Biomedical subjects

M I Zakowski

Publications and source records attributed to M I Zakowski.

14 recordsLinked to original sources

PubMed2001

Perineural antinociceptive effect of opioids in a rat model.

BACKGROUND: The research on conductive analgesia induced by perineural opioids generated a large body of conflicting data. In this study we reassessed the antinociceptive response to perineural administration of morphine, fentanyl or meperidine in a rat model. METHODS: Analgesia was assessed using the hind paw withdrawal latency (HPWL) response to radiant heat. The opioid dose producing 20% of maximal possible effect (20%MPE) for systemic analgesia was calculated for each drug. Then sciatic blockade was performed with the dose corresponding to 20%MPE. The injected hind paw was used to measure direct perineural effect and the contralateral hind paw was used as an indicator of systemic effect. RESULTS: The response latency produced by morphine or fentanyl was not significantly different for ipsilateral (perineural effect) or contralateral (systemic effect) paw (27+/-11 vs. 28+/-16 and 3l+/-16 vs. 23+/-16 s, respectively). However, the meperidine group showed significantly higher %MPE for the ipsilateral paw (79+/-32 s) than for the contralateral paw (27+/-22 s). CONCLUSIONS: The results indicate that perineural fentanyl or morphine do not produce analgesia. Perineural block produced by meperidine was attributed to local anesthetic-like effect, rather than to drug interaction with opioid receptor.

Analgesia↗

PubMed1997

Sufentanil transfer in the human placenta during in vitro perfusion.

PURPOSE: Sufentanil, a lipophilic opioid, is used to provide analgesia for labour and Caesarean section, but may cause neonatal depression. Factors affecting placental transfer of sufentanil were investigated using human placentas. STUDY DESIGN: Transfer and uptake of sufentanil by the human placenta were studied using a single pass (open) in vitro perfusion model. The effects of change in sufentanil concentration (1-100 ng.ml-1) and change in fetal pH (range 7.4-6.8) on placental transfer were studied. Placental metabolism of sufentanil and the effects of maternal protein content (fresh human plasma, albumin 4%, Media 199) on placental transfer were also investigated utilizing a closed (recirculated) in vitro perfusion system. RESULTS: Sufentanil transfer was 2% at five minutes and plateaued at 12% by 45 min. The clearance index (CI = sufentanil clearance/antipyrine clearance) was 0.56 +/- 0.2 for maternal to fetal (MTF) and 0.44 +/- 0.2 in the fetal to maternal (FTM) directions (P = NS). The CI was 0.5 +/- 0.2 for 1 ng.ml-1 and 0.61 +/- 0.3 for 100 ng.ml-1 sufentanil concentration (P = N.S.). The placenta contained 7.1 +/- 2 and 9.8 +/- 3 ng.g-1 sufentanil following MTF and FTM perfusions for 90 min at 1 ng.ml-1. The placenta did not metabolize sufentanil. After one hour MTF washout, placental sufentanil content was 2.3 +/- .5 ng.g-1 with 0.08 ng.ml-1 sufentanil in the umbilical vein. Maternal plasma decreased MTF CI from 0.41 +/- 0.1 for albumin and 0.4 +/- 0.1 for Media 199 to 0.17 +/- .06 for plasma (P < 0.05). Decreasing fetal pH increased MTF CI from 0.57 +/- .13 at pH 7.4 to 1.6 +/- .4 at pH 6.8 (P < 0.05). CONCLUSION: Sufentanil crossed the placenta by passive diffusion and accumulated in placental tissue, which acted as a drug depot, slowing the initial transfer. Placental transfer was decreased by maternal plasma proteins, but not by albumin. Fetal acidosis increased placental transfer. Due to its low initial umbilical vein concentration, sufentanil may be the opioid of choice when delivery is imminent (< 45 min).

Acidosis↗

PubMed1996

Hemodynamic effects of intrathecal fentanyl in nonlaboring term parturients.

STUDY OBJECTIVE: To determine the effect of intrathecal fentanyl on maternal hemodynamics. DESIGN: Prospective. SETTING: Labor and delivery suite of a university medical center. PATIENTS: 23 ASA status I nonlaboring term parturients presenting for elective cesarean section. INTERVENTIONS: Patients were given either 1,200 ml lactated Ringer's Solution (Group 1, n = 12) or no intravenous (i.v.) fluid (Group 2, n = 11). A combined spinal-epidural technique was then performed. Fentanyl 25 micrograms was administered intrathecally through a 24-gauge Sprotte or 25-gauge Whitacre spinal needle. After completion of the hemodynamic study, a catheter was threaded into the epidural space for local anesthetic administration. MEASUREMENTS AND MAIN RESULTS: Baseline hemodynamic data [systolic (SBP), diastolic, and mean arterial pressure, heart rate, stroke volume, cardiac output, end-diastolic volume, and ejection fraction] were obtained in triplicate using noninvasive blood pressure monitoring and impedance cardiography. After administration of intrathecal fentanyl, hemodynamic measurements were recorded at 3-minute intervals for 30 minutes. These values were compared with baseline for both groups. Ten patients in each group completed the study. Intrathecal fentanyl administration did not result in any maternal hemodynamic changes in Group 1, and a few small statistically significant changes in Group 2. Measured SBP was always greater than 100 mmHg in all patients during the study. CONCLUSION: Intrathecal administration of fentanyl 25 micrograms in nonlaboring term parturients does not produce clinically important maternal hemodynamic changes.

Adult↗

PubMed1995

Hot plate versus tail flick: evaluation of acute tolerance to continuous morphine infusion in the rat model.

The development of tolerance to continuous morphine infusion (2, 4 and 6 mg x kg(-1) x hr(-1) was assessed in rats using two different methods for evaluation of nociception, tail flick (TF) and hot plate (HP). The influence of repeated testing on nociception was evaluated using two regimens; series 1 was tested repeatedly 1, 2, 4, 6, and 8 hr after initiating the morphine infusion and series 2 was tested only twice, at maximum morphine effect and at 8 hr. Both, TF and HP showed pain threshold elevation after the morphine administration of 4 or 6 mg x kg(-1) x hr(-1), which reached a maximum at 2 hr after the start of the infusion. HP: reduction of the effect was found in group 4 mg x kg(-1) x hr(-1) in the series subjected to repeated testing; group 6 mg x kg(-1) x hr(-1) showed reduced effect in both sides. TF: the response latencies did not show reduction at 8 hr. Since TF is predominantly a spinal response and HP is predominantly supraspinal, the results suggest that tolerance during the first 8 hr of morphine infusion develops mainly at supraspinal level.

Analgesics, Opioid↗

PubMed1995

Intrathecal administration of liposomal morphine in a mouse model.

The authors determined the duration of analgesia, toxicity, and neuraxial distribution of liposomal morphine after intrathecal administration in the mouse. Analgesic duration was determined using the tail-flick test after intrathecal injection of 12.5, 25, or 50 micrograms of plain or liposomal morphine (n = 6 mice/dose/formulation). Toxicity of the formulations was compared by estimating LD50. Neuraxial morphine distribution was determined after 20 micrograms of plain or liposomal morphine. The excised spinal cord and brain were divided into five segments at 1 min, and at 1, 4, and 8 h after injection for both formulations. In addition, for the liposomal morphine, similar sections were obtained at 24 h (n = 6 mice/formulation/time point). Segmental morphine concentration was quantified using radioimmunoassay. Liposomal encapsulation significantly prolonged duration of analgesia for the 25-micrograms (13.4 +/- 1.64 [SE] vs 4.1 +/- 0.5 h) and 50-micrograms doses (16.8 +/- 4.0 vs 4.6 +/- 1.0 h). The estimated LD50 was 200 (confidence interval 151-257 micrograms) for plain morphine, but was not determinable for the liposomal formulation, since no deaths occurred at the largest dose level which could be tested (371 micrograms). For plain morphine, the drug was not confined to a specific neuraxial segment, and segmental levels declined rapidly. After liposomal morphine, the most morphine was concentrated and persisted in the low spinal cord segment at each time interval. These results show that a single dose of liposomal morphine produces prolonged analgesia with decreased toxicity compared to the plain formulation.

Animals↗

PubMed1994

Prolonged analgesia and decreased toxicity with liposomal morphine in a mouse model.

