Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats

2016 ◽  
Vol 124 (4) ◽  
pp. 945-957 ◽  
Author(s):  
Michael J. Emery ◽  
Chase C. Groves ◽  
Timothy N. Kruse ◽  
Chen Shi ◽  
Gregory W. Terman
Keyword(s):  
Time Course ◽  
Repeated Administration ◽  
Respiratory Arrest ◽  
Chronic Morphine ◽  
Length Of Treatment ◽  
Respiratory Parameters ◽  
Effective Doses ◽  
Sedation And Analgesia ◽  
Ventilatory Depression ◽  
Chronic Pain Therapy

Abstract Background Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. Methods Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography–respirometry. Results Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (−41.4 ± 7.0%, mean ± SD) and hypercapnic response (−80.9 ± 15.7%) as found for morphine-naive (−35.5 ± 16.9% and −67.7 ± 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. Conclusions In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation.

Therapeutic Orphans

PEDIATRICS ◽  
1992 ◽  
Vol 89 (4) ◽  
pp. 688-689
Author(s):  
STEVEN J. WEISMAN ◽  
NEIL L. SCHECHTER
Keyword(s):  
Case Report ◽  
Respiratory Arrest ◽  
Intravenous Sedation ◽  
Safe Technique ◽  
Sedation And Analgesia

To the Editor.— The report by Yaster et al, “Midazolam-Fentanyl Intravenous Sedation in Children: Case Report of Respiratory Arrest,”1 is the first we are aware of in the pediatric literature which reviews and promotes the use of this method of sedation and analgesia for children. Unfortunately,the title of the article and some of its emphasis may have the unfortunate consequence of delaying acceptance of this generally safe technique which is clearly not the intent

Effect of chronic morphine treatment on time-course of free radical processes

2007 ◽  
Vol 1 (3) ◽  
pp. 245-248
Author(s):  
D. A. Miskevich ◽  
N. E. Petushok ◽  
V. V. Lelevich ◽  
S. V. Lelevich ◽  
A. N. Borodinsky
Keyword(s):  
Free Radical ◽  
Time Course ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Free Radical Processes ◽  
Chronic Morphine Treatment ◽  
Radical Processes

PK Comparability of VWF/FVIII Concentrates after Repeated Dosing

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4523-4523
Author(s):  
Ulrich Kronthaler ◽  
Marcus Stockschlaeder ◽  
Gerhard Dickneite
Keyword(s):  
Plasma Level ◽  
Half Life ◽  
Time Course ◽  
Peak Level ◽  
Repeated Administration ◽  
Pharmacokinetic Analysis ◽  
Close Monitoring ◽  
Perioperative Bleeding ◽  
Repeated Dosing ◽  
Trough Levels

Abstract Introduction: Appropriate correction of hemostasis in VWD is essential not only to stop acute perioperative bleeding, but also to promote postoperative wound healing. In order to prevent a drop of the VWF plasma level below the hemostatically necessary concentration, repeated infusions of VWF containing concentrates are required. Plasma derived VWF/FVIII concentrates vary, however, in several aspects such as the VWF/FVIII ratio. As therapy of VWD primarily aims at correcting functional VWF level, the question arises, whether VWF/FVIII concentrates differ with regard to the plasma level of FVIII resulting from repeated concentrate infusions. Methods: The goal of the present study was to compare VWF and FVIII levels after repeated administration of 150 IU (VWF:RCo)/kg (7 doses at 4-hour intervals). Two plasma derived VWF/FVIII concentrates, Humate-P®/Haemate® P and Wilate®, were selected for the comparison. The concentrates were administered as i.v. bolus to CHB rabbits (n=6/group). Blood samples were collected for close monitoring of the resulting substitution levels. The VWF and FVIII levels were quantified using commercially available ELISA assays. Results: Pharmacokinetic analysis (AUC, Cmax, half-life, MRT, clearance) demonstrated that the time course of VWF plasma levels were similar. The ratio of the VWF AUC of Humate-P®(Haemate® P)/Wilate® was 0.98 and the maximal VWF plasma concentration of Humate-P®/Haemate® P was slightly higher, at a ratio of 1,16. In contrast, the FVIII levels continuously accumulated upon treatment with Wilate® leading to trough levels, which were about 1,6 fold higher compared to Humate-P®/Haemate® P (Figure). Accordingly, also the peak FVIII level was 1,7 fold higher upon treatment with Wilate®, while the half-life of FVIII did not differ substantially between the two concentrates. The FVIII trough level of Wilate® together with its higher peak level resulted in an AUC, which was 2 fold higher (p<0.0001) than observed for Humate-P®/Haemate® P. Conclusion: Against the background of Wilate® containing a two fold higher FVIII concentration compared to Humate-P®/Haemate® P, such differential effects appear plausible. At nominally equal VWF:RCof repeated doses, the associated AUC with respect to FVIII:Ag of Humate-P®/Haemate® P was significantly lower, as compared to Wilate®. This is obviously due to the lower FVIII content in the Humate-P®/Haemate® P product. Therefore, a lower accumulation of FVIII trough levels was observed for Humate-P®/Haemate® P as compared to Wilate®. Figure Figure

Development of Neuropathy in Patients With Myeloma Treated With Thalidomide: Patterns of Occurrence and the Role of Electrophysiologic Monitoring

2006 ◽  
Vol 24 (27) ◽  
pp. 4507-4514 ◽  
Author(s):  
Linda Mileshkin ◽  
Richard Stark ◽  
Bruce Day ◽  
John F. Seymour ◽  
Jerome B. Zeldis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Time Course ◽  
Dose Intensity ◽  
Multicenter Trial ◽  
Duration Of Treatment ◽  
Related Factors ◽  
Prior Therapy ◽  
Length Of Treatment ◽  
Electrophysiological Studies ◽  
Clinically Significant

Purpose Peripheral neuropathy frequently limits the duration of treatment with thalidomide for patients with multiple myeloma. We assessed the time course of occurrence, possible predictive factors, and the utility of serial nerve electrophysiological studies (NES) for detecting onset of neuropathy. Patients and Methods Seventy-five patients with relapsed/refractory myeloma were enrolled onto a multicenter trial of dose-escalating thalidomide with or without interferon. Patients underwent clinical assessment plus NES at baseline and every 3 months. Time to development of neuropathy according to clinical or NES criteria was compared. Patient and treatment-related factors were compared as predictors of neuropathy. Results Thirty-nine percent had some NES abnormalities at baseline. Patients received thalidomide at a median dose-intensity of 373 mg/d. Thirty-one of 75 patients (41%) developed neuropathy during thalidomide treatment; 11 patients (15%) discontinued treatment with thalidomide due to neuropathy. The actuarial incidence of neuropathy increased from 38% at 6 months to 73% at 12 months, with 81% of responding patients developing this complication. Serial NES did not reliably predict the imminent development of clinical neuropathy requiring thalidomide cessation, nor were patient age, sex, or prior therapy predictive. Patients who developed neuropathy had a longer duration of thalidomide exposure (median, 268 v 89 days; P = .0001). Cumulative dose or dose-intensity received was not predictive. Conclusion The majority of patients will develop peripheral neuropathy given sufficient length of treatment with thalidomide. To minimize the risk of neurotoxicity, therapy should be limited to less than 6 months. Electrophysiologic monitoring provides no clear benefit versus careful clinical evaluation for the development of clinically significant neuropathy.

Midazolam-Fentanyl Intravenous Sedation in Children: Case Report of Respiratory Arrest

PEDIATRICS ◽  
1990 ◽  
Vol 86 (3) ◽  
pp. 463-467
Author(s):  
Myron Yaster ◽  
David G. Nichols ◽  
Jayant K. Deshpande ◽  
Randall C. Wetzel
Keyword(s):  
Case Report ◽  
Physical Restraint ◽  
Respiratory Arrest ◽  
Route Of Administration ◽  
Intravenous Sedation ◽  
Parental Anxiety ◽  
Safety And Efficacy ◽  
Therapeutic Procedures ◽  
Sedation And Analgesia ◽  
Separation From Parents

Children undergoing diagnostic or therapeutic procedures are often frightened and uncooperative. This fear may be exacerbated by parental anxiety, by separation from parents, and by pain or the anticipation of pain from the procedure itself. To achieve satisfactory sedation and analgesia, various drugs administered alone and in combination have been recommended using either an oral,1 intramuscular,2-5 intravenous,6-8 or a rectal9,10 route of administration. Although each has some purported advantage, none of the drugs or techniques that are currently available are absolutely safe or completely reliable.11-14 Because of this concern for safety and efficacy, many children experiencing procedure-related pain are often inadequately treated with analgesics and are immobilized primarily by physical restraint.

Repeated administration of orexin into the thalamic paraventricular nucleus inhibits the development of morphine-induced analgesia

2021 ◽  
Vol 28 ◽  
Author(s):  
Fatemeh Samani ◽  
Masoumeh Kourosh Arami
Keyword(s):  
Paraventricular Nucleus ◽  
Formalin Test ◽  
Repeated Administration ◽  
Treated Group ◽  
Pain Modulation ◽  
Morphine Injection ◽  
Chronic Morphine ◽  
Analgesic Effects ◽  
Male Wistar Rats ◽  
The Brain

Background: Hypothalamic neuropeptides, orexins, play pivotal roles in nociception and pain modulation. Objective: In this study, we investigated the effect of the administration of orexin into the paraventricular nucleus (PVT) on the development of morphine-induced analgesia in rats. Method. Male Wistar rats weighing 250-300 g received subcutaneous (s.c.) chronic morphine (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two experimental groups in which the orexin (100 μM, 200 nl) and its vehicle were microinjected into the PVT nucleus for 7 days before each morphine injection. Then, the formalin test was performed for the assessment of pain-related behaviors. Results: The results demonstrated that the rats pretreated by intra-PVT orexin exhibited higher pain-related behaviors than the morphine-treated group. The analgesic effects of morphine were significantly lower in orexin plus morphine-treated rats than the vehicle plus morphine-treated ones. Conclusion: Our findings suggested that the animals receiving the prolonged intra-PVT application of orexin before morphine injection demonstrated a significant increase in the development of nociceptive behaviors in all phases. Therefore, the present study highlighted a new area of the brain involved in the effect of orexin on analgesia induced by morphine.

