Myositis caused by hydroxyurea in a patient with chronic myelogenous leukemia

A 59-year-old man with chronic myelogenous leukemia (CML) had a white-blood-cell (WBC) count of 55,400/microliter when admitted in July 1997, and was placed on oral hydroxyurea (HU) of 1,500 mg/day. Treatment with 600 MU/day of interferon alpha (IFN alpha) was started on August 5. HU was discontinued when the patient's WBC count dropped to 8,100/microliter on August 18. However, HU was resumed about a month later, after his WBC count increased to 10,100/microliter, but discontinued when the patient started to complain of chills, high fever, and bilateral femoral pain. HU treatment was initiated again one week later, after the patient's WBC count had begun rising but ceased again after he experienced chills, high fever, and bilateral femoral pain. The patient's myogenetic enzymes were found to be increasing the following day, and a lymphocyte stimulation test (LST) with HU showed a high stimulation index of 41.7%. The elevation of myogenetic enzymes and the results of the LST suggested that myositis due to HU was the cause of the patient's clinical manifestations. His myositis spontaneously disappeared after HU was discontinued. Although the patient is no longer receiving HU, IFN alpha has brought his CML under control. To our knowledge, this is the first reported case of myositis caused by HU.     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

OBJECTIVE: The objective of the study was to determine the major factors that underlie auditory/audiological performance measures in an elderly population, with particular emphasis on finding those factors responsible for speech understanding under specific conditions of interference. DESIGN: Audiological status and auditory performance of a group of elderly (60- to 81-yr-old) and normal-hearing young (18- to 30-yr-old) individuals was determined through a test battery. When present, the hearing loss of elderly subjects was symmetrical in the two ears and, at most, moderate. The battery included tests of speech intelligibility on the word and sentence levels, with and without the presence of interfering speech. In addition to pure-tone and speech reception thresholds, perception of spectrally or temporally distorted speech as well as auditory resolution of frequency, time, and space were tested. Two tests received special consideration: the Speech Perception In Noise Test and the Modified Rhyme Reverberation Test. Taking the overall results as well as various subsets of the results, principal component analyses were conducted to identify major factors underlying auditory performance. RESULTS: The factors extracted by the principal component analyses present a portrayal of the auditory performance profile in which effects of interference, high-frequency hearing, and basic auditory function play a major role. Interference factors include general susceptibility to noise as well as segregation of concurrent speech sounds on the basis of temporal dissimilarities and spatial separation. Comparison of factors extracted from various subsets of tests indicate that factors underlying the decline of the "cocktail party effect" in the elderly are addressed mostly by tests specifically designed to assess speech understanding in spatially distributed babble or in a reverberant environment. CONCLUSIONS: Factor analysis of test measures obtained from a group of elderly individuals with normal hearing or mild-to-moderate hearing loss led to two main findings. First, it portrayed hearing loss as a component of different factors rather than as a factor on its own. Second, the independence of measures of speech understanding in babble or reverberation from other measures suggests that such tests should become an integral part of audiological test batteries designed to assess auditory functions in aging.     

Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia

The aim of this analysis was to evaluate the efficacy of alpha-interferon (alpha-IFN) regimens in late chronic phase (diagnosis >12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The alpha-IFN programs were sequential studies with human leukocyte alpha-IFN (seven patients), recombinant alpha-IFN alone (15 patients) or with IFN-gamma (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive <35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that alpha-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.     

High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase

PURPOSE: A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS: Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS: Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION: High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.     

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.     

Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-alpha (IFN-alpha), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-alpha results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-alpha on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-alpha therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-alpha, whereas 22, 23, and 25 patients received IFN-alpha for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-alpha therapy administered for > or = 6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2. 1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-alpha therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight > or = 110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-alpha for less than 6 months before transplant, who were < or = 50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% +/- 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-alpha when the patient is < or = 50 years of age and has an HLA-compatible unrelated volunteer donor.     

Big BU/CY is associated with a favorable long-term outcome in patients allotransplanted for chronic myelogenous leukemia in chronic phase

Twenty-six adult patients, median age 36 years (range 21-53) with chronic myeloid leukemia in first chronic phase were allotransplanted between October 1989 and May 1995. The preparative regimen consisted of busulphan 16 mg/kg and cyclophosphamide 200 mg/kg (big BU/CY). Cyclosporin A and methotrexate were used for GVHD prophylaxis. Twenty-two donors were HLA-identical siblings and four donors were mismatched for one antigen of class I. The global incidence of acute GVHD was 50%, that of severe aGVHD (grades 3-4) was 11%; the global incidence of chronic GVHD was 30%. No patients developed veno-occlusive disease of the liver or interstitial pneumonia. Five patients died, one of relapse, four of transplant-related causes, mostly related to aGVHD; thus, the transplant-related mortality was 16%. Twenty-one patients are alive, in remission, with a median follow-up of 55 months (range 24-90); actuarial probability of survival is 78% (CI 64-96). Our study shows that this conditioning regimen is relatively easy to administer and seems to be as effective as, if not superior to, regimens containing TBI, in patients with chronic myeloid leukemia in chronic phase and the transplant-related mortality is not excessive even in older patients.     