Inadequate control of postoperative pain remains a major clinical problem. A reliable method of providing long-lasting postoperative analgesia with a single dose would be very useful. We synthesized a liposomal morphine formulation and compared it to free morphine with regard to duration of analgesia in the mouse. Analgesia was assessed after intraperitoneal injection using the tail-flick test. The systemic toxicity after administration of liposomal and free morphine was compared. The release rate of morphine from liposomes in vitro was also evaluated. The lethal intraperitoneal dose of free morphine in 50% of mice (LD50) was 400 mg/kg. The maximum safe (non-lethal) dose of free morphine was 130 mg/kg. The highest dose of liposomal morphine administered (1650 mg/kg) did not cause death in any animal. Duration of analgesia was significantly prolonged with the highest dose of liposomal morphine (21.5 +/- 5.3 h) compared to the maximum safe dose of free morphine (3.7 +/- 0.75 h), P < 0.01. In vitro experiments showed a slow release rate of morphine from the liposome depot. Prolonged analgesia and decreased systemic toxicity for liposomal morphine are explained by sustained release of morphine from the liposomal depot. These results suggest that liposomal narcotic formulations may provide prolonged analgesia with single-dose administration.

Analgesia↗

PubMed1994

Transfer and uptake of alfentanil in the human placenta during in vitro perfusion.

Alfentanil, a short-acting lipophilic opioid, is used for labor analgesia and cesarean section and may cause neonatal depression. However, direct placental alfentanil transfer has not been studied. We measured placental alfentanil transfer and uptake during in vitro perfusion. Placenta lobules from healthy parturients were perfused with biophase at pH 7.4, 95%:5% O2:CO2. Maternal to fetal (MTF, n = 10) and fetal to maternal (FTM, n = 10) transfer were examined during perfusion with alfentanil 10 ng/mL, antipyrine, and creatinine for 1 h. Thereafter, both MTF and FTM placentas were assayed for alfentanil content (n = 3), or perfused with biophase for 1 h to determine drug washout and then assayed for alfentanil content (n = 3). After the 1 h washout, the remaining MTF placentas (n = 4) were then perfused MTF with high-dose alfentanil 1000 ng/mL to assess saturability of placental transfer. The remaining FTM placentas (n = 4) were then perfused with alfentanil 10 ng/mL in the MTF direction to verify that the same alfentanil transfer characteristics found between placentas were valid when the direction of drug transfer was reversed in the same placenta. Alfentanil was rapidly transferred (< 5 min) across the placenta both MTF and FTM. During MTF transfer, fetal effluent reached a plateau at 2.2 ng/mL between 35 and 55 min, and was unmeasurable 30 min into washout. During FTM transfer, maternal effluent reached a plateau at 1.9 ng/mL at 25-45 min, and was absent after 20-45 min of washout.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗

PubMed1993

Assessing local anesthetic effect using the mouse tail flick test.

We used the tail flick test to quantify duration of local anesthetic-induced conduction block in the mouse. Using a baseline tail flick latency (TFL) between 1.0 and 2.5 sec, sensory block was considered present if TFL was > or = 4 sec. Two 20-microL local anesthetic injections were made on opposite sides of the tail base. TFL was tested every 10 min, and local block duration was interpreted as the time to return of TFL to < 4 sec. We tested three different concentrations of procaine (1%, 2%, and 4%), tetracaine (0.125%, 0.5%, and 1%), and lidocaine (0.5%, 1%, and 2%) with and without epinephrine. The testing method could discriminate between the duration of the various local anesthetic concentrations used. For the 1% concentrations, the duration of sensory block was 2 +/- 4 min (S.D.) for procaine, 20 +/- 10 min for lidocaine, 40 +/- 10 min for tetracaine, and 66 +/- 15 min for lidocaine with epinephrine. We found this to be a simple and reliable means of assessing local anesthetic conduction block in the mouse.

Anesthesia, Local↗

PubMed1993

A two-dose epidural morphine regimen in cesarean section patients: pharmacokinetic profile.

The maternal pharmacokinetics, metabolism of, and possible neonatal transmission of epidural morphine in cesarean section patients were investigated. Maternal plasma, breast milk, and maternal and neonatal urine concentrations of unconjugated and conjugated (UM and CM) morphine were measured in patients given two 5-mg doses of epidural morphine for post-cesarean section analgesia. The first dose was administered after delivery and the second dose 24 h later. Maternal venous blood samples (n = 10) were collected at times 0, 0.25, 0.5, 1, 2, 3, 4, 6, 12, and 24 h after each dose, and maternal urine was collected for three consecutive 24-h periods (n = 30). Maternal breast milk (n = 30), and neonatal urine samples (n = 20) were also collected. Serum, urine, and breast milk UM and CM levels were measured using radioimmunoassay. Pharmacokinetic values were calculated using noncompartmental analysis. The results were expressed as mean +/- 1 s.e. mean and analyzed using repeated measures analysis of variance and the paired t-test. Maternal serum UM remained 40-50% higher, and CM 50-100% higher in the first hour following dose 2 than the respective values after dose 1 (P < 0.05). Values for AUC, AUMC, T1/2, and MRT increased 28%, 83%, 35% and 36%, respectively, with the second dose (P < 0.05), while CI decreased 19% (P < 0.05) with no significant difference in Vss. Total urinary excretion of morphine decreased significantly from 1.98 +/- 0.15 mg on day 1 to 1.6 +/- 0.2 mg and 0.19 +/- 0.002 mg on days 2 and 3, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Electrocardiographic changes during cesarean section: a cause for concern?

A Holter monitor was used to record ST segment changes during cesarean section in 170 consecutive healthy parturients starting 2 h before and ending 3 h after surgery. Lumbar epidural anesthesia (LEA, n = 120) or subarachnoid anesthesia (SA, n = 50) was used. Transthoracic 2-D echocardiograms were obtained in 30 patients from the LEA group. ST depression or elevation occurred 160 times in 44 patients from both groups. Ninety-eight percent of these changes occurred between induction of anesthesia and the end of surgery, with 78% of the episodes registering -1 mV. In the LEA group, the number of episodes tended to increase after delivery, but in the SA group, the frequency remained constant. ST segment depression was recorded in 38% and 14% of patients in the LEA and SA groups, respectively (P < 0.05, x2 analysis). No wall motion abnormality was noted in the echocardiogram during ST segment depression. Neither the 12-lead electrocardiogram nor plasma myocardial specific creatine kinase suggested myocardial damage. The operative events, alone or in combination, including hypertension, tachycardia, hypotension, bradycardia, air embolism (precordial Doppler) were neither specific nor sensitive as predictors of ST segment change (stepwise logistic regression). Tachycardia was associated with ST segment changes in 10% of time epochs (5 min) (P = 0.05, x2 analysis). Thus, ST segment changes during cesarean section are not caused by myocardial ischemia and are not of any clinical consequence.

Adult↗

PubMed1992

A two-dose epidural morphine regimen for cesarean section patients: therapeutic efficacy.

A single dose of epidural morphine (EM) usually produces 24 h of post-cesarean section (CS) analgesia and patients require supplemental analgesics beyond this period. This study assesses if a second dose of EM administered 24 h after the first one offers superior therapeutic efficacy compared to conventional analgesics. Patients (n = 100) were randomized to receive one or two doses of epidural morphine. In all patients, EM 5 mg was administered after delivery. After 24 h patients received epidurally either normal saline (n = 50, Group 1) or morphine 5 mg (n = 50, Group 2). An independent observer used a visual analogue scale to assess nausea, itching, and analgesia 24 h after each injection. Results were expressed as mean +/- 1 s.e. mean and analyzed using nonparametric methods. The second dose of EM produced a significantly lower incidence and severity of nausea and itching than did the first dose (P < 0.01) in Group 2 with no difference in analgesia. The second day postoperative pain score in Group 1 was significantly greater than the first day score in the same group, and significantly greater than the severity score in Group 2. Only 36% of patients receiving two doses of EM required supplemental analgesics beyond 48 h compared to 76% of those receiving one dose (P < 0.01). No serious complications were noted. In summary, the use of a second dose of EM for post-CS analgesia produces better analgesia and reduces the need for oral analgesics. The second dose produced fewer side-effects, probably due to acute tolerance to morphine.

Adult↗

PubMed1992

Uptake and distribution of bupivacaine and morphine after intrathecal administration in parturients: effects of epinephrine.

This study examines the plasma pharmacokinetics of bupivacaine and morphine and the urinary excretion of morphine administered for spinal anesthesia for cesarean section. Patients received 12 mg of hyperbaric bupivacaine and 0.6 mg of morphine with either 0.2 mL of normal saline (plain, n = 15) or 0.2 mg of epinephrine (n = 15). Venous blood and urine were collected at 0, 0.25, 0.5, 1, 2, 3, 6, 12, and 24 h. Total and unconjugated morphine (UCM) in plasma and urine were measured using radioimmunoassay, and plasma bupivacaine was measured by gas chromatography. Results were expressed as mean +/- SE and analyzed using Student's t-test at P less than 0.05. In the epinephrine group, plasma bupivacaine peaked at 15 min and remained approximately 30% higher (P less than 0.05) at 0.25, 0.5, and 1 h than in the plain group, which peaked at 30 min. Although UCM peaked at 3 h in both groups, the plasma levels remained approximately 66% lower in the epinephrine group. In the epinephrine group, bupivacaine had a smaller volume of distribution at steady state, and morphine had a more rapid clearance, shorter t1/2 beta, and smaller area under the curve compared with the plain group (P less than 0.05). Only 45% +/- 5% and 31% +/- 3% of morphine was recovered in the urine in the plain and epinephrine group, respectively (P less than 0.05). In conclusion, epinephrine added to a bupivacaine-morphine mixture increases the initial systemic uptake of bupivacaine and decreases the absorption and urinary excretion of morphine from the intrathecal space.

Adult↗

PubMed1992

A rat sciatic nerve model for independent assessment of sensory and motor block induced by local anesthetics.

The purpose of this study was to develop a reliable model to independently quantify motor and sensory block produced by local anesthetics. The sciatic nerve was blocked in 52 rats by injecting 0.2 mL of 0.125%, 0.25%, 0.5%, or 0.75% bupivacaine (n = 13 for each concentration). Accurate needle placement was achieved using a nerve stimulator at 0.2 mA and 1 Hz. Ten control rats received 0.9% saline (n = 5) or sham nerve stimulation (n = 5). Motor block was assessed by measuring hindpaw grip strength with a dynamometer. Sensory block was determined by measuring hindpaw withdrawal latency from radiant heat. The intensity of both motor and sensory block measured at 30-min intervals was plotted against time until full recovery to obtain the area under the curve. Intergroup comparisons using analysis of variance showed increasing area under the curve with increasing concentrations of bupivacaine for motor blocks (P < 0.05 for all intergroup comparisons except 0.5% vs 0.75%) and sensory blocks (P < 0.05 for all intergroup comparisons). Normal saline or sham nerve stimulation did not result in any motor or sensory block.

Animals↗

PubMedDate not supplied

The hypothermic action of epidural and subarachnoid morphine in parturients.

Sublingual body temperatures were measured before and at 0.5, 1, 2, 3, 4, 8, 12, and 24 hours after administration of epidural or subarachnoid morphine in four groups of patients (n = 15 in each group) undergoing cesarean delivery with regional anesthesia. All patients were acutely hydrated with 1200 ml warmed lactated Ringer's solution. Group 1 received 5 mg epidural morphine; Group 2, 5 ml epidural saline; Group 3, 0.5 mg subarachnoid morphine, and Group 4, 0.5 ml subarachnoid saline. The results were expressed as means +/- SEM and analyzed using analysis of variance at p less than 0.05. Body temperature decreased significantly in all the four groups after anesthesia. The maximum decreases in Groups 1, 2, 3, and 4, respectively, were 0.95 +/- 0.1, 0.9 +/- 0.1, 1.4 +/- 0.2, and 0.8 +/- 0.13 degrees C and occurred at 0.5, 1, 2, and 1 hour, respectively. The decrease was greater in the subarachnoid morphine group than in the other groups (p less than 0.03). At any of the measurement periods, the temperatures in the two epidural groups did not differ from each other. However, the temperature in the subarachnoid morphine group remained significantly lower than the corresponding temperature in the control group for up to 24 hours. It is concluded that subarachnoid morphine intensifies the hypothermic action of spinal anesthesia in parturients.

Adult↗