LEUCOVORIN RESCUE SCHEDULES FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE | Clinical Situation | Laboratory Findings |
Leucovorin Dosage and Duration
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| Normal Methotrexate Elimination |
Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.
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15 mg PO, IM or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
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| Delayed Late Methotrexate Elimination |
Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.
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Continue 15 mg PO, IM or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.
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| Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury |
Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL
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150 mg IV q 3 hours, untilmethotrexate level is lessthan 1 micromolar; then15 mg IV q 3 hours, untilmethotrexate level is less than 0.05 micromolar.
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BOX WARNING
WARNINGS
METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY. BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):
METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY.
DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.
PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.) HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED.
METHOTREXATE FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY.
1. Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate (See CONTRAINDICATIONS).
2. Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.
3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug Interactions.)
4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)
5. Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
6. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
7. Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.
8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
9. Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.)
10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.
11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
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GLUCAGEN SUMMARY
GlucaGen [glucagon (rDNA origin) for injection] manufactured by Novo Nordisk A/S is produced by expression of recombinant DNA in a saccharomyces cerevisiae vector with subsequent purification.
For the treatment of hypoglycemia:
GlucaGen is used to treat severe hypoglycemic (low blood sugar) reactions which may occur in patients with diabetes treated with insulin.
Because GlucaGen depletes glycogen stores, the patient should be given supplemental carbohydrates as soon as he/she awakens and is able to swallow, especially children or adolescents.
Medical evaluation is recommended for all patients who experience severe hypoglycemia.
For use as a diagnostic aid:
GlucaGen is indicated for use during radiologic examinations to temporarily inhibit movement of the gastrointestinal tract. Glucagon is as effective for this examination as are the anticholinergic drugs. However, the addition of the anticholinergic agent may result in increased side effects. Because GlucaGen depletes glycogen stores, the patient should be given oral carbohydrates as soon as the procedure is completed.
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NEWS HIGHLIGHTS
Published Studies Related to Glucagen (Glucagon)
Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study. [2009.07]
CONCLUSIONS: Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.
Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). [2009.07]
CONCLUSIONS: Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.
The effects of two different hypocaloric diets on glucagon-like peptide 1 in obese adults, relation with insulin response after weight loss. [2009.07]
OBJECTIVE: Few studies have investigated the effect of type of diets on GLP-1 concentrations. The aim of this study was to compare the effect of two diets on circulating GLP-1 levels and the relation with insulin response after weight loss... CONCLUSION: A hypocaloric diet with a low fat percentage decreased GLP-1 levels with a direct correlation with insulin levels. Nevertheless, patients with a hypocaloric diet with a low carbohydrate percentage treatment did not change GLP-1 levels. Diet macronutrient manipulation on GLP-1 response could be useful in an obesity nutrition therapy.
Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects. [2009.05]
AIMS: Albiglutide is a glucagon-like peptide-1 (GLP-1) mimetic generated by genetic fusion of a dipeptidyl peptidase-IV-resistant GLP-1 dimer to human albumin. Albiglutide was designed to retain the therapeutic effects of native GLP-1 while extending its duration of action. This study was conducted to determine the pharmacokinetics and initial safety/tolerability profile of albiglutide in non-diabetic volunteers... CONCLUSIONS: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.
Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects. [2009.03]
BACKGROUND: A previous study of healthy subjects showed that intake of 6 g cinnamon with rice pudding reduced postprandial blood glucose and the gastric emptying rate (GER) without affecting satiety. OBJECTIVE: The objective was to study the effect of 1 and 3 g cinnamon on GER, postprandial blood glucose, plasma concentrations of insulin and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)], the ghrelin response, and satiety in healthy subjects... CONCLUSIONS: Ingestion of 3 g cinnamon reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose, GIP, the ghrelin concentration, satiety, or GER in healthy subjects. The results indicate a relation between the amount of cinnamon consumed and the decrease in insulin concentration.
Clinical Trials Related to Glucagen (Glucagon)
A Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of Very Low Dose-Glucagon in Subjects With Type 1 Diabetes Mellitus [Completed]
The purpose of this study is to identify the safest dose of very low dose glucagon to prevent
hypoglycemia in patients with Type I diabetes who use insulin pumps and to measure the the
amount of glucagon in the blood and see how the body responds to the glucagon.
Influence of Glucagon Inhibition in Relation to the Anti-Diabetic Effect of Glucagon-Like Peptide-1 (GLP-1) in Patients With Type 2 Diabetes Mellitus [Active, not recruiting]
Incretinbased treatment of patients with type 2 diabetes mellitus (T2DM) has increasing
interest. The incretin glucagon-like peptide-1 (GLP-1) stimulates beta-cells to increased
secretion and production of insulin. Glucose sensitivity is enhanced, apoptosis inhibited -
progression in disease is potentially stopped. The alpha-cell is also influenced by GLP-1 as
infusion lowers plasmaglucose (PG) levels in patients with type 1 diabetes mellitus (T1DM)
(C-peptide negative) by inhibition of glucagon and thereby decreased hepatic
glucoseproduction (HGP). Further Vilsboll et al has proved normalization of the
glacgonostatic effect of glucose in patients with T2DM. As an attempt to elucidate
glucose-intolerance in patients with T2DM further Knop et al investigated the
glucagonresponse to both oral glucose tolerance test (OGTT) and a following iso-glycemic
clamp. He saw a sufficient suppression of glucagon when glucose was introduced intravenously
but the suppression of glucagon was attenuated and delayed when glucose was given orally.
