Comparison of the analgesic efficacy and plasma concentrations of high-dose intra-articular and intramuscular morphine for knee arthroscopy*

Malaysia is a multi-ethnic society whereby the impact of pharmacogenetic differences between ethnic groups may contribute significantly to variability in clinical therapy. One of the leading causes of mortality in Malaysia is cardiovascular disease (CVD), which accounts for up to 26% of all hospital deaths annually. Clopidogrel is used as an adjunct treatment in the secondary prevention of cardiovascular events. CYP2C19 plays an integral part in the metabolism of clopidogrel to the active metabolite clopi-H4. However, CYP2C19 genetic polymorphism, prominent in Malaysians, could influence target clopi-H4 plasma concentrations for clinical efficacy. This study addresses how inter-ethnicity variability within the Malaysian population impacts the attainment of clopi-H4 target plasma concentration under different CYP2C19 polymorphisms through pharmacokinetic (PK) modelling. We illustrated a statistically significant difference (P < 0.001) in the clopi-H4 Cmax between the extensive metabolisers (EM) and poor metabolisers (PM) phenotypes with either Malay or Malaysian Chinese population groups. Furthermore, the number of PM individuals with peak clopi-H4 concentrations below the minimum therapeutic level was partially recovered using a high-dose strategy (600 mg loading dose followed by a 150 mg maintenance dose), which resulted in an approximate 50% increase in subjects attaining the minimum clopi-H4 plasma concentration for a therapeutic effect.

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Toxic Effects of High-dose Meloxicam and Carprofen on Female CD1 Mice

Journal of the American Association for Laboratory Animal Science ◽

10.30802/aalas-jaalas-21-000071 ◽

2021 ◽

Author(s):

Lon V Kendall ◽

Alexandra L Bailey ◽

Benjamin Singh ◽

Whitney McGee

Keyword(s):

Analgesic Efficacy ◽

Occult Blood ◽

Fecal Occult Blood Testing ◽

Fecal Occult Blood ◽

High Dose ◽

Serum Chemistry ◽

Clinical Safety ◽

Once Daily ◽

Fecal Occult ◽

Clinically Significant

The nonsteroidal anti-inflammatory drugs meloxicam and carprofen are commonly used as analgesics in mice. The current recommended doses of meloxicam at 0.2-1.0 mg/kg once daily and carprofen at 5-10 mg/kg twice daily may not be adequate to provide analgesia in mice. Several studies have suggested that doses up to 20 mg/kg of meloxicam and carprofen are needed to provide analgesic efficacy. This study investigated the clinical safety of these higher doses of meloxicam and carprofen by evaluating their potential for renal and gastrointestinal toxicity. Female CD-1 mice were given 20 mg/kg of either meloxicam, carprofen, or an equivalent volume of saline subcutaneously once daily for 3 or 7 d. On day 4, mice treated for 3 d were euthanized, and on days 8 and 15, mice treated for 7 d were euthanized. Blood was collected by cardiocentesis for serum chemistry analysis. Feces was collected from the colon for fecal occult blood testing, and tissues were collected for histopathology. No clinically significant changes in serum chemistry profiles were found in the drug-treated mice at any time point as compared with the saline controls. Fecal occult blood and histologic evidence of gastritis was associated with meloxicam administration in mice evaluated at days 4 and 8. By day 15, there was no association with meloxicam treatment and the presence of fecal occult blood or gastritis. There was no association between fecal occult blood and gastritis in the carprofen or saline-treated mice regardless of the treatment durations. These findings suggest that 20 mg/kg of meloxicam in mice causes gastric toxicity when given for 3 or 7 d and should be used cautiously; however, carprofen at 20 mg/kg appears to have minimal toxic effectswith regard to the parameters measured.

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Analgesic Efficacy of a Combination of Fentanyl and a Japanese Herbal Medicine “Yokukansan” in Rats with Acute Inflammatory Pain

Medicines ◽

10.3390/medicines7120075 ◽

2020 ◽

Vol 7 (12) ◽

pp. 75

Author(s):

Yuko Akanuma ◽

Mami Kato ◽

Yasunori Takayama ◽

Hideshi Ikemoto ◽

Naoki Adachi ◽

...

Keyword(s):

Inflammatory Pain ◽

Late Phase ◽

Analgesic Efficacy ◽

Opioid Tolerance ◽

High Dose ◽

Erk Pathway ◽

Single High Dose ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Combined Use

Background: Fentanyl can induce acute opioid tolerance and postoperative hyperalgesia when administered at a single high dose; thus, this study examined the analgesic efficacy of a combination of fentanyl and Yokukansan (YKS). Methods: Rats were divided into control, formalin-injected (FOR), YKS-treated+FOR (YKS), fentanyl-treated+FOR (FEN), and YKS+FEN+FOR (YKS+FEN) groups. Acute pain was induced via subcutaneous injection of formalin into the paw. The time engaged in pain-related behavior was measured. Results: In the early (0–10 min) and intermediate (10–20 min) phases, pain-related behavior in the YKS+FEN group was significantly inhibited compared with the FOR group. In the late phase (20–60 min), pain-related behavior in the FEN group was the longest and significantly increased compared with the YKS group. We explored the influence on the extracellular signal-regulated kinase (ERK) pathway in the spinal cord, and YKS suppressed the phosphorylated ERK expression, which may be related to the analgesic effect of YKS in the late phase. Conclusions: These findings suggest that YKS could reduce the use of fentanyl and combined use of YKS and fentanyl is considered clinically useful.