An evaluation of phase I cancer clinical trial designs

Phase I clinical trials are designed to identify an appropriate dose for experimentation in phase II and III studies. I present the results from a simulation study to evaluate the performance of nine phase I designs involving the standard design, the two-stage modified Storer's design, the two-stage Korn's design, the one-stage modified continual reassessment method (CRM) designs, and the two-stage modified CRM designs. I compare the performance of the above phase I designs in terms of the following criteria: (i) the proportion of the recommended maximum tolerated dose (MTD) at each dose level; (ii) the proportion of patients treated at each dose level; (iii) the average number of patients to complete the trial; (iv) the probability of toxicity observed; and (v) the average number of cohorts to complete the trial. In general, the one-stage modified CRM II and CRM III designs perform well compared with the other designs considered in this study. The one-stage modified CRM II and III designs require much fewer numbers of cohorts than do the two-stage modified CRM II and III designs. The one-stage modified CRM II and III designs avoid the criticisms of the original CRM by reducing the average number of cohorts and toxicity incidences, while estimating the MTD more accurately than does the standard design.     

Determinants of prognosis in late chronic-phase chronic myelogenous leukemia

PURPOSE: Since interferon alfa (IFN-A) became an established treatment in chronic myelogenous leukemia (CML), more patients are referred to tertiary centers in late chronic phase (ie, > 12 months after diagnosis). Trials conducted in this phase cannot be evaluated precisely unless the features that determine prognosis in late chronic-phase CML are identified. The purpose of this study is to define the prognostic determinants of late chronic-phase CML. PATIENTS AND METHODS: From 1980 to 1997,257 consecutive CML patients referred in late chronic phase were studied. Their clinical characteristics at the time of referral and their association with survival were investigated. A staging model was designed. RESULTS: The median survival from time of referral was 43 months. Pretreatment characteristics associated with worse outcome included older age, poor performance status, splenomegaly, low albumin level, high percentage of blasts or basophils in peripheral blood (PB) or bone marrow, longer duration of chronic phase, and poor-risk group as defined by the Synthesis model. Prior exposure to IFN-A was not associated with worse outcome. By multivariate analysis, characteristics associated with shorter survival were age of 60 years or older, time from diagnosis of 3 years or greater, performance status of 1 or greater, PB basophils of 7% or greater, spleen 10 cm or greater, PB blasts 3% or greater, and albumin level less than 4 g/dL. A model that included age, duration of chronic phase, performance status, and PB basophils was generated. Patients with no, one, two, or three or greater adverse factors had median survivals of 71, 49, 26, and 19 months, respectively. CONCLUSION: A staging model for late chronic-phase CML can stratify patients in four groups with significantly different outcomes. If confirmed in independent populations, such a model could be considered in the analysis of future trials of treatment strategies in late chronic-phase CML.     

Increased risk of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in a county of Hesse, Germany

The incidence of acute and chronic myelogenous leukemia has been compared for the two neighbouring regions of Marburg and Giessen in Hesse (Germany). The investigation was based on the incident cases of the years 1983-1989 which have been diagnosed in the hematological departments of the universities of the two regions. The epidemiological evaluation of the data has been carried out in terms of a historical follow-up study, and shows an increased relative risk for the region around Marburg with a particular elevation for one community within this region. Potential determinants are discussed and focus on trinitrotoluene (TNT) and decomposition products which are known to contaminate the soil of this community, in some places severely, due to insufficient removal of remnants of the TNT production in large underground plants during World War II.     

Adams-Oliver syndrome: a case with juvenile chronic myelogenous leukemia and chylothorax

We report on a patient with Adams-Oliver syndrome and report new findings: a chylous pleural effusion and juvenile chronic myelogenous leukemia. Also, our patient had congenital heart disease, confirming that heart lesions are a manifestation in this syndrome. The major manifestations of this disorder are summarized. Included are cases not previously recognized as having Adams-Oliver syndrome identified in a literature survey. Distal limb deficiency is commonest with more frequent and more severe involvement of the lower limbs. Scalp defects are the second commonest manifestation, while an underlying skull defect is not infrequent. Cutis marmorata telangiectatica and dilated scalp veins are significant signs of this condition. This review highlights unresolved questions about Adams-Oliver syndrome.     

Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha

In 1994, the Italian and the German Chronic myeloid leukemia (CML) trials comparing interferon-alpha (IFN-alpha) with conventional chemotherapy were published. The survival advantage in favor of IFN-alpha compared with hydroxyurea (HU; 72 v 52 months) was significant in the Italian (P < .002), but not in the German trial (66 v 56 months, P < .44). We set up a collaborative study to identify the reasons for the different outcomes. There are major differences in the trial protocols concerning admission criteria, treatment strategy, and definitions. The German patients were older and more seriously sick. Fifty-two of the 327 patients in the German IFN and HU arms did not fulfil Italian admission criteria, and 41 of the 322 Italian patients did not fulfil German admission criteria. Using mutually uniform admission criteria, the median survival times of the IFN patients are 76 (Italian) and 72 (German) months (P = .56). The Italian group administered IFN combined with HU as needed, whereas the German group strictly used IFN as monotherapy with rerandomization to busulfan (BU) or HU after IFN resistance or intolerability. The differences seen between the Italian and the German trial results can be accounted for by objective differences in study design, especially the admission criteria, treatment strategy, and bias due to intention to treat analysis. The detailed analysis of the data suggests that the combination of IFN with HU as needed is more effective than either agent alone.     

Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase

Chronic myelogenous leukemia (CML) has a progressive course but little is known about the biologic characteristics of disease progression. This study was designed to assess the changes in cell proliferative characteristics, apoptosis, the expression of the bcl-2 and c-myc genes between the time of initial diagnosis and entrance into the blastic phase of the disease. We observed that the rate of cell proliferation decreased and the cell death rate did not significantly change as the disease accelerated. The level of bcl-2 expression was significantly higher in accelerated/blastic phase cells than in the chronic phase cells in the population as a whole, however, the bcl-2 expression level did not change in blast cell subpopulation. c-myc Expression was significantly higher in the blast cell subpopulation of accelerated/blastic phase than in that of earlier phases of the disease. In conclusion, the characteristics of CML cells, namely proliferation rate, c-myc and bcl-2 change during the course of the disease. It is possible that the change in c-myc expression plays a causative role in evolution of the blastic phase from the chronic phase.     

Statistical graphics in pharmacokinetics and pharmacodynamics: a tutorial

OBJECTIVE: To discuss the use of statistical graphics in the analysis of pharmacokinetics and pharmacodynamics data. METHODS: Information on graphic techniques and their application was retrieved from a MEDLINE search (January 1980-March 1997) of the English-language literature and bibliographic reviews of review articles and books. Data used to generate plots were extracted from some new drug applications submitted to the Food and Drug Administration and by simulation. DATA SYNTHESIS: In carrying out data analysis, we should look at data in several ways, construct a number of plots, and do several analyses, letting the results of each step suggest the next. The information from a plot should be relevant to the goals of the analysis. Thus, in choosing a graphic method, it is necessary to match the capabilities of the method to the need in the context of the application. For example, if linear relationships among variables in a set of multidimensional data are relevant, scatter plots such as the pairs plot with smoothing is likely to be more informative than other graphic methods. It is necessary to recognize what kinds of perceived structure are attributable to the data, and what kinds are artifacts of the display technique itself when using graphs for data analysis. CONCLUSIONS: Graphic techniques enable the data analyst to explore data thoroughly, look for patterns and relationships, confirm or disprove the expected, and discover new phenomena. An important element of statistical graphic techniques is flexibility, both in tailoring the analysis to the structure of the data and in responding to patterns that successive steps of analysis uncover. Statistical graphics can and should be used to enhance numeric statistical analyses.     

The kinetics and extent of engraftment of chronic myelogenous leukemia cells in non-obese diabetic/severe combined immunodeficiency mice reflect the phase of the donor's disease: an in vivo model of chronic myelogenous leukemia biology

In vitro studies have provided little consensus on the kinetic abnormality underlying the myeloid expansion of chronic myelogenous leukemia (CML). Transplantation of human CML cells into non-obese diabetic mice with severe immunodeficiency disease (NOD/SCID mice) may therefore be a useful model. A CML cell line (BV173) and peripheral blood cells collected from CML patients in chronic phase (CP), accelerated phase (AP), or blastic phase (BP) were injected into preirradiated NOD/SCID mice. Animals were killed at serial intervals; cell suspensions and/or tissue sections from different organs were studied by immunohistochemistry and/or flow cytometry using antihuman CD45 monoclonal antibodies (MoAbs), and by fluorescence in situ hybridization (FISH) for the BCR-ABL fusion gene. One hour after injection, cells were sequestered in the lungs and liver, but 2 weeks later they were no longer detectable in either site. Similar short-term kinetics were observed using 51Cr-labeled cells. The first signs of engraftment for BV173, AP, and BP cells were detected in the bone marrow (BM) at 4 weeks. At 8 weeks the median percentages of human cells in murine marrow were 4% (range, 1 to 9) for CP, 11% (range, 5 to 36) for AP, 38.5% (range, 18 to 79) for BP, and 54% (range, 31 to 69) for BV173. CP cells progressively infiltrated BM (21%) and spleen (6%) by 18 to 20 weeks; no animals injected with the cell line or BP cells survived beyond 12 weeks. The rate of increase in human cell numbers was higher for BP (7.3%/week) as compared with CP (0.9%/week) and AP (0. 5%/week). FISH analysis with BCR and ABL probes showed that some of the human cells engrafting after injection of CP cells lacked a BCR-ABL gene and were presumably normal. We conclude that CML cells proliferate in NOD/SCID mice with kinetics that recapitulate the phase of the donor's disease, thus providing an in vivo model of CML biology.     

