Month: February 2013

Diagnosis of Myelofibrosis

February 22, 2013 Hematology No comments ,

Current diagnosis of PMF is based on the 2008 World Health Organization (WHO) criteria, which enlist histopathologic, morphologic, clinical, and molecular-cytogenetic variables. The diagnosis of post-PV or post-ET MF is according to IWG-MRT criteria.

Table 1 Diagnostic Criteria of Myelofibrosis

In all 3 MF variants, typical laboratory features include anemia, peripheral blood leukoerythroblastosis, dacryocytosis, leukocytosis/thrombocytosis, increased lactate dehydrogenase (LDH), excess circulating blasts or CD34+ cells, and bone marrow fibrosis, osteosclerosis, and angiogenesis.

Occasionally, overt bone marrow fibrosis might be absent (ie, prefibrotic PMF) and, in the presence of thrombocytosis, a spurious diagnosis of ET is made. The possibility of prefibrotic PMF, as opposed to ET, should be considered in the presence of persistently increased serum LDH, anemia, leukoerythroblastosis, anemia, leukoerythroblastosis, increased circulating CD34+ cell count, and marked splenomegaly. It is underscored that the distinction between ET and prefibrotic PMF is clinically relevant because both OS and leukemia-free survival are significantly inferior in the latter.

The differential diagnosis of PMF should also include bone marrow fibrosis associated with noneoplastic or other neoplastic conditions, including metastatic cancer, lymphoid neoplasm, or another myeloid malignancy, especially CML, MDS, chronic myelomonocytic leukemia (CMML), or AML. The presence of JAK2 or MPL mutation reliably excludes reative bone marrow fibrosis or a nonmyeloid malignancy.

Drug Targets and Cell Signaling Pathways

February 18, 2013 Cytogenetics, Pharmacology No comments , ,

There are cell signaling pathways and they are Erb pathway, VEGF pathway, PARP pathway, IGF-1 pathway, Hedgehog (Hh) pathway, and Ubiquitin-Proteosome pathway.

Erb pathway

There are four types of Erb receptors including EGFr (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Ligands of these receptors bind to Erb receptors, then dimerization happens, finally the tyrosine kinase of receptors are activated, which results in first increased tumor proliferation, angiogenesis, growth, and metastases potential; and second decreased apoptosis.

VEGF pathway

VEGF family includes VEGFR-1, VEGFR-2, and VEGFR-3. VEGF pathway is activated and cell signal is transmitted, as a results increased angiogenesis, lymphangiogenesis happens.

PARP pathway

PARP is involved in the DNA repair after DNA damage due to radiation therapy, chemotherapy and so on. PARP inhibitors can prevent the DNA repair after DNA damage, which results in persistent DNA damage and finally the apoptosis 0r cancer cell death.

IGF-1 pathway

IGF-1 pathway provides a potent proliferative signaling that stimulates growth in many different cell types and blocks apoptosis including cancer cells.

Hedgehog (Hh) pathway

Hh pathway is relative to cell proliferation, survival, and angiogenesis.

Ubiquitin-Proteosome pathway

This path is involved in the ubiquitination and proteasomal degradation of CRL substrates, which is important for normal cell cycle regulation and DNA replication related to cancer cell growth.

Conditioning Regimen for Hematopoietic Stem Cell Transplation (HSCT)

February 18, 2013 Chemotherapy, Hematology, Pharmacokinetics, Therapeutics No comments ,

There are two categories of HSCT, autologous HSCT (ASCT) and allogeneic HSCT (allo-SCT). For patients being considered for ASCT, the most common reason for choosing a particular conditioning regimen is the disease for which transplantation is being considered. For patients being considered for allo-SCT, the initial choice of a conditioning regimen is based on the disease and the condition of the recipient at the time of transplantation. And a major consideration for allo-SCT is whether to administer a myeloblative conditioning regimen or a reduced-intensity regimen.

When choosing between myeloablative or reduced-intensity conditioning, providers analyze a number of factors, including the age, the comorbidities, the disease and its stage at the time of transplantation, the source of stem cells being used, the degree to which human leukocyte antigen matches, and the preference of the patient.

To evaluate the efficacy and safety of different conditioning regimens, five aspects should be considered, including toxicity, risk of relapse, hematopoietic engraftment, treatment-related mortality, and overall survival.

Conditioning Regimens for ASCT

Table 1 Conditioning Regimens and Specific Malignancy

Conditioning RegimenSpecific Malignancy
1Gemcitabine plus busulfan plus melphalanRelapsed non-Hodgkin lymphoma
2Gemcitabine plus busulfan plus melphalanRefractory Hodgkin lymphoma
3Busulfan plus cyclophosphamide plus etoposidenon-Hodgkin or Hodgkin lymphoma
4Busulfan plus bortezomibMultiple myeloma (relapse after first ASCT)
5MelphalanMultiple myeloma

 

1. Gemcitabine/Busulfan/Melphalan for relapsed non-Hodgkin lymphoma

Gemcitabine, intravenous infusion over 4.5 hrs per day with a total dose of 2550 mg/m2 per day (maximum tolerated dose). Busulfan, intravenously in 4 daily doses targeted to an area under the curve (AUC) of 4000 μM*min per day. Melphalan, on days minus 3 and minus 2, 60 mg/m2 per day.

