Sixth Doses Research Articles

Irinotecan-mediated diarrhea is mainly correlated with intestinal exposure to SN-38: Critical role of gut Ugt

Background and purposeIrinotecan-induced diarrhea (IID) results from intestinal damages by its active metabolite SN-38. Alleviation of these damages has focused on lowering luminal SN-38 concentrations. However, it is unclear if the enteric bioavailability of SN-38 is mostly dependent on luminal SN-38 concentrations. Experimental approachIrinotecan (50 mg/kg, i.p. once daily for 6 days) was administered to female wildtype FVB, Mdr1a (−/−), Mrp2 (−/−) and Bcrp1 (−/−) mice for pharmacokinetic (PK), toxicokinetic (TK) and biodistribution studies. Plasma PK/TK profiles and tissues drug distribution were determined after first or sixth daily doses, along with activities of blood and gut esterases and intestinal Ugts. Caco-2 cells and bile-cannulate mice were used to further investigate intestinal and biliary disposition of irinotecan and its metabolites. Key resultsSignificant differences in IID severity were observed with the susceptible rank of Bcrp1(−/−) > wildtype FVB > Mdr1a(−/−) > Mrp2(−/−). This rank order did not correlate with biliary excretion rates of SN-38/SN-38G. Rather, the severity was best correlated (R = 0.805) with the intestinal ratio of Css SN-38/SN-38G, a measure of gut Ugt activity. On the contrary, IID was poorly correlated with plasma AUC ratio of SN-38/SN-38G (R = 0.227). Increased intestinal esterase activities due to repeated dosing and gut efflux transporter functionality are the other key factors that determine SN-38 enteric exposures. Conclusion and implicationsIntestinal SN-38 exposure is mainly affected by intestinal Ugt activities and blood esterase activities, and strongly correlated with severity of IID. Modulating intestinal SN-38 concentration and gut Ugt expression should be the focus of future studies to alleviate IID.

Pharmacokinetics and Pharmacodynamics of Extended-Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open-Label Study.

To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). Prospective, open-label, PK study. Intensive care units at a large, academic, tertiary-care medical center. Ten critically ill adults who were receiving cefepime 2g intravenously every 8hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses. Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin ), and minimum inhibitory concentration breakpoint of 8µg/ml for the pathogen (MIC8 ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT>MIC8 ), 100% fT>4×MIC8 (optimal), percentage of time fT>4×MIC8 (%fT>4×MIC8 ) at steady state, and ratio of Cmin to MIC8 (fCmin /MIC8 ). Total CRRT effluent flow rate was a mean±SD of 30.1±5.4ml/kg/hr, CRRT clearance was 39.6±9.9ml/min, and half-life was 5.3±1.7hours. Sieving coefficient or saturation coefficient were 0.83±0.13 and 0.69±0.22, respectively. First and steady-state dose Cmin were 23.4±10.1µg/ml and 45.2±14.6µg/ml, respectively. All patients achieved 100% fT>MIC8 on first and steady-state doses. First and steady-state dose 100% fT>4×MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT>4×MIC8 at steady state was 97.5%. The fCmin /MIC8 was 2.92±1.26 for the first dose and 5.65±1.83 at steady state. Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT>MIC8 in all patients and an appropriate fCmin /MIC8 for both first and steady-state doses. All but one patient achieved 100% fT>4×MIC8 at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

Response to neoadjuvant chemotherapy in breast cancer in a resource limited environment

Objective: Assess the outcome of neoadjuvant chemotherapy using Adriamycin and Cyclophosphamide followed by Paclitaxel (AC-P regime) in breast cancer.Methods: A prospective observational study of newly diagnosed breast cancer patients with palpable breast lumps on neoadjuvant chemotherapy of AC-P regime. Age of the patients, tumour size, stage, estrogen, progestogen and HER2 receptor status were noted. Tumour size measured at presentation, first, third, fifth, sixth and eighth doses to determine response as defined by the UICC method i.e. complete clinical response, partial clinical response, stable disease and progressive disease.Results: Complete clinical response was observed in 40% of 35 patients studied. Complete clinical response was found in 81.8% tumours less than 5cm in diameter while 20.8% of tumours greater 5cm.had complete clinical response. (X2 =11.6, p= 0.001) Eighty-eight percent complied with treatment schedule. Mastectomy was done in 34.2%, Breast conservation surgery (BCS) in 14.2%, and 17.1% lost to follow up.Conclusion: Neoadjