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Biomedical subjects

D D Denson

Publications and source records attributed to D D Denson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics.

BACKGROUND: Development of tolerance to opioid analgesics occurs often in patients with cancer-related pain. Cross-tolerance among opioid analgesics provides the physician with a major management problem. Incomplete cross-tolerance among opioid analgesics has been demonstrated to occur in animals and humans. The current study provides clinical evidence of the incomplete cross-tolerance of methadone with a number of mu-opioid agonist analgesics in patients with advanced cancer-related pain. RESULTS: Patients presented in the current study had cancer-related pain refractory to other mu--opioid receptor agonist analgesics as evidenced by inadequate analgesia despite escalation of opioid dose. All patients were adequately managed by conversion of their opioid dose to methadone. Additionally, the dose of methadone required to establish and maintain analgesia in these patients was modest compared with previous opioid dose requirements. CONCLUSIONS: Methadone is a potent opioid analgesic that demonstrates incomplete cross-tolerance with other mu-opioid receptor agonist analgesics. Conversion of the opioid-tolerant patient with cancer-related pain to methadone may represent an important therapeutic option in the management of patients with this difficult problem.

Adolescent↗
PubMed1993

Pharmacokinetics of intravenous and epidural ropivacaine in the rhesus monkey.

Ropivacaine is a new long-acting amide local anesthetic which is possibly less cardiotoxic than bupivacaine. The absorption and disposition of ropivacaine were characterized in six rhesus monkeys in an open two-way crossover study following intravenous and epidural administration. For these studies, animals were anesthetized for placement of intravenous and intraarterial catheters. For the epidural studies, a PE-10 catheter was also inserted 3 cm into the lumbar epidural space. After recovery from anesthesia, animals received ropivacaine 1 mg kg-1 intravenously over 1 min or 10 mg of ropivacaine epidurally (two 1 ml doses of 0.5%, 5 min apart), and arterial blood samples were obtained over 5 h. Serum ropivacaine concentrations were determined by gas chromatography with NP detection. Concentration-time data following i.v. and epidural administration were fitted simultaneously. Initial parameter estimates were obtained by analyzing each route separately. Input rates and their corresponding extent of absorption were estimated using deconvolution. Mean (+/- SD) disposition parameters included: Vss = 1.11 +/- 0.198 l kg-1; CL = 0.711 +/- 0.158 l h-1 kg-1; t1/2,z = 2.07 +/- 0.438 h. Mean (+/- SD) absorption parameters included: F1 = 0.506 +/- 0.221; t1/2,kal = 0.060 +/- 0.078 h; F2 = 0.444 +/- 0.182; t1/2,ka2 = 6.45 +/- 11.09 h. Ropivacaine's biphasic absorption and bioavailability are similar to those of other amide local anesthetics. The biphasic absorption may be related to partitioning into fat or regional changes in blood flow induced by the drug.

Amides↗
PubMed1991

Stability of methadone hydrochloride in 0.9% sodium chloride injection in single-dose plastic containers.

The stability of methadone hydrochloride in 0.9% sodium chloride injection in flexible polyvinyl chloride containers was studied. Commercially available methadone hydrochloride 20 mg/mL and 25-mL single-dose bags of 0.9% sodium chloride injection were used. Six samples each were prepared at methadone hydrochloride concentrations of 1, 2, and 5 mg/mL. The solutions were stored at room temperature and were not protected from light. Immediately after preparation and after two, three, and four weeks of storage, each of the 18 samples was divided into three aliquots, each of which was analyzed in duplicate for methadone hydrochloride concentration by gas chromatography. There was less than 10% change in methadone hydrochloride concentration in any sample throughout the four-week study period. Methadone hydrochloride at concentrations of 1, 2, and 5 mg/mL prepared in commercially available flexible polyvinyl chloride containers of 0.9% sodium chloride injection and stored at room temperature without deliberate protection from light is stable for at least four weeks.

Drug Packaging↗
PubMed1990

Recovery of morphine from a controlled-release preparation. A source of opioid abuse.

MS-Contin (Purdue-Fredrick, Norwalk, CT) is a controlled-release preparation of morphine sulfate that has demonstrated efficacy in the management of chronic cancer pain problems. It has recently come to the attention of the authors that MS-Contin represents a potential source of opioid abuse through the extraction and intravenous injection of the morphine from this preparation. The authors describe a simple aqueous extraction method that was used to quantitatively determine the extent to which morphine could be obtained from MS-Contin tablets.

Adult↗
PubMed1990

Pharmacokinetics of continuous intravenous infusion of methadone in the early post-burn period.

The pharmacokinetics of methadone were studied in 14 patients with acute, severe burns and receiving an intravenous infusion of methadone to control their pain. Serum methadone concentrations were measured by gas chromatography on 5 mL arterial blood samples obtained at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 and 24 hours after the start of infusion. Albumin and Alpha-1-Acid glycoprotein (AAG) were measured by radial immunodiffusion. Serum methadone concentration-time data were fit with the appropriate sum of exponentials equation using iterative nonlinear regression analysis. All serum methadone concentration-time data were best described by a monoexponential equation. Estimates of Vd (180 +/- 62 L) were not significantly different from those predicted for Vc from body weight using literature values (156 +/- 41). Estimates of Vd were, however, significantly lower than those predicted for Vz using literature values (282 +/- 74) (P less than 0.001). In addition, CL values (53.0 +/- 19.3 L/h) were significantly higher than those predicted from body weight using literature values (9.2 +/- 2.3 L/h) (P less than 0.001). These changes resulted in estimates of the elimination half-life for methadone of 2.6 +/- 1.1 h. Methadone protein binding was independent of both albumin and AAG concentration. Multiple regression demonstrated that the significant predictors of CL in the early post burn injury period were serum albumin, days post injury and age. The coefficient of determination (r2) for this model was 0.8190. In summary, methadone CL is markedly elevated while the Vc is essentially unchanged during the early post burn injury period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The correlation between predicted and measured patient specific analgesic concentrations after intravenous titration: a guide for initial maintenance requirements with methadone.

The relationship between the analgesic methadone concentrations measured and those predicted using a pharmacokinetic approach were assessed in 22 patients referred for long-term management of severe pain with intravenous methadone. Five milligrams of methadone were administered IV every 10 minutes until the patient reported a visual analog scale (VAS) pain score of less than or equal to 2. Initial maintenance infusion rates were chosen based on the number of 5 mg doses required to produce satisfactory analgesia. Overall, the methadone concentrations predicted using pharmacokinetic modeling were in excellent agreement with those actually measured. Over 95% of the variance in the data was explained using this model (r2 = 0.9704). Using the rapid titration paradigm described here, one can obtain a reasonable estimate of patient specific analgesic (target) concentration as well as initial infusion requirements for methadone.

Humans↗
PubMed1990

Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans.

The purpose of this study was to characterize the pharmacodynamics and pharmacokinetics of three concentrations of the new long-acting amide local anesthetic, ropivacaine, given epidurally in 15 physical status ASA I or II patients for elective lower-extremity orthopedic procedures using a nonrandomized open-label design. Three groups of five patients each received either 0.5%, 0.75%, or 1.0% ropivacaine. Upper and lower levels of analgesia to pinprick were determined at frequent intervals until normal sensation had completely returned. Motor blockade was assessed by use of a modified Bromage scale after each determination of level of analgesia. Fifteen venous blood samples were collected over 12 h after ropivacaine injection. Pharmacokinetic parameters were derived using serum concentration-time data. No significant differences were found between the three groups in terms of onset or recovery of motor and sensory blockade. Median maximum thoracic levels of analgesia achieved were 8, 6, and 5 for the 0.5%, 0.75%, and 1.0% groups, respectively, and occurred at 29 +/- 11, 37 +/- 21, and 30 +/- 9 min. Respective times to two-segment regression were 2.8 +/- 1.0, 3.0 +/- 0.5, and 2.9 +/- 0.6 h. Total durations of sensory blockade were 5.4 +/- 0.7, 6.5 +/- 0.4, and 6.8 +/- 0.8 h, respectively. No statistically significant differences were noted between the three groups in terms of clearance (CL). The mean residence time (MRT) was significantly longer for the 0.5% group when compared with the 1% group. The peak concentration (Cmax) for the 0.5% group was found to be significantly lower than for either the 0.75% or 1% groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

The effect of pH-adjusted 2-chloroprocaine on the onset of epidural analgesia in pregnant patients in the lying and sitting position during the first stage of labor.

