This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6... more This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m(-2)), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate-corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in K(trans) and k(ep) were observed but V(e), a secondary dynamic contrast-enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m(-2), the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 +/- 25.8 microg/mL, 29 +/- 6.4 microg/mL x d, 8.0 +/- 1.77 microg/mL, and 0.43 +/- 0.07 microg/mL x d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m(-2), with a plateau thereafter. Doses in the range of 1,200 mg m(-2) have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate-corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.
Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other... more Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other known psychotropic drugs. In rodents minaprine is active in most models of depression and is thought to exert this activity by enhancing serotonergic and dopaminergic transmission. In humans minaprine has been shown to be more effective than placebo in the treatment of major depressive episodes as defined by the DSM-III. In the present study, the efficacy and safety of minaprine (100 mg b.i.d.) in the treatment of major depressive disorders (DSM-III) were compared with those of imipramine (50 b.i.d.) in 104 patients, in a 4-week randomized, double-blind, multicentre trial. The two drugs were comparable in efficacy as judged by the Hamilton Depression Rating Scale, a Clinical Global impression and a Zung Self-Rating Scale. The onset of activity appeared to be significantly more rapid with minaprine. The incidence and intensity of unwanted effects was significantly higher in the imipramine treatment group.
A series of studies in human subjects of potential interactions of lornoxicam with some other dru... more A series of studies in human subjects of potential interactions of lornoxicam with some other drugs is reviewed. No evidence of kinetic interaction was found with the antacids Maalox or Solugastrol, nor was there evidence of influence on antipyrine clearance. Lornoxicam reduced warfarin clearance and enhanced its hypoprothrombinaemic effect. It did not influence glibenclamide kinetics, but plasma insulin concentrations were significantly higher and plasma glucose concentrations significantly lower when lornoxicam and glibenclamide were co-administered. Lornoxicam produced a modest reduction in digoxin clearance, but no other clear evidence of interaction was seen. Lornoxicam significantly antagonized the diuretic and natriuretic actions of frusemide.
Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instil... more Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.
Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipy... more Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipyrine elimination in 11 of 12 healthy volunteers. Anomalous results in one subject are presented and discussed.
AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA(®)) designed for the treatm... more AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA(®)) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase I dose escalation study 28 patients with heavily pre-treated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics (PK), anti-tumor activity and pharmacodynamics (PD). Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. PK assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%) with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin refractory patients. In 13 patients who received doses of ≥1.5mg/kg AFM13 the overall response rate was 23...
Gastro-oesophageal reflux disease (GORD) symptoms have a significant impact on patients&a... more Gastro-oesophageal reflux disease (GORD) symptoms have a significant impact on patients' well-being. Onset of symptom relief is therefore an important consideration in GORD treatment. The primary objective was to compare the efficacy of rabeprazole (20 mg) and omeprazole (20 mg) regarding onset of heartburn control during the first 7 days of treatment in patients with erosive oesophagitis. Secondary objectives included maintenance of sustained heartburn control, control of other GORD symptoms (e.g. acid regurgitation, epigastric pain, dysphagia), effect on quality of life, patient satisfaction with treatment, and adverse events. In this multicentre, randomized, parallel-group, double-blind, comparative study, performed in Europe and Iceland, patients with endoscopically confirmed erosive oesophagitis were randomized to receive once-daily treatment with rabeprazole 20 mg (n=358) or omeprazole 20 mg (n=359) for 7 days. Symptoms were recorded (scored on a 5-point Likert scale) twice daily by the patients on their diary cards. Median time to reach heartburn control was 1.5 days for both the rabeprazole and omeprazole groups (p<0.43). The results were similar between treatments for other study parameters. Both treatments were well tolerated. Unlike previous studies, no significant differences were found between treatments with rabeprazole (20 mg) and omeprazole (20 mg) in this study. Further studies are needed to evaluate the potential benefit of fast-acting proton-pump inhibitors, such as rabeprazole, with respect to onset of symptom control in erosive GORD.
Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin m... more Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.
Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer d... more Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.
Human Psychopharmacology: Clinical and Experimental, 1993
... inflammatory Drug on Lithium Pharmacokinetics M. RAVIC', I. SALAS-HERRERA', A. JOHN... more ... inflammatory Drug on Lithium Pharmacokinetics M. RAVIC', I. SALAS-HERRERA', A. JOHNSTON', P. TURNER'*, K. FOLEY' and D. 'Department of Clinical Pharmacology, St. ... clearance values and apparent volumes of distribu-tion found with lithium (Avery, 1980). ...
This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6... more This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m(-2)), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate-corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in K(trans) and k(ep) were observed but V(e), a secondary dynamic contrast-enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m(-2), the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 +/- 25.8 microg/mL, 29 +/- 6.4 microg/mL x d, 8.0 +/- 1.77 microg/mL, and 0.43 +/- 0.07 microg/mL x d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m(-2), with a plateau thereafter. Doses in the range of 1,200 mg m(-2) have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate-corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.
Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other... more Minaprine dihydrochloride is an aminopyridazine derivative which is chemically unrelated to other known psychotropic drugs. In rodents minaprine is active in most models of depression and is thought to exert this activity by enhancing serotonergic and dopaminergic transmission. In humans minaprine has been shown to be more effective than placebo in the treatment of major depressive episodes as defined by the DSM-III. In the present study, the efficacy and safety of minaprine (100 mg b.i.d.) in the treatment of major depressive disorders (DSM-III) were compared with those of imipramine (50 b.i.d.) in 104 patients, in a 4-week randomized, double-blind, multicentre trial. The two drugs were comparable in efficacy as judged by the Hamilton Depression Rating Scale, a Clinical Global impression and a Zung Self-Rating Scale. The onset of activity appeared to be significantly more rapid with minaprine. The incidence and intensity of unwanted effects was significantly higher in the imipramine treatment group.
A series of studies in human subjects of potential interactions of lornoxicam with some other dru... more A series of studies in human subjects of potential interactions of lornoxicam with some other drugs is reviewed. No evidence of kinetic interaction was found with the antacids Maalox or Solugastrol, nor was there evidence of influence on antipyrine clearance. Lornoxicam reduced warfarin clearance and enhanced its hypoprothrombinaemic effect. It did not influence glibenclamide kinetics, but plasma insulin concentrations were significantly higher and plasma glucose concentrations significantly lower when lornoxicam and glibenclamide were co-administered. Lornoxicam produced a modest reduction in digoxin clearance, but no other clear evidence of interaction was seen. Lornoxicam significantly antagonized the diuretic and natriuretic actions of frusemide.
Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instil... more Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.
Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipy... more Treatment with lornoxicam 4 mg twice daily for 14 d did not produce any change in salivary antipyrine elimination in 11 of 12 healthy volunteers. Anomalous results in one subject are presented and discussed.
AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA(®)) designed for the treatm... more AFM13 is a bispecific, tetravalent chimeric antibody construct (TandA(®)) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase I dose escalation study 28 patients with heavily pre-treated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics (PK), anti-tumor activity and pharmacodynamics (PD). Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. PK assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%) with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin refractory patients. In 13 patients who received doses of ≥1.5mg/kg AFM13 the overall response rate was 23...
Gastro-oesophageal reflux disease (GORD) symptoms have a significant impact on patients&a... more Gastro-oesophageal reflux disease (GORD) symptoms have a significant impact on patients' well-being. Onset of symptom relief is therefore an important consideration in GORD treatment. The primary objective was to compare the efficacy of rabeprazole (20 mg) and omeprazole (20 mg) regarding onset of heartburn control during the first 7 days of treatment in patients with erosive oesophagitis. Secondary objectives included maintenance of sustained heartburn control, control of other GORD symptoms (e.g. acid regurgitation, epigastric pain, dysphagia), effect on quality of life, patient satisfaction with treatment, and adverse events. In this multicentre, randomized, parallel-group, double-blind, comparative study, performed in Europe and Iceland, patients with endoscopically confirmed erosive oesophagitis were randomized to receive once-daily treatment with rabeprazole 20 mg (n=358) or omeprazole 20 mg (n=359) for 7 days. Symptoms were recorded (scored on a 5-point Likert scale) twice daily by the patients on their diary cards. Median time to reach heartburn control was 1.5 days for both the rabeprazole and omeprazole groups (p<0.43). The results were similar between treatments for other study parameters. Both treatments were well tolerated. Unlike previous studies, no significant differences were found between treatments with rabeprazole (20 mg) and omeprazole (20 mg) in this study. Further studies are needed to evaluate the potential benefit of fast-acting proton-pump inhibitors, such as rabeprazole, with respect to onset of symptom control in erosive GORD.
Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin m... more Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.
Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer d... more Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.
Human Psychopharmacology: Clinical and Experimental, 1993
... inflammatory Drug on Lithium Pharmacokinetics M. RAVIC', I. SALAS-HERRERA', A. JOHN... more ... inflammatory Drug on Lithium Pharmacokinetics M. RAVIC', I. SALAS-HERRERA', A. JOHNSTON', P. TURNER'*, K. FOLEY' and D. 'Department of Clinical Pharmacology, St. ... clearance values and apparent volumes of distribu-tion found with lithium (Avery, 1980). ...
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Papers by Miroslav Ravic