. They were randomized in a ratio of 4:3 to receive either the contraceptive patch or the oral contraceptive (OC) pills. Contraceptive efficacy, cycle control, compliance, patch adhesion and safety were evaluated. The study shows that the contraceptive patch is comparable to a combination OC in contraceptive efficacy and cycle control. Compliance was better with the weekly contraceptive patch than with the OC. A total of 4.6% of all patches were replaced for either complete (1.8 %) or partial (2.8%) detachment. Both treatments were similarly well tolerated. However, application site reactions, breast discomfort, and dysmenorrhea were significantly more common in the patch group.

Contraindications

The physician should weigh the risks and benefits of using hormonal contraceptive patch as the same as the combination OC pills. It is not recommended for patients with a personal or family history of thrombosis, cardiovascular disease, severe hypertension and diabetes with vascular involvement, migraine, undiagnosed abnormal genital bleeding, hepatocellular disease with abnormal liver function and hypersensitivity to any component of the product. Moreover, analyses of phase III data suggest that EVRA may be less effective in users with body weight > 90 kg than in users with lower body weights.

Conclusions

EVRA is an easy-to-use, weekly, non-invasive form of reversible birth control that does not require surgical procedures or daily dosing. It allows the hormones to directly enter the bloodstream through the skin, which may help to reduce loss of doses due to vomiting and diarrhoea. Compliance problems with OC have been well documented. This product may help women who do not have a regular pill-taking routine. On the other hand, application site reaction, patch detachment and medication cost per cycle may be a concern if comparing with the OC pills. There are many birth control options available including hormonal and non-hormonal contraceptives. Physician should discuss with the users and help them to choose which contraceptive method is most appropriate for their individual needs and lifestyle.

References

  1. Micromedex
  2. Marie-Claude Audet, Michele Moreau, William D.Koltun, Arthur S.Waldbaum, Gary Shangold, Alan C.Fisher, George W.Creasy, for the ORTHO EVRA/EVRA 004 study group. Evaluation of Contraceptive Efficacy and Cycle Control of a Transdermal Contraceptive Patch vs an Oral Contraceptive. American Medical Association 2001. JAMA May 9,2001; Vol.285, No.18: 2347-2354.
  3. EVRA Product Information, JANSSEN-CILAG, a Johnson & Johnson company.
  4. EVRA web site, http://www.evra.com.hk/

G6PD deficiency

posted Nov 24, 2009, 12:51 AM by DERC 藥物教育資源中心

(Originally posted on 2004-10-20)

Drugs and chemicals to be avoided in Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest enzyme disorder of human beings and a globally important cause of neonatal jaundice, which can lead to kernicterus and death or spastic cerebral palsy. It can also lead to life-threatening haemolytic crises in childhood and at later ages, by interacting with specific drugs and with fava beans in the diet.

The best known morbid effect of G6PD deficiency is hemolysis induced by oxidative drugs. When prescribing drugs for G6PD-deficient subjects, two points should be kept in mind: (1) different genetic variants of G6PD deficiency entail different susceptibility to the hemolytic risk from drugs; thus a drug found to be safe in some G6PD-deficient subjects may not be equally safe in others; (2) the risk and severity of hemolysis is almost always dose-related.

Drugs and chemicals may be separated into those that must be avoided by G6PD-deficient subjects (such as sulphonamides, quinolones, nitrofurantoin), and those that do not readily precipitate hemolysis but must nevertheless be prescribed with caution.

Very few G6PD-deficient individuals with chronic non-spherocytic haemolytic anaemia have haemolysis even in the absence of an exogenous trigger. These patients must be regarded as being at high risk of severe exacerbation of haemolysis following administration of ANY of the drugs listed in the following tables1:

Drugs & chemicals with definite risk of haemolysis in most G6PD-deficient individuals:

Acetanilid2Primaquined,1
Dapsone & sulphonesa,1Quinolonese,1
Furazolidone2Sulphonamidesf,1
Isobutyl nitrate2Sulfacetamide2
Methylthioninium chloride1 (Methylene blue)Sulfamethoxazole2 (e.g. Septrin)
Naphthaleneb,c,2Sulfanilamide2
Nitrofurantoin1Sulfapyridine2
Niridazole1Toluidine bluec,2
Pamaquin1Trinitrotoluenec,2 (TNT)
Phenazopyridine2 (Pyridium) 

Drugs & chemicals with possible risk of haemolysis in most G6PD-deficient individualsg

Aspirinh,1Menadione1
Ascorbic acidi,2,3 (Vitamin C)Probenecid1
Chloramphenicol2,3 (Kemicetine)Quinidinej,1
Chloroquinej,1Quininej,1

Footnotes:

  1. Higher doses for dermatitis herpetiformis more likely to cause problems1;
  2. In mothball;
  3. Chemicals;
  4. 30mg weekly for 8 weeks has been found to be without undue harmful effects in African and Asian people1;
  5. Quinolones include: ciprofloxacin1, levofloxacin3, moxifloxacin3, nalidixic acid1, norfloxacin1 & ofloxacin1;
  6. Including co-trimoxazole; some sulphonamides, e.g. sulfadiazine, have been tested and found not to be haemolytic in many G6PD-deficient individuals1;
  7. Drugs in this table can probably be given in normal therapeutic doses to G6PD deficiency without non-spherocytic haemolytic anaemia2
  8. Acceptable up to a dose at least 1g daily in most G6PD-deficiency individuals1
  9. Very high therapeutic doses (~80g administered intravenously) have precipitated severe, even fatal, haemolysis2
  10. Acceptable in acute malaria1.

The tables in this bulletin are compiled based on the most updated reference materials available at the time of publication, and are therefore not intended to be comprehensive. Other drugs and chemicals might later found to be incompatible with G-6PD deficiency, the reader is advised to exercise caution and clinical judgment when using these tables.

Reference

  1. British National Formulary 46; September 2003, p447-448.
  2. Beutler E. "G6PD deficiency." Blood 1994; 84: p3613-3636.
  3. Micromedex Healthcare Series, Volume 119, 2004.

Method to apply Malathion Emulsion 0.5%

posted Nov 24, 2009, 12:49 AM by DERC 藥物教育資源中心

(Originally posted on 2004-10-04)

Method to apply Malathion Emulsion 0.5%

  1. Take a hot bath and pat the skin dry with a towel.
  2. Apply Malathion Emulsion to entire skin surface from the neck down including armpit, finger webs and toe webs.
  3. Do not wash or bath for 24 hours.
  4. Reapply the lotion to any area of skin which is washed during the 24 hours following application.
  5. Clothing and bedding may be washed or dry cleaned in the normal way.
  6. Seek medical advice if symptom persists 10 days afterward.

Malathion 0.5% 疥瘡乳劑用法:

  1. 先用熱水沐浴。
  2. 把乳劑由頸部以下,包括陰毛及指間部位,用排筆塗搽。待乳劑乾後,穿回當時所穿之衣服。
  3. 若此段期間曾洗手,則洗手後必需重新塗上。
  4. 24小時後,用熱水沐浴並換上潔淨衣服。
  5. 患者所穿著過之衣服、被單及枕袋等,都必需清潔妥當。
  6. 若病徵持續多過十天,應立即請教醫生。

IV compatibilities

posted Nov 24, 2009, 12:47 AM by DERC 藥物教育資源中心

(Originally posted on 2004-06-13)

The following information can serve as a quick reference for in-patient pharmacist to check IV orders written by doctors for very commonly used parenterals.

Drugs compatible with D5W only:

  • Amiodarone
  • Acetylcysteine
  • ATP
  • Labetolol

Drugs compatible with NS only:

  • DDAVP
  • Dihydralazine
  • Frusemide
  • Phenytoin

Drugs compatible with both D5W & NS:

  • Aminophylline
  • Ca Gluconate*
  • Digoxin
  • Diltiazem
  • Dobutrex
  • Dopamine
  • Esmolol
  • Glyceryl trinitrate
  • Heparin
  • Hydrocortisone
  • Isoprenaline
  • Isosorbibe dinitrate
  • KCl
  • MgSO4*
  • Naloxone
  • Pantoprazole
  • Streptokinase
  • Tramadol*
  • Tranexamic acid

* also compatible with Lactated Ringer's

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