Hemoperitoneum due to splenic rupture in a CAPD patient with chronic myelogenous leukemia

BACKGROUND: Due to the expression of urease, Helicobacter pylori is able to establish itself in the human stomach under acidic conditions. A novel host defence mechanism was recently proposed, suggesting that the formation of salivary nitrite in symbiosis with facultative anaerobic bacteria in the oropharynx, is aimed at enhancing the antimicrobial activity of gastric juice. AIMS: To investigate whether the addition of nitrite in physiological concentrations influences the resistance of H pylori to acid. METHODS: H pylori cultured from fresh gastric Biopsy specimens was exposed for 30 minutes to normal saline and to HCl/KCl buffer (0.2M) at pH 2 with urea (5 mM) added. The influence of potassium nitrite (50-1000 mumol/l) on bacterial survival was determined. RESULTS: Addition of nitrite (1 mM) to acidic solutions (pH 2) resulted in complete kill of H pylori within 30 minutes exposure time whereas acid alone allowed the organism to survive (p < 0.001). The antimicrobial effect of nitrite at pH 2 against H pylori was dose dependent and complete kill of organisms occurred at concentrations > or = 500 mumol/l. CONCLUSION: Acidified nitrite has anti-bacterial activity against H pylori. This should prompt further research into the effect of salivary nitrite on the survival of H pylori in the human stomach.     

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial)

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.     

Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children

Administration of GH-releasing peptide-2 (GHRP-2) represents a potential mode of therapy for children of short stature with inadequate secretion of GH. Requisite information to determine the dosing route and frequency for GHRP-2 consists of the pharmacokinetics (PK) and pharmacodynamics (PD) for this compound, neither of which have been previously evaluated in children. The purpose of this study was to characterize the PK and PD of GHRP-2 in children with short stature. Ten prepubertal children (nine boys and one girl; 7.7 +/- 2.4 yr old) received a single 1 microg/kg i.v. dose of GHRP-2 over 1 min, followed by repeated (n = 9) blood sampling over 2 h. GHRP-2 and GH were quantitated by specific RIA methods. PK parameters were calculated from curve fitting of GHRP-2 and GH vs. time data. Posttreatment plasma GH concentrations (normalized for pretreatment values) were used as the effect measurement. PD parameters were generated using the sigmoid Emax model. Disposition of GHRP-2 best fit a biexponential function. GHRP-2 PK parameters (mean +/- SD) were: alpha = 13.4 +/- 9.7 h(-1), beta = 1.3 +/- 0.3 h(-1), t(1/2beta) = 0.55 +/- 0.14 h, AUC(0-infinity) = 2.02 +/- 1.37 ng/mL x h, Cmax = 7.4 +/- 3.8 ng/mL, plasma clearance = 0.66 +/- 0.32 L/h x kg, and apparent volume of distribution = 0.32 +/- 0.14 L/kg. PK parameters for GH were: appearance rate constant = 5.9 +/- 3.1 h(-1), elimination t(1/2) = 0.37 +/- 0.15 h, lag time = 0.05 +/- 0.01 h, Cmax = 50.7 +/- 17.2 ng/mL, Tmax = 0.42 +/- 0.16 h, and AUC(0-infinity) = 47.9 +/- 26.1 ng/mL x h. PD parameters for GHRP-2 were: Ke0 = 1.13 +/- 0.94 h(-1), gamma = 13.15 +/- 9.44, E0 = 6.63 +/- 4.86 ng/mL (GH), Emax = 67.5 +/- 23.5 ng/mL (GH), and EC50 = 1.09 +/- 0.59 ng/mL. We concluded that 1) GHRP-2 produced a predictable and significant (i.e. compared to pretreatment values) increase in plasma GH concentrations; 2) the PK-PD link model enabled quantitative assessment of GHRP-2 modulation of serum GH levels; and 3) definition of the EC50 for GHRP-2 will enable PD and PK evaluations of extravascular dosing regimens for children.