2. Gemcitabine/Busulfan/Melphalan for refractory Hodgkin lymphoma

Gemcitabine, intravenous infusion for 10 mg/m2 per minute over 4.5 hrs on days minus 8 and minus 3. Busulfan, intravenously targeted to an AUC of 4000 μM*min per day for 4 daily doses. Melphalan, given at 60 mg/m2 per day for 2 days on days minus 3 and minus 2.

3. Busulfan/Cyclophosphamide/Etoposide for non-Hodgkin or Hodgkin lymphoma

Busulfan, infusion at a test dose of 0.8 mg/kg for 2 hrs between days minus 14 and minus 11. The test dose is used for pharmacokinetic testing. The remaining busulfan dose is calculated to achieve a total AUC of 20,000 μM*min. One-fourth of this dose is given as a 3-hour infusion on day minus 8, during which a second pharmacokinetic analysis is done. The same daily busulfan dose is administered on days minus 7, minus 6, and minus 5, unless the pharmacokinetic results for day minus 8 showed total AUC outside the target range plus or minus 20%. Etoposide is administered at a dose of 1400 mg/m2 on day minus 4 followed by cyclophosphamide 2.5 g/m2 per day on days minus 3 and minus 2.

4. Busulfan/Bortezomib for mutiple myeloma

Busulfan, infusion at a test dose of 0.8 mg/kg for 2 hrs between days minus 12 and minus 9. Following pharmacokinetic sampling, individualized pharmacokinetic-directed dosing of busulfan is recommended to achieve a total AUC for the regimen of 20,000 μM*min, with intravenous infusion over 3 hrs each day from days minus 5 to minus 2. Bortezomib is administered 1.3 mg/m2 intravenously on day minus 1.

5. Melphalan for mutiple myeloma

High-dose melphalan forms the backbone of the conditioning regimen for the vast majority of patients undergoing ASCT for multiple myeloma. However, patients given the same elevated dose of melphalan may experience up to 5-fold variation in total exposure as measured by AUC. The median dose of melphalan is 192 mg/m2.

Conditioning Regimens for allo-SCT

Table 2 Conditioning Regimens and Specific Diseases

Conditioning RegimenSpecific Diseases
1Busulfan plus fludarabineVariety of hematological malignancies
2Fludarabine plus busulfanMalignant and non-malignant diseases (pediatric)
3Fludarabine plus busulfanLymphoma

 

1. Busulfan/Fludarabine for variety of hematological malignancies

Busulfan, a test dose of intravenous busulfan 0.8 mg/kg is administered approximately 1 week prior to the start of conditioning, and a desired AUC is calculated from the busulfan clearance dose levels. Dose levels are escalated in 20% increments from 4800 to 5766 to 7603 and finally to 8663 μM*min per 24 hours, from days minus 7 to day minus 3. The infusion is given over 90 hours all together. Fludarabine is administered 30 mg/m2 per day on days minus 7 to minus 3.

2. Fludarabine/Busulfan for malignant and non-malignant diseases (pediatric)

3. Fludarabine/Busulfan for lymphoma

Busulfan is targeted to three levels of AUC of 3500 μM*min per day, 5300 μM*min per day, and over 5300 μM*min per day. All three groups are along with intravenous fludarabine.

Reduced-Intensity Conditioning Regimen

1. Fludarabine plus cyclophosphamide, with or without anti-thymocyte globulin for severe aplastic anemia.

2. 2 Gy total body irradiation alone or with fludarabine for hematological malignancies.

3. Clofarabine plus total lymphocyte irradiation plus anti-thymocyte globulin for variety of hematological malignancies.

4. Alemtuzumab alone for relapsed/refractory chronic lymphocytic leukemia.

UCSF/SFGH/VASF Guidelines for Antimicrobial Use in Adults

February 16, 2013 Infectious Diseases, Pharmacokinetics No comments ,

Below is the guideline for adults antimicrobial use, including the renal impairment dosage adjustment. UCSF School of Pharmacy provides the information of this guideline and I translated portion of the table into Chinese. I hope this information will help anyone who need it.

