scholarly journals Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
James Jackson ◽  
Betsy McCollum ◽  
Judy Ognibene ◽  
Francisco J. Diaz ◽  
Jose de Leon
Keyword(s):  
Valproic Acid ◽  
Tuberous Sclerosis ◽  
Plasma Concentrations ◽  
High Dose ◽  
Strongly Correlated ◽  
Divalproex Sodium ◽  
Day Case ◽  
Metabolic Capacity ◽  
Normal Dose ◽  
High Doses

Valproic acid (VPA) can autoinduce its own metabolism. Cases requiring VPA doses >4000 mg/day to obtain therapeutic plasma concentrations, such as these 3 cases, have never been published. Case 1 received VPA for seizures and schizophrenia and had >50 VPA concentrations in 4 years. A high dose of 5,250 mg/day of VPA concentrate was prescribed for years but this dose led to an intoxication when switched to the enterocoated divalproex sodium formulation, requiring a normal dose of 2000 mg/day. VPA metabolic capacity was significantly higher (t=-9.6; df = 6.3,p<0.001) during the VPA concentrate therapy, possibly due to autoinduction in that formulation. Case 2 had VPA for schizoaffective psychosis with 10 VPA concentrations during an 8-week admission. To maintain a VPA level≥50 μg/mL, VPA doses increased from 1500 to 4000 mg/day. Case 3 had tuberous sclerosis and epilepsy and was followed up for >4 years with 137 VPA concentrations. To maintain VPA concentrations≥50 μg/mL, VPA doses increased from 3,375 to 10,500 mg/day. In Cases 2 and 3, the duration of admission and the VPA dose were strongly correlated (raround 0.90;p<0.001) with almost no change after controlling for VPA concentrations, indicating progressive autoinduction that increased with time.

scholarly journals Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

2008 ◽  
Vol 53 (1) ◽  
pp. 180-185 ◽  
Author(s):  
Johan Ursing ◽  
Poul-Erik Kofoed ◽  
Amabelia Rodrigues ◽  
Yngve Bergqvist ◽  
Lars Rombo
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Standard Dose ◽  
High Dose ◽  
Routine Practice ◽  
Double Dose ◽  
Normal Dose ◽  
Guinea Bissau ◽  
High Doses ◽  
Low Prevalence

ABSTRACT High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg−1, respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg−1 each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg−1) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

Effect of High-Dose Intravenous Eletriptan on Coronary Artery Diameter

Cephalalgia ◽  
2004 ◽  
Vol 24 (7) ◽  
pp. 515-521 ◽  
Author(s):  
JA Goldstein ◽  
KD Massey ◽  
S Kirby ◽  
M Gibson ◽  
J Hettiarachchi ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Standard Dose ◽  
Plasma Concentrations ◽  
Significant Coronary Artery Disease ◽  
Safety Margin ◽  
High Dose ◽  
Coronary Artery Diameter ◽  
Clinically Significant ◽  
Artery Disease ◽  
High Doses

The goal of this study was to evaluate the coronary vasoconstrictive effects of high doses of eletriptan compared with a standard dose of sumatriptan. Patients with no clinically significant coronary artery disease were randomized to receive high-dose intravenous eletriptan ( n = 24) vs a standard dose of sumatriptan ( n = 18; 6 mg subcutaneously) vs placebo ( n = 18). Serial angiograms were obtained. The primary non-inferiority analysis found equivalence between the mean maximum change in left anterior descending coronary artery diameter for eletriptan, -22% [95% confidence interval (CI) -26, -19], and sumatriptan, -19% (95% CI -22, -16). The change due to placebo was -16% (95% CI -20, -12). No individual cases of clinically significant vasoconstriction were observed. The results confirm that eletriptan has a broad cardiovascular safety margin, with plasma concentrations comparable to three to five times the Cmax of an oral 80-mg dose associated with modest vasoconstriction equivalent to standard therapeutic doses of sumatriptan.

scholarly journals Predictive hazard markers for the ranking of pulmonary toxicity of nanomaterials

2020 ◽  
Author(s):  
Chinatsu Nishida ◽  
Hiroto Izumi ◽  
Taisuke Tomonaga ◽  
Jun-ichi Takeshita ◽  
Kei Yamasaki ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Pulmonary Toxicity ◽  
Quantitative Polymerase Chain Reaction ◽  
Intratracheal Instillation ◽  
Inflammatory Cells ◽  
Control Group ◽  
High Dose ◽  
Strongly Correlated ◽  
Rat Lungs ◽  
High Doses

Abstract Background We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Four nanomaterials, nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were intratracheally administered into rat lungs at 0.8 mg/kg BW or 4 mg/kg BW as low and high doses, respectively. Five chemokine genes (C-X-C motif chemokine 5 (CXCL5), C-C motif chemokine 2 (CCL2), C-C motif chemokine 7 (CCL7), C-X-C motif chemokine 10 (CXCL10), and C-X-C motif chemokine 11 (CXCL11) ) were selected using cDNA microarray analysis at 1 month after instillation of NiO in the high dose group. The mRNA expression of these 5 genes in the lung tissues were evaluated at 3 days, 1week, 1 month, 3 months and 6 months after instillation of the 4 nanomaterials, using real-time quantitative polymerase chain reaction (RT-qPCR) during the observation periods. Results An increased expression of CXCL5 in the NiO and CeO2 groups was persistently higher than in the control group, and that in the TiO2 and ZnO groups was transiently higher than in the control group. CCL2 and CCL7 also showed an increasing tendency similar to CXCL5, although there was not a persistent significance. The receiver operating characteristic (ROC) results of nanomaterial toxicity with the expression level of each gene showed a considerable relationship between the pulmonary toxicity ranking of nanomaterials and the expression of CXCL5, CCL2 and CCL7, with area under the curves (AUC) of 0.95 or higher at 1 week and 1 month. The expression levels of these 3 genes also moderately or strongly correlated with the degree of inflammatory cells in the lung tissues. Conclusion Our results suggest that 3 chemokine genes, especially CXCL5, followed by CCL2 and CCL7, can be useful as biomarkers for the ranking of the pulmonary toxicity of nanomaterials.

The Influence of Serotonin on Clot Retraction and the Thrombelastogram

1958 ◽  
Vol 02 (01/02) ◽  
pp. 111-124 ◽  
Author(s):  
E Deutsch ◽  
K Martiny
Keyword(s):  
Human Plasma ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Specific Effect ◽  
High Dose ◽  
Clot Retraction ◽  
Platelet Counts ◽  
Essential Value ◽  
High Doses ◽  
Free Plasma

Summary1. Normal platelets are necessary for induction of normal clot retraction.2. Serotonin does not induce retraction in human platelet-free plasma-clots or enhance clot firmness as measured in the coagulogram.3. Serotonin does not improve clot retraction or firmness in plasma clots with sub-optimal platelet counts.4. Methylserotonin inhibits clot retraction of platelet-rich plasma to a certain extent in moderate doses, whereas, high doses are ineffective. BOL 148 has a similar, but less significant action. There is a possibility that these effects are specific antiserotonin-effects.5. LSD 25 was ineffective in all concentrations used.6. Largactil and reserpin inhibit retraction in high doses. There seems to be a non specific effect caused by the high dose.7. Reserpine does not release a retraction-inducing agent from the platelets, which could be detected in the centrifuged platelet-free plasma used for the incubation.8. Serotonin does not replace the retraction-cofactor of Hartert, or the dialyzable factor of Lüscher in synthetic clotting substrates.9. Serotonin is of no essential value in inducing normal retraction of human plasma clots.

Influence of β-D-mannuronic acid, as a new member of non-steroidal anti-inflammatory drugs family, on expression pattern of chemokines and their receptors in rheumatoid arthritis

2019 ◽  
Vol 16 ◽  
Author(s):  
Mona Aslani ◽  
Arman Ahmadzadeh ◽  
Zahra Aghazadeh ◽  
Majid Zaki-Dizaji ◽  
Laleh Sharifi ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mrna Expression ◽  
Surface Expression ◽  
Phase Iii ◽  
Cell Surface Expression ◽  
Optimum Dose ◽  
High Dose ◽  
Mannuronic Acid ◽  
Anti Inflammatory ◽  
High Doses

Background: : Based on the encouraging results of phase III clinical trial of β-D-mannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. Methods:: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. Results:: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression down-regulated significantly followed by treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by treatment of these cells with high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by treatment of these cells with high dose of M2000 and optimum dose of diclofenac. Conclusion:: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

scholarly journals Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

2021 ◽  
Author(s):  
Riitta Niinimäki ◽  
Henri Aarnivala ◽  
Joanna Banerjee ◽  
Tytti Pokka ◽  
Kaisa Vepsäläinen ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Optimal Dosage ◽  
High Dose Methotrexate ◽  
Reduced Dose ◽  
Dose Methotrexate ◽  
Antileukemic Effect ◽  
Folinic Acid Rescue ◽  
High Doses

