Dose-titration Method Research Articles

Clinical, Pharmacodynamic, and Pharmacokinetic Evaluation of BNC105P: A Phase I Trial of a Novel Vascular Disrupting Agent and Inhibitor of Cancer Cell Proliferation

To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced.

Phase 1 First-in-Human Trial of the Vascular Disrupting Agent Plinabulin(NPI-2358) in Patients with Solid Tumors or Lymphomas

Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies. Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow. Thirty-eight patients were enrolled. A dose of 30 mg/m² was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m² (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m². Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L. At the RP2D of 30 mg/m², plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents.

Comparison between different methods of adjustment of thyroxin replacement dose after total thyroidectomy for bengin thyroid disease

Introduction: Levothyroxin (T4) is commonly employed to correct thyroid hormone deficiency from various causes, and as total thyroidectomy is increasingly used to treat benign thyroid conditions, lifelong treatment with optimal dose of thyroxin (T4) is required which is difficult to predict. This study investigated factors that might predict the ideal T4 dose, and testing the body mass index as predictive factor with the aim of reducing delays in achieving normal thyroid function after surgery. Methods: This study was conducted on 52 patients presented with benign thyroid disease and operated upon with total thyroidectomy. The patients were prospectively randomized into two comparable groups of patients. One group of patients was given the routinely used titration method of thyroid replacement therapy, while the other used an algorithm for T4 dosage based on patient weight (postoperative weight) which was subsequently applied in previous published literatures. Patient and operative variables that might predict time to achieve normal thyroid function and optimal T4 replacement dose were examined. Results: The median time to achieve normal thyroid function was 16 (range 8–33) weeks in the first group in which the traditional titration method was used and large changes in T4 dose needed. But it was only 8 (range 4-17) weeks in the second group in which the weight algorithm was used. In multivariate analysis, the best predictor of optimal T4 dose was body weight. The use of a weight-related algorithm improved time to achieve normal thyroid function. There was a much stronger association between the L-T4 dosage and body mass. Conclusion: The T4 replacement dosage after total thyroidectomy is largely influenced by body weight particularly in subjects with high BMI values. Use of a weight-related algorithm shortens the time required to attain a stable dose of L-T4 compared with use of standard T4 dose-titration methods

Seizure Threshold in a Large Sample

We sought to examine the relationship of seizure threshold (ST) to age and other demographic characteristics in a large sample where ST was determined by the dose titration (DT) method. We also compared the resulting stimulation levels to estimates predicted by an age-based formula, the half-age (HA) method. In a multicenter prospective study, patients received a standardized course of bilateral electroconvulsive therapy for major depression using a brief pulse device. The ST was determined at the first treatment using a fixed algorithm of stimulations. Subsequent seizures were induced at a level 50% higher than the empirically determined ST. We only included data from subjects receiving methohexital anesthesia. We correlated ST with demographic and clinical characteristics of the sample. The actual dosing levels at the second treatment were compared with estimates based on HA. Of the original 531 subjects, 402 met criteria for the current analysis. The ST was positively correlated with age. Male patients had slightly higher ST than female patients. Neither race, severity of illness, psychosis, nor use of psychotropic medications affected ST. Little variability in titrated ST was observed among our patients. An ST of 40 ("percent of charge") or lower was found in 97.5% of patients, with either 20 or 40 in 80% of patients. Ninety-six percent of the patients were treated at the 3 levels of 15%, 30%, or 60%. Estimated HA stimulus levels offered a wider range of choices compared with this particular algorithm used for ST determination at an average level of 18% above the determined ST. Seizure threshold correlates strongly with age, whereas there is a weaker relation between ST and sex. There was little individual variation of ST determined by the DT method among subjects, possibly because of the wide spacing between steps of this particular titration algorithm. Half-age estimates were 18% above the empirically determined ST. This suggests that the use of the HA estimates at the first treatment may result in fewer stimulations compared with the DT method.

The Effects of Age and Sex on Electroconvulsive Therapy Using Remifentanil as the Sole Anesthetic Agent

This study examines electroencephalographic (EEG) and motor seizure duration and dynamic energy according to age and sex using remifentanil anesthesia in standard electroconvulsive therapy (ECT). In an earlier study, we showed that remifentanil provides superior anesthesia for ECT in terms of providing adequate seizure duration with lower stimulus doses in patients refractory to maximal ECT settings with methohexital. Patients, refractory to maximal ECT settings with methohexital, received remifentanil as the sole anesthetic agent. Stimulus dose was determined by the dose-titration method. Electroencephalographic seizure duration, motor seizure duration, and dynamic energy in joules (j) were compared between male and female subjects and among patients aged 40 years or younger, older than 40 years but aged 65 years or younger, and older than 65 years. Seventy-two patients were included in the study. There was no significant difference in remifentanil doses between female and male subjects. There was no significant statistical difference between female and male subjects regarding motor seizure duration, EEG seizure duration, or dynamic energy (P > 0.05). There were significant statistical differences among different groups in terms of motor seizure duration, EEG seizure duration, and dynamic energy (P< 0.05). The younger age group had longer motor and EEG seizure durations and required lower dynamic energy. There is no significant effect of sex on ECT with remifentanil anesthesia regarding EEG or motor seizure durations or dynamic energy; however, statistically significant differences were observed based upon age. Younger patients had both increased motor and EEG seizure duration compared with older patients who may require higher stimulus doses than younger patients for comparable motor and EEG seizure durations.

Optimization of thyroxine replacement therapy after total or near-total thyroidectomy for benign thyroid disease

Total or near-total thyroidectomy is increasingly used to treat benign thyroid conditions. Lifelong treatment with thyroxine (T4) is then required, but the optimal dose is difficult to predict. This study investigated factors that might predict the ideal T4 dose, with the aim of reducing delays in achieving normal thyroid function after surgery. Data on 98 patients who underwent total or near-total thyroidectomy for benign disease were reviewed retrospectively. Patient and operative variables that might predict time to achieve normal thyroid function and optimal T4 replacement dose were examined. These data were then used to formulate an algorithm for T4 dosage, based on patient weight, that was subsequently applied prospectively to a comparable group of 27 patients. The median time to achieve normal thyroid function was 14.5 (range 2-120) weeks before introduction of the algorithm, and was greater in patients needing large changes in T4 dose. In multivariate analysis, the best predictors of optimal T4 dose were bodyweight (r = 0.46, P < 0.001) and age (r = -0.32, P = 0.002). Subsequent use of a weight-related algorithm improved time to achieve normal thyroid function. The T4 replacement dosage after total or near-total thyroidectomy is largely influenced by bodyweight. Use of a weight-related algorithm improves patient care compared with use of standard T4 dose-titration methods.

Antidepressant Effect of Ketamine During ECT

Back to table of contents Previous article Next article Letter to the EditorFull AccessAntidepressant Effect of Ketamine During ECTROBERT OSTROFF, M.D., MARBIELA GONZALES, M.D., and GERARD SANACORA, M.D., ROBERT OSTROFFSearch for more papers by this author, M.D., MARBIELA GONZALESSearch for more papers by this author, M.D., and GERARD SANACORASearch for more papers by this author, M.D., Hamden, Conn.Published Online:1 Jul 2005https://doi.org/10.1176/appi.ajp.162.7.1385AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: There has been recent interest in the use of ketamine as anesthesia for ECT because of its low anticonvulsant effects and possible reduction of cognitive side effects (1). Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, has also been shown to have putative antidepressant effects (2–4). The following case serves to highlight the possible antidepressant effects of ketamine in a patient who unintentionally received an induction dose alone during two failed ECT sessions.Ms. A was a 47-year-old white woman who was hospitalized for an episode of severe depression in the context of a 20-year history of schizoaffective disorder. Ms. A had been treated for depression with ECT 8 years previously and had experienced profound confusion and short-term memory problems. However, she did respond, with remission of her depression. The current episode of depression had persisted for 16 weeks, during which she did not respond to venlafaxine, bupropion, sertraline, olanzapine, or lamotrigine. She had been simultaneously taking valproic acid. Ms. A’s depression was characterized by profound dysphoria, anergia, anorexia, insomnia, anhedonia, and passive suicidal ideation. There was no observed or reported mood variability, except for mild morning worsening of the dysphoria. She was hospitalized because of a decline in her activities of daily living to the point of not dressing herself without assistance.Ms. A complained of severe memory problems, although her score on the Mini-Mental Status Examination was 30 of 30. The results of an EEG and magnetic resonance imaging were normal. Ms. A was withdrawn from valproic acid, 1500 mg/day, and lamotrigine, 50 mg/day, 24 hours before her first ECT treatment. For the index ECT treatment, ketamine was used as an induction agent at a dose of 0.5 mg/kg because we have found that it reduces cognitive side effects in some patients. Ms. A had no previous exposure to ketamine. Bifrontal lead placement was used, and a stimulus with the Spectrum 5000 Q ECT apparatus (MECTA Corp., Lake Oswego, Ore.) was administered by using the dose-titration method. The cuff method was used to monitor the motor seizure, and the electrical seizure was monitored with an EEG. No motor or electrical seizure was observed during the first treatment session.Ms. A reported an immediate improvement of her mood after regaining consciousness. This improvement continued the next day when she awoke in the morning and reported a subjective improvement in well-being and an appetite for the first time in 2 weeks. The following day, ECT was again administered with the dose-titration method because we assumed that the antiepileptic agents interfered with the induction of a seizure during the first treatment session. Again, no electrical or motor seizure was observed. Strikingly, Ms. A reported a further improvement in her mood that persisted the following day. Her core symptoms, interest, energy, motivation, mood, and appetite all improved. On our 0–10-point rating scale of clinical improvement, Ms. A rated herself at 7, having initially rated herself at 2. Session 2 fell on a Friday, so there was an extra day to observe Ms. A’s response.Forty-eight hours after her second ECT session, Ms. A still noted improvement. She did note some decline in her mood and felt that the improvement was starting to dissipate. Because of the timing of the treatments, we had 5 days to observe her clear improvement over baseline in response to ketamine. At session 3, a full grand mal seizure was observed. Three more treatment sessions were necessary before remission was reached.Ketamine, as both an adjunctive dose (3) and an inductive dose (4), has been noted to improve mood in patients undergoing surgery. Two studies have demonstrated its potential antidepressant effects in major depression (2, 3). Of interest, acute administration of NMDA antagonists has been demonstrated to induce neurogenesis, a characteristic seen in many antidepressant agents. NMDA-mediated involvement of the glutamatergic system in the pathophysiology of depression is of growing interest (5, 6). Ketamine is also a weak dopamine transporter antagonist and can be psychotomimetic. Its role as a primary anesthetic agent in ECT deserves more study. It may have its greatest use in patients with severe nonpsychotic depression.

Seizure threshold rise during electroconvulsive therapy in schizophrenic patients

A rise in seizure threshold during a course of electroconvulsive therapy (ECT) has been demonstrated in patients with depression and mania, but no information has been available as to whether the same result occurs in schizophrenia. Ninety-three patients with schizophrenia underwent estimation of the seizure threshold by the dose-titration method, at the first and second, seventh, fourteenth, and twentieth treatments over an index ECT course. The 3-week stabilization period was used as a response criterion. Eighty-six patients (92%) showed a rise in threshold. The magnitude of increment was 269±244%. The rise in seizure threshold could be predicted by the number of treatments, initial seizure threshold and EEG seizure duration, and these factors explained 42% of the variance.

A comparison of stimulus dosing methods for electroconvulsive therapy

Aims and MethodsA prospective study comparing initial electroconvulsive therapy treatment doses determined by empirical dose titration with estimates derived from two simple dose prediction methods and a fixed-dose regimen (275 mC).ResultsThirty-three patients had seizure thresholds between 25 mC and 403 mC. The dose titration method led to a mean initial treatment dose of 195 mC that was intermediate between those predicted by the age method (275 mC) and the half-age method (137 mC). Estimates were within acceptable limits in 33% of cases for the age method, 64% for the half-age method and 40% for the fixed-dose method.Clinical ImplicationsEither dose prediction or dose titration methods may be more appropriate in different clinical situations. The half-age method appears to be a more accurate predictor of optimum initial treatment dose.

Electroconvulsive Therapy and Subdural Hemorrhage

Electroconvulsive therapy (ECT) was used to treat severe depressive illness in two patients, one of whom had undergone recent neurosurgery for subdural hemorrhage (SDH) and another with a concurrent SDH in the absence of raised intracranial pressure. Although the second patient died 1 month after the completion of ECT, in neither case did ECT extend the SDH or lead to other intracranial complications. It would seem that ECT can be performed safely in the presence of SDH without mass effect or after surgical drainage of SDH, although clinicians should proceed cautiously in close collaboration with neurosurgical colleagues, review neuroimaging scans at regular intervals during and after the course of ECT, and use the dose-titration method of treatment with unilateral electrode placement away from the site of the lesion or surgery to minimize adverse effects.

Considerations on Cumulative Response Rate in a Dose-finding Study Conducted by Dose Titration method

Considerations on Cumulative Response Rate in a Dose-finding Study Conducted by Dose Titration method