Table 1 UCSF/SFGH/VASF Guidelines for Antimicrobial Use in Adults

成人抗微生物药物剂量调整
药物CrCl>50ml/minCrCl 10-50ml/minCrCl<10ml/min (ESRD not on HD)IHDCRRT备注
阿昔洛韦单纯疱疹病毒感染 5mg/kg/dose IV Q8h5mg/kg/dose IV Q12-24h2.5mg/kg IV Q24h2.5mg/kg IV*1,then 2.5mg/kg IV QPM(give post HD on HD days)5mg/kg IV Q24h
单纯疱疹病毒性脑炎/带状疱疹 10mg/kg/dose IV Q8h10mg/kg/dose IV Q12-24h5mg/kg IV Q24h5mg/kg IV*1,then 5mg/kg IV QPM5-10mg/kg IV Q12-24h
阿莫西林500-1000mg po TID250-500mg po BID250mg po QD暂缺暂缺
两性霉素B Dose on total body weight0.6-1.0mg/kg IV Q24h不变 不变 Dosage reductions in renal disease are not necessary.However,due to the nephrotoxic potential of the drug, reducing the dose or holding the drug in the setting of a rising serum creatinine may be warranted.Dosage reductions in renal disease are not necessary.However,due to the nephrotoxic potential of the drug, reducing the dose or holding the drug in the setting of a rising serum creatinine may be warranted.
两性霉素B脂质体 Dose on total body weight侵袭性霉菌感染 3-5mg/kg IV Q24h Doses up to 10mg/kg have been used for invasive mucormycosis 预防(heme-onc) 1mg/kg IV Q24h不变 不变 Dosage reductions in renal disease are not necessary.However,due to the nephrotoxic potential of the drug, reducing the dose or holding the drug in the setting of a rising serum creatinine may be warranted.Dosage reductions in renal disease are not necessary.However,due to the nephrotoxic potential of the drug, reducing the dose or holding the drug in the setting of a rising serum creatinine may be warranted.
阿米卡星>=60ml/min 15-20mg/kg/dose IV Q24h40-60ml/min 5-7.5mg/kg IV Q12h 20-40ml/min 5mg/kg IV Q12h-24h<20ml/min 5mg/kg loading dose (Consult pharmacy for maintenance dose)5mg/kg IV*1, then 3mg/kg IV post HD5mg/kg IV*1, then 3mg/kg IV Q24h
Dose is based on ideal body weight (IBW) except in obese patients or those under their ideal body weight. Use actual body weight if patient weight is less than IBW. Use adjusted body weight (ABW) in patients who are obese. Amikacin is generally used as a second-line aminoglycoside because of its increased cost and need to send out levels. (more…)

Make a provider and patient education for levothyroxine

February 13, 2013 Adverse Drug Reactions, Cardiology, Drug Informatics, Drug Interactions, Pharmacokinetics, Pharmacotherapy, Pharmacy Education, Therapeutics 3 comments , , , ,

Today I would like to write something about levothyroxine. My hospital uses levothyroxine often. Everyday there are lots of patients prescribed with levothyroxine. I do believe it is necessary to write below for education, which is not only for patients but also providers. The reference I use comes from U.S. FDA’s official drug information database.

Indications and Usage

Levothyroxine sodium is used for the following indications:

Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Contraindications

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. Finally, levothyroxine is contraindicated in patients with hypersensitivity to any of the inactive ingredients in levothyroxine.

Dosage and Administration

  • The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.
  • The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.

To acheive the two goals above, it depends on variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions (e.g., pregnancy, concomitant medications, and the specific nature of the condition being treated). As a result Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters.

Levothyroxine sodium tablets are administered as a single daily dose.

Table 1 The Indication and Dosages of Levothyroxine

Indication and UsageDosage
1HypothyroidismIndividuals who are at low risk of coronary artery diseaseStarting at 1.7 mcg/kg/day (Full dose). Adjusting dosage in 12.5-25 mcg increments until clinically euthyroid and serum TSH has normalized.
If myxedema coma, administer intravenously rather than orallyIndividuals older than 50 yrs or under 50 yrs with underlying cardiac diseaseStarting from 25-50 mcg/day, with increments of 12.5-25 mcg/day at 6-8 week intervals until clinical euthyroid and the serum TSH has normalized
Elderly individualsStarting from 12.5-25 mcg/day, with increments of 12.5-25 mcg/day at 4-6 week intervals until clinical euthyroid and the serum TSH has normalized
Individuals with severe hypothyroidismStarting from 12.5-25 mcg/day, with increments of 25 mcg/day at 2-4 week intervals until clinical euthyroid and the serum TSH has normalized
Secondary or tertiary hypothyroidismDosage as above but titrated until clinically euthyroid and serum free-T4 level is restored to the upper half of the normal range
2TSH Suppression – various types of euthyroid goiters and thyroid cancerWell-differentiated thyroid cancer> 2 mcg/kg/day (Target: TSH suppressed to <0.1 mU/L)
Contraindicated if the serum TSH is already suppressedWell-differentiated thyroid cancer (high risk)Target: TSH suppressed to <0.01 mU/L
Benign nodules and nontoxic multinodular goiter (controversial)Target: TSH suppressed to between 0.1 to either 0.5 or 1.0 mU/L

 

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to monitor therapy. The frequence of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization.

Monitor (more…)