Abstract Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

scholarly journals AB0601 RAPID AND SUSTAINED EFFICACY OF AN INDUCTION TREATMENT WITH A TRIPLE THERAPY INCLUDING HIGH-DOSE INTRAVENOUS IMMUNOGLOBULINS, METHOTREXATE AND GLUCOCORTICOIDS IN ANTI-3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE MYOPATHY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1597.1-1597
Author(s):  
E. Treppo ◽  
M. Infantino ◽  
M. Benucci ◽  
V. Ravagnani ◽  
B. Palterer ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Antibody Titer ◽  
Intravenous Immunoglobulins ◽  
High Dose ◽  
Sustained Remission ◽  
Red Rice ◽  
Gradual Improvement ◽  
High Doses ◽  
High Dose Ivig

Background:Anti-3-hydroxy-3-methylglutaryl-coenzime A reductase (HMGCR) myopathy is a new entity, which has been clearly associated to statin use, even if it can be diagnosed in patients without a history of exposure to statin or even in the childhood (1).Objectives:The aim of the study is to describe the efficacy of a triple therapy regimen consisting in high-doses of intravenous immunoglobulins (IVIG), methotrexate (MTX), and glucocorticoids (GC) in 16 patients with Anti-HMGCR myopathy enrolled in 6 specialized centres.Methods:A total of 16 patients with anti-HMGCR myopathy (7 females; 9 males) were collected. Mean (±standard deviation) age at the onset of disease was 72.4±10.3 years old. All patients were diagnosed having anti-HMGCR myopathy [anti-HMGCR antibodies were measured by chemiluminescence assay (BioFlash, Inova, CA)] (2). Median follow-up was 29.5 months (interquartile range: 15.75-60 months). Anti-HMGCR antibodies were available in the follow-up in 8/16 patients.Results:Thirteen out of 16 patients (81.3%) had been exposed to statin (1/13 to red rice), 3/16 (18.7%) were not exposed. As induction therapy, 11/16 patients have been treated with triple therapy (high-dose IVIG, MTX and GC), 2/16 with double therapy (high-dose IVIG and GC), 2/16 have been treated with GC alone, the patient exposed to red rice resolved only with red rice suspension. Clinical remission and normalization of CPK values within month +24 were obtained in all the patients. All the patients were in remission at the last follow-up. Gradual improvement started soon from the first month, and among the 13 patients treated with an aggressive immunosuppresssive therapy including IVIG (13/13), GC (13/13) and methotrexate (11/13), 9/13 normalized the CPK value within 6 months. Clinical and laboratory response was accompanied by significant decrease or normalization of the anti-HMGCR antibody titer. All the patients were either not taking GC (56.3%), or were taking low doses of GC (43.7%) at the last follow-up. Four patients had stopped GC within 6 months. No serious side effects were recorded. After persistent remission, a maintenance immunosuppressive therapy was then administered. Only 3 relapses in 3 different cases were recorded, all of them during drug-free remission in long-term follow-up. Reinduction was again effective in all.Conclusion:Anti-HMGCR myopathy is a rare and serious myopathy which usually affects older people during statin treatment. After statin suspension, a rapid and sustained remission can be achieved by induction with a triple aggressive therapy consisting in medium-to high doses of GC, high-dose IVIG, and MTX (3). GC should be tapered as soon as possible. Relapse appears infrequent during maintenance treatment. Monitoring anti-HMGCR antibody titer may be clinically relevant.References:[1]AL Mammen et al. N Engl J Med. 2016;374:664-9[2]Musset L et al. Autoimmun Rev. 2016;15:983-93.[3]Aggarwal A et al. Scand J Rheumatol. 2019; 1-7.Acknowledgments:We thank MD Francesca Grosso and MD Valentina Mecheri from the University of Florence, MD Angela Zuppa and MD Chiara De Michelis, from San Martino Hospital, Genova, for their valued collaboration in data collectionDisclosure of Interests:Elena Treppo: None declared, Maria Infantino: None declared, Maurizio Benucci: None declared, Viviana Ravagnani: None declared, Boaz Palterer: None declared, Marina Grandis: None declared, Martina Fabris: None declared, Paola Tomietto: None declared, Mariangela Manfredi: None declared, Arianna Sonaglia: None declared, Maria Grazia Giudizi: None declared, Francesca Ligobbi: None declared, Daniele Cammelli: None declared, Paola Parronchi: None declared, Salvatore De Vita Consultant of: Roche, GSK, Speakers bureau: Roche, GSK, Novartis, Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer

Epidural Clonidine or Bupivacaine as the Sole Analgesic Agent during and after Abdominal Surgery 

1999 ◽  
Vol 90 (5) ◽  
pp. 1354-1362 ◽  
Author(s):  
Marc De Kock ◽  
Philippe Gautier ◽  
Athanassia Pavlopoulou ◽  
Marc Jonniaux ◽  
Patricia Lavand'homme
Keyword(s):  
High Dose ◽  
General Anesthetics ◽  
Visual Analogue Pain ◽  
Pain Scores ◽  
Arterial Blood ◽  
Sedation Scores ◽  
Group 3 ◽  
Group 2 ◽  
High Doses ◽  
Group 1