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Conception Rate and Reproductive Hormone Secretion in Holstein Cows Immunized against Inhibin and Subjected to the Ovsynch Protocol

Animals ◽

10.3390/ani10020313 ◽

2020 ◽

Vol 10 (2) ◽

pp. 313 ◽

Cited By ~ 2

Author(s):

Rihong Guo ◽

Fang Chen ◽

Cheng Mei ◽

Zicun Dai ◽

Leyan Yan ◽

...

Keyword(s):

Dairy Cows ◽

Reproductive Performance ◽

Luteal Phase ◽

Low Dose ◽

Follicle Stimulating Hormone ◽

Hormone Secretion ◽

Plasma Concentrations ◽

High Dose ◽

Reproductive Hormone ◽

Conception Rates

This study was conducted to investigate the feasibility of improving fertility in dairy cows via immunization against inhibin. Thirty-two cows were divided into Control (n = 11), Low-dose (n = 10) and High-dose (n = 11) groups. The High-dose and Low-dose cows were treated with 1 and 0.5 mg of the inhibin immunogen, respectively. All the cows were subjected to the Ovsynch protocol from the day of antigen administration and were artificially inseminated. Blood samples were serially collected over a 24-day period from the start of the Ovsynch protocol to 14 days after insemination. The results showed that immunization against inhibin dose-dependently increased the plasma concentrations of follicle-stimulating hormone (FSH), estradiol (E2), and activin A, but decreased progesterone (P4) concentrations in the luteal phase. Immunization also increased the plasma interferon (IFN)-τ concentrations in pregnant cows on day 14 after initial insemination. The conception rates in High-dose (45.5%) and Low-dose (40%) cows marginally increased compared to that in Control cows (27.3%), but the increases were not significant (p > 0.05). In conclusion, a single immunization against inhibin has the potential to improve conception rates, despite impaired luteal development. To further improve the reproductive performance of dairy cows, additional luteal-stimulating treatments are suggested in combination with immunization against inhibin and Ovsynch techniques.

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Effects of acetylsalicylic acid on pulmonary vascular tone and membrane permeability in blood-perfused dog lung

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.6.2561 ◽

1993 ◽

Vol 75 (6) ◽

pp. 2561-2569 ◽

Cited By ~ 3

Author(s):

K. Kambara ◽

M. Arakawa ◽

T. Segawa ◽

F. Ando ◽

M. Ohno ◽

...

Keyword(s):

Acetylsalicylic Acid ◽

Extravascular Lung Water ◽

Vascular Tone ◽

Low Dose ◽

Pressor Response ◽

Plasma Concentrations ◽

High Dose ◽

Constant Flow ◽

Lung Water ◽

Pulmonary Vasoconstriction

We studied the effects of acetylsalicylic acid (ASA) on pressor response, microvascular filtration coefficient (Kf), extravascular lung water, and plasma concentrations of cyclooxygenase- and 5-lipoxygenase-derived products in 21 blood-perfused dog lungs with constant flow. The lungs were perfused for 1 h with an intrapulmonary injection of saline as vehicle (n = 5), a low dose of ASA [136 +/- 25 (SD) micrograms/ml perfusate; n = 5], a high dose of ASA (1,006 +/- 278 micrograms/ml perfusate; n = 6), or alloxan (1,000 mg; n = 5). Alloxan significantly increased Kf and extravascular lung water, whereas neither the low nor high dose of ASA increased Kf or extravascular lung water. The ASA-induced increase in vascular resistance did not correlate with the extent of the decrease in perfusate 6-keto-prostaglandin F1 alpha or the ratio of perfusate 6-ketoprostaglandin F1 alpha to thromboxane B2. Moreover, ASA did not enhance the generation of perfusate leukotrienes B4, D4, or E4. We conclude that pulmonary microvascular permeability is unaltered by ASA and that neither the decrease in plasma prostacyclin nor the increase in plasma sulfidopeptide leukotrienes may account for ASA-induced pulmonary vasoconstriction.

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Toremifene: pharmacologic and pharmacokinetic basis of reversing multidrug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.9.1359 ◽

1989 ◽

Vol 7 (9) ◽

pp. 1359-1364 ◽

Cited By ~ 66

Author(s):

M W DeGregorio ◽

J M Ford ◽

C C Benz ◽

V J Wiebe

Keyword(s):

Estrogen Receptor Status ◽

Plasma Concentrations ◽

Multidrug Resistant ◽

High Dose ◽

Human Breast ◽

Human Breast Cell Line ◽

Human Breast Cell ◽

Mcf 7 ◽

Resistant Cells

Triphenylethylene compounds, such as tamoxifen, have shown chemosensitizing activity independent of estrogen receptor status in doxorubicin-resistant cells. We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX. In addition, we examined the chemosensitizing activity of unbound plasma toremifene and its metabolites isolated from patients treated with toremifene doses of 20 to 400 mg/d. MCF-7/DOX cells were exposed to ultrafiltrate plasma specimens in the absence and presence of doxorubicin. These latter studies were single-blinded. Toremifene and its major metabolites were capable of sensitizing multidrug-resistant cells to doxorubicin. The degree of chemosensitizing activity in vitro correlated with the plasma concentrations of toremifene and its metabolites (P less than .05). Plasma samples isolated from patients receiving high-dose toremifene (400 mg/d) had the greatest chemosensitizing activity. We present evidence that toremifene and its metabolites can sensitize resistant MCF-7/DOX cells to doxorubicin, that this effect is concentration-dependent, and that sensitizing activity can be detected at clinically achieved concentrations.

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