The purpose of this prospective, randomized, double-blind study was to compare the epidural onset time of 2% 2-chloroprocaine with pH-adjusted 2-chloroprocaine administered in either the sitting or supine position in pregnant patients during the first stage of labor. Patients in Groups I and III received the control solution in the sitting and supine position, respectively. Patients in Groups II and IV received the buffered solution in the sitting and supine position, respectively. The pH and pCO2 of the control and buffered solutions differed significantly. The pH and pCO2 of the control and buffered solutions were 4.38 +/- 0.01, 18.4 +/- 2.2 mm Hg and 7.70 +/- 0.04, 114.9 +/- 3.0 mmHg, respectively. A statistically significant reduction in the time of onset of analgesia in the pH-adjusted groups was noted. Groups I and II had onset times of 4 +/- 1.2 and 4.3 +/- 1.0, whereas Groups II and IV had onset times of 2.6 +/- 0.9 and 2.7 +/- 0.6 min., respectively. There were no intergroup differences in the cephalad spread of analgesia or duration of analgesia. Position had no effect on the onset of analgesia at the S2-3 dermatomes nor on the bilateral cephalad spread of the epidural study solutions. Our results indicate that a pregnant patient may be dosed in the lateral supine position without adversely affecting the caudad or cephalad spread of plain or pH-adjusted 2% 2-chloroprocaine, which is clinically important because the incidence of aortocaval compression is increased in the supine position when compared with the lateral supine position.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

The effect of pH and PCO2 on epidural analgesia with 2% 2-chloroprocaine.

Increasing the pH of local anesthetics with sodium bicarbonate has been reported to hasten their onset of action. The purpose of this study was to compare the onset and duration of epidural analgesia with the use of sodium bicarbonate and tromethamine to increase the pH of 2% chloroprocaine (2CP). Five groups of patients were studied: Group I received 2CP; Group II received 2CP buffered to a pH of 7.1 with tromethamine; Group III received 2CP buffered to a pH of 7.1 with sodium bicarbonate; Group IV received 2CP buffered to a pH of 7.7 with tromethamine; and Group V received 2CP buffered to a pH of 7.7 with sodium bicarbonate. The final pH and PCO2 of each solution were measured. Time to onset of analgesia was significantly delayed with either of the tromethamine buffered groups (II [5.6 +/- 1.0 minutes] and IV [5.4 +/- 0.4 minutes]) when compared with data from the unbuffered control (I [4.4 +/- 0.1 minutes]) and the sodium bicarbonate buffered (III [4.5 +/- 0.8 minutes] groups and Group V [2.7 +/- 0.9 minutes]). Only when sodium bicarbonate buffer adjusted to pH 7.7 (Group IV) was onset significantly more rapid than the unbuffered 2CP (I) and tromethamine buffered 2CP (II and IV). Multiple regression analysis revealed that onset times were significantly related to both pH and PCO2. The coefficient of determination for this model was 0.5156.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Rapid estimation of unbound lidocaine clearance in cardiac patients: implications for reducing toxicity.

The clearance (CL), volume of distribution (Vd) and elimination half-life (t1/2), based on unbound and total concentration-time data, were estimated using two serum lidocaine concentrations drawn approximately 6 and 12 hours after the initiation of continuous intravenous lidocaine therapy in nine patients with myocardial infarction (MI) (in the immediate postinfarct period) and in 12 patients with ventricular arrhythmias. No significant intergroup differences were found for any of the parameters based on unbound or total lidocaine concentration-time data. A significant (P less than .01) correlation was found between measured unbound lidocaine and unbound lidocaine concentrations predicted using alpha-1-acid glycoprotein (AAGP) and total serum lidocaine concentrations. However, the predicted values were significantly lower than the measured values for both groups (P less than .001). Significant correlations were found between total and unbound volumes of distribution and between total and unbound clearances. Coefficients of determination (r2) for these correlations were 0.6906 and 0.9178 respectively. The relationship between total and unbound clearance allows rapid estimation of unbound clearance from two total serum lidocaine concentrations. Unbound clearance can then be used to determine patient-specific maximum infusion rates and reduce the risk of central nervous system toxicity from lidocaine.

Adult↗
PubMed1988

Pharmacokinetics of bupivacaine following caudal anesthesia in infants.

Pharmacokinetics and protein binding of bupivacaine were studied after caudal injection of 2.5 mg/kg in 13 ASA PS 1 infants (1-6 months of age) scheduled for elective hernia repair. Blood was sampled at frequent intervals from 5 min to 600 min in all but one patients. Additional samples were taken at 720 and 840 min in five patients. Bupivacaine concentration was measured using gas chromatography. Protein binding was measured using ultrafiltration. Peak serum concentrations ranged between 0.55 and 1.93 micrograms/ml. The time to reach the peak ranged from 10 to 60 min. Terminal half-life (T1/2 beta) was 7.7 +/- 2.4h (mean +/- SD), the volume of distribution (Vss) was 3.9 +/- 2.01.kg, and the total body clearance (CL) was 7.1 +/- 3.2 ml.min.kg-1. The free fraction was markedly increased (0.16 +/- 0.07) when compared with published adult values, and showed a highly significant negative correlation with age. Alpha 1 acid glycoprotein measured in the same infants correlated significantly with age. In conclusion, pharmacokinetics of caudal bupivacaine in infants are characterized by Cmax of total drug similar to those observed in adults after epidural injection. The free fraction is increased at least until 6 months of life. This suggests caution in the use of bupivacaine in infants until we understand the clinical significance of this increased free fraction.