Background The rationale of this study was to compare high-dose epidural clonidine with a more commonly used agent, such as bupivacaine. This was performed to give a more objective idea of the relative analgesic potency of epidural clonidine. Methods Sixty patients undergoing intestinal surgery during propofol anesthesia were studied. At induction, the patients received epidurally a dose of 10 micrograms/kg [corrected] clonidine in 7 ml saline followed by an infusion of 6 micrograms [corrected] x kg(-1) x h(-1) (7 ml/h) (group 1, n = 20), a dose of 7 ml bupivacaine, 0.5%, followed by 7 ml/h bupivacaine, 0.25% (group 2, n = 20), or a dose of 7 ml bupivacaine, 0.25%, followed by 7 ml/h bupivacaine, 0.125% (group 3, n = 20). Intraoperatively, increases in arterial blood pressure or heart rate not responding to propofol (0.5 mg/kg) were treated with intravenous alfentanil (0.05 mg/kg). Additional doses of propofol were given to maintain an adequate bispectral index. The epidural infusions were maintained for 12 h. In cases of subjective visual analogue pain scores up to 5 cm at rest or up to 8 cm during coughing, the patients were given access to a patient-controlled analgesia device. Results During anesthesia, patients in group 1 required less propofol than those in groups 2 and 3 (78 [36-142] mg vs. 229 [184-252] mg and 362 [295-458] mg; P &lt; 0.05) and less alfentanil than patients in group 3 (0 [0-0] mg vs. 11 [6-20] mg; P &lt; 0.05). Analgesia lasted 380 min (range, 180-645 min) in group 1 versus 30 min (range, 25-40 min) in group 2 and 22 min (range, 12.5-42 min) in group 3 (P &lt; 0.05). There was no suggestion of a hemodynamic difference among the three groups except for heart rates that were significantly reduced in patients in group 1. Sedation scores were significantly higher in this group during the first 2 h postoperatively. Conclusion Our results show that high doses of epidural clonidine potentiate general anesthetics and provide more efficient postoperative analgesia than the two bupivacaine dosage regimens investigated.

scholarly journals Quantifying prescribed high dose opioids in the community and risk of overdose

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Joe Schofield ◽  
Deborah Steven ◽  
Rebecca Foster ◽  
Catriona Matheson ◽  
Alexander Baldacchino ◽  
...  
Keyword(s):  
Risk Factors ◽  
Service Improvement ◽  
High Dose ◽  
Opioid Overdose ◽  
Opioid Prescribing ◽  
Patient Level ◽  
Strong Opioid ◽  
High Doses ◽  
Strong Opioids ◽  
Very High

Abstract Background Opioid prescribing for a range of health issues is increasing globally. The risk of fatal and non-fatal overdose is increased among people prescribed strong opioids: in high doses in the context of polypharmacy (the use of multiple medications at the same time), especially with other sedatives; and among people with multiple morbidities including cardiorespiratory, hepatic and renal conditions. This study described and quantified the prescribing of strong opioids, comorbidities and other overdose risk factors among those prescribed strong opioids, and factors associated with high/very high opioid dosage in a regional health authority in Scotland as part of a wider service improvement exercise. Methods Participating practices ran searches to identify patients prescribed strong opioids and their characteristics, polypharmacy, and other overdose risk factors. Data were anonymised before being analysed at practice and patient-level. Morphine Equivalent Doses were calculated for patients based on drug/dose information and classed as Low/Medium/High/Very High. Descriptive statistics were generated on the strong opioid patient population and overdose risk factors. The relationship between the prescribing of strong opioids and practice/patient-level factors was investigated using linear and logistic regression models. Results Eighty-five percent (46/54) of GP practices participated. 12.4% (42,382/341,240) of individuals in participating practices were prescribed opioids and, of these, one third (14,079/42,382) were prescribed strong opioids. The most common comorbidities and overdose risk factors among strong opioid recipients were pain (67.2%), cardiovascular disease (43.2%), and mental health problems (39.3%). There was a positive significant relationship between level of social deprivation among practice caseload and level of strong opioid prescribing (p < 0.001). People prescribed strong opioids tended to be older (mean 59.7 years) and female (8638, 61.4%) and, among a subset of patients, age, gender and opioid drug class were significantly associated with prescribing of High/Very High doses. Conclusions Our findings have identified a large population at potential risk of prescription opioid overdose. There is a need to explore pragmatic models of tailored interventions which may reduce the risk of overdose within this group and clinical practice may need to be tightened to minimise overdose risk for individuals prescribed high dose opioids.

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