Effect of a Synthetic Immunomodulator on the Regulation of Gamma Interferon and Interleukin-10 Production during Salmonella Sepsis in Itys Mice

1997 ◽  
Vol 10 (3) ◽  
pp. 167-174 ◽  
Author(s):  
S. Ferlat ◽  
C. Bottex-Gauthier ◽  
M. Li ◽  
F. Picot ◽  
D. Vidal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Time Course ◽  
Repeated Administration ◽  
Interleukin 10 ◽  
Spleen Cells ◽  
Post Challenge ◽  
Bacterial Growth Rate ◽  
Nonspecific Resistance ◽  
Ifn Γ

The present study examined the in vivo capacity of diHDA-glycerol, a new chemically defined compound that we synthesized, to enhance nonspecific resistance of Itys mice to a virulent Salmonella typhimurium challenge (>LD50). This compound derives from (E)-10 hydroxy-2 decenoic acid (10-HDA), a fatty acid isolated from Royal Jelly. Bacterial growth rate within the spleen, interferon-gamma (IFN-γ), interleukin-10 (IL-10), and nitric oxide (NO) levels were measured in splenocyte cultures from diHDA-glycerol-pretreated mice or saline infected controls, at various time intervals after infectious challenge. Repeated administration of diHDA-glycerol before bacterial inoculation resulted in increased bacterial clearance from the spleen, starting in the second week of infection, whereas in control mice, bacterial proliferation led to death beyond day 13 after challenge. In addition, spleen cells from infected mice produced elevated levels of IFN-γ but failed to produce IL-10. In contrast, on the second week post challenge, the time course of cytokine responses was modified by the pretreatment. Spleen cells from diHDA-glycerol pretreated mice exhibited significantly lower levels of IFN-γ and significantlty higher levels of the anti-inflammatory cytokine IL-10, when compared with those in infected controls. Furthermore, on the second week post challenge, the restored functional capacity of splenocytes to produce nitric oxide (NO) was apparently linked with diHDA-glycerol pretreatment. These results suggest that diHDA-glycerol accelerates some macrophage functions resulting in a more adequate modulation of the balance of inflammatory mediators and consequently, in an enhanced host defense against Salmonella infection.

Lung inflammation and vascular remodeling after repeated allergen challenge detected noninvasively by MRI

2007 ◽  
Vol 292 (3) ◽  
pp. L644-L653 ◽  
Author(s):  
Bruno Tigani ◽  
Catherine Cannet ◽  
Harry Karmouty-Quintana ◽  
François-Xavier Blé ◽  
Stefan Zurbruegg ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Vascular Permeability ◽  
Vascular Remodeling ◽  
Lung Inflammation ◽  
Time Course ◽  
Repeated Administration ◽  
Brown Norway ◽  
Intratracheal Administration ◽  
Dce Mri ◽  
Fluid Analysis

Magnetic resonance imaging (MRI) has been used previously to follow noninvasively inflammatory processes in rat acute models of lung inflammation. Here the technique was applied to a model involving repeated intratracheal administration of ovalbumin (OA). Anatomical MRI was performed at different time points with respect to a single or multiple OA challenges in Brown Norway rats actively sensitized to the allergen. Vascular permeability was assessed using dynamic contrast-enhanced MRI (DCE-MRI). Bronchoalveolar lavage (BAL) fluid analysis and histology were performed to validate the MRI data. The time course of MRI signals after a single OA challenge reached a maximum at 48 h and decreased significantly at 96 h. After the second and subsequent challenges, the maximum signal occurred at 6 h with a time-dependent decline over the remainder of the time course. A reduction of the inflammatory response following repeated administration of OA was also detected by BAL fluid analysis. The decrease in vascular permeability assessed by DCE-MRI in repeatedly OA-challenged rats was consistent with the thickening of the vascular wall for vessels of diameter up to 300 μm revealed by histology. Angiogenesis of vessels smaller than 30 μm was also detected histologically. These results suggest that MRI can be used to detect the inflammatory response and vascular remodeling associated with chronic airway inflammation in rat models involving repeated administration of allergen. As the contrast agent used in the DCE-MRI experiments is approved for clinical use, there is potential to translate the approach to patients.

scholarly journals The time course of dopamine and serotonin levels in mouse brains after repeated administration of methamphetamine

1984 ◽  
Vol 36 ◽  
pp. 148
Author(s):  
Ritsuko Takano ◽  
Toshinori Yamamoto ◽  
Toru Egashira ◽  
Yasumitsu Yamanaka
Keyword(s):  
Time Course ◽  
Repeated Administration
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