Anesthesia, Caudal↗
PubMed1988

Pharmacokinetics of coumarin and 7-hydroxycoumarin in the rhesus monkey after intravenous and peroral administration.

Coumarin (C, Venalot) and 7-hydroxycoumarin (7-OHC) were administered in a dose of 1 mg/kg to rhesus monkeys intravenously and perorally. The concentrations of C, 7-OHC and their metabolite, 7-hydroxycoumarin glucuronide (7-OHCG) were measured in whole blood. The terminal half-life, t1/2, the apparent distribution volume, Vd, and the total clearance, CL, of C and 7-OHC after i.v. administration are 1.64 +/- 0.41 h and 0.8 +/- 0.29 h, 2.55 +/- 0.95 l/kg and 6.96 +/- 3.44 l/kg, and 19.05 +/- 5.41 ml/min/kg and 103.7 +/- 34.4 ml/min/kg (mean +/- SEM), respectively. The rates of absorption of C and 7-OHC are 12.8 +/- 2.38 and 4.62 +/- 1.08 h-1, respectively. The rate of metabolism of C via 7-OHC to 7-OHCG is 7.96 +/- 2.16 h-1 and that of 7-OHC to 7-OHCG is 27.99 +/- 11.73. The p.o. absolute bioavailability is 45 +/- 14% for C and 17.0 +/- 5% for 7-OHC. The pharmacokinetics of C in the rhesus monkey are similar to that in the dog. In man the p.o. absolute bioavailability is only 3.4%.

Administration, Oral↗
PubMed1988

Does diazepam really reduce the cardiotoxic effects of intravenous bupivacaine?

The effect of diazepam on the cardiovascular toxicity of bupivacaine was investigated in a rat model. Under chloral hydrate (400 mg/kg intraperitoneal) anesthesia, unilateral femoral venous and bilateral femoral arterial cannulae were placed for administration of drugs, for blood sampling, and for continuous qualitative monitoring of arterial blood pressure. Lead II ECG was continuously recorded and a tracheostomy performed to increase FIO2 by use of a "T-piece." Four groups of 24 to 36 rats each were studied. All rats received IV bupivacaine 2 mg/kg, within 10 seconds. Group I, the control group, received only bupivacaine. Groups II and III received IV diazepam 0.2 mg/kg, or diazepam vehicle in an equivalent volume, respectively. Five minutes after this pretreatment, groups II and III received IV bupivacaine 2 mg/kg. Group IV was given diazepam, 0.2 mg/kg, 30 seconds after injection of 2 mg/kg bupivacaine. A marked respiratory and metabolic acidosis occurred in all rats but was significantly worse in groups II and III. No rat in the study became hypoxemic. Serious arrhythmias (ventricular or supraventricular tachycardia) were noted in all groups, but the incidence was significantly higher in the group of rats given diazepam pretreatment than in the other three groups. It is concluded that IV diazepam 0.2 mg/kg given 5 minutes before administration of IV bupivacaine 2 mg/kg increases the incidence of serious cardiac arrhythmias. Second, this increase is not solely due to increased acidosis, because the rats receiving the vehicle (group III) developed equivalent acidosis but did not develop increased arrhythmias.

Acidosis, Respiratory↗
PubMed1987

Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects.

The absolute bioavailability of hydromorphone was investigated in eight healthy male subjects by a cross-over design (with washout period of two weeks) after intravenous (2 mg), peroral (4 mg) and rectal (3 mg) administration of hydromorphone. The use of saliva hydromorphone concentrations as a noninvasive technique in pharmacokinetic evaluation was investigated, and the clinical effects after the three routes of administration were determined. Hydromorphone has an absolute bioavailability of 51.35 +/- 29.29% and 36.33 +/- 29.60% after peroral and rectal administration, respectively. More side effects were observed after intravenous administration of hydromorphone than after rectal or peroral dosing. The saliva sampling for the hydromorphone concentration was found to be a useful noninvasive technique for the estimation of the elimination half-life of hydromorphone.

Administration, Oral↗