The aim of this study is to elucidate the glucose intolerance further. Due to the complex
interactions and mutual feed-back regulation between the pancreatic hormones and the PG level
this protocol includes five days. All days include a euglycemic-clamp, patients with T2DM
(n=10) are clamped at their fasting PG as are healthy control subjects (n=10). During the
clamp either GLP-1 alone; GLP-1 in combination with somatostatin, insulin and glucagon; or
somatostatin, insulin and glucagon are infused and blood samples are drawn.
The design of the study makes it possible to isolate the effect of each hormone. Further we
will be able to enlighten the effect of GLP-1 on the increase in glucose turn-over it
induces.
The essential part in this design will be hormone concentrations and the response parameter
the amount of glucose (AUC) it takes to create the euglycemic-clamp.
Sensor-Augmented Insulin Delivery: Insulin Plus Glucagon vs Insulin Alone [Recruiting]
This study aims to test an insulin and glucagon delivery algorithm designed to be used in
conjunction with a continuous glucose monitoring system. This combined glucose
sensing/hormone delivery approach is a step on the way to eventual development of an
artificial (or automated) pancreas. The insulin and glucagon delivery algorithm is based on
the difference between the current blood glucose and the target glucose (proportional error)
and the rate of change in blood glucose (derivative error), both adjusted for the recent
glucose history. This algorithm is called the Fading Memory Proportional-Derivative (FMPD)
Insulin and Glucagon Delivery Algorithm. The principal investigator of this study has
published previous research regarding the use of this algorithm and found it to be
well-suited to control blood glucose in type 1 diabetic animals. The addition of glucagon
was helpful; better glycemic control with fewer glucose excursions were observed when small
intermittent infusions of subcutaneous glucagon were given during times of impending low
blood sugar (Ward et al. 2008).
The objective of the current human study is to compare glycemic control in persons with Type
1 Diabetes using the FMPD Insulin plus Glucagon Delivery Algorithm vs. the FMPD Insulin-Alone
Algorithm. Subjects will undergo two 28-hour sensor-augmented glycemic control studies.
Each subject will be fitted with two short term continuous glucose monitoring systems and two
subcutaneous infusion catheters. These catheters will allow for SC delivery of insulin and
glucagon (or insulin plus a glucagon placebo). The accuracy of the wire sensors will be
verified every 10 minutes with a venous blood glucose test. For the first 4 hours, the
insulin and glucagon delivery will be controlled by venous blood in order to assess and
compare the accuracy of the two sensors, after which the more accurate sensor (if it remains
accurate) will control the FMPD algorithm. The main outcomes of our study are time spent in
the target range (70 - 180 mg/dl) and the percentage of studies requiring intervention due to
hypoglycemia (glucose < 70 mg/dl). The accuracy of the sensors over the life of the study
will also be evaluated.
The specific system used in this study of frequent blood testing and the use of two separate
infusion pumps is not feasible for every day use for individuals with diabetes. However, if
the glucose control algorithm (with or without the use of glucagon) provides effective blood
glucose management over long time periods the calculation program may be integrated into a
continuous blood glucose monitoring system with an insulin and glucagon pump.
GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia [Recruiting]
In order to investigate the mechanisms underlying the hyperglucagonemia characterizing
patients with type 2 diabetes mellitus (T2DM) we wish to test the following hypothesis: Do
pancreatic alpha-cells exhibit inappropriate glucagon responses to substances released from
the small intestine (GIP, GLP-2 and GLP-2) in patients with T2DM?
Glucagon in the Treatment of Hypoglycemia in Newborn Infants of Diabetic Mothers [Recruiting]
Thesis Infants of diabetic mothers are at high risk to develop hypoglycemia after birth.
After birth, glucose and ketone bodies are the main substrates of brain energy. Under normal
condition, the adrenergic response seen immediately after birth suppresses insulin release
and stimulates glucagon secretion which enhances gluconeogenesis and ketogenesis.
An inversion of the insulin/glucagon ratio is seen soon after birth as a normal, physiologic
phenomenon. Consequently, a post delivery glucose nadir is reached between 30 to 90 minutes
after birth, followed by a spontaneous recovery before 3-4 hours of age.
In infants of diabetic mothers, this inversion of the ratio is postponed and a more profound
and sustained hypoglycemia is seen.
Early feeding is of great importance to diminish the severity and incidence of hypoglycemia.
But, if despite an appropriate calorie intake, low levels of sugar are seen, an intravenous
infusion of glucose should be commenced. In case that IV glucose is not effective or can't be
supplied immediately, intramuscular glucagon is a therapeutic alternative.
We hypothesize that a single intramuscular injection of glucagon together with the
appropriate oral intake of nutrients is a safe and an effective alternative to the IV
infusion of glucose alone in the treatment of hypoglycemia in term infants of diabetic
mothers.
Methods Appropriately grown or large for date, term infants of insulin treated diabetic
mothers, with no other known medical problems, are potential candidates for our study.
Hypoglycemia will be defined as serum glucose level lower than 45 mg%. Infants of diabetic
mothers will arrive to the nursery and immediately receive early feeding before 30 minutes of
life. At that time, glucose will be checked. If glucose level is lower than 45 mg%,
treatment with IV glucose or IM glucagon will be initiated. Glucose will be checked every
hour for 4 hours and then every 3 hours (before each meal) for the next 20 hours.
In case blood glucose level is lower than 20 mg% or falls below 45 mg% despite glucagon
treatment, IV glucose will immediately be instituted.
Our aim is to check that IM Glucagon is as good as IV glucose in the treatment of
hypoglycemia in infants of diabetic mothers. We will compare glucose levels after treatment
with IV glucose and IM glucagon, the time till normalization of glucose and full feeding is
achieved and the number of hospitalization days in both groups.
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Page last updated: 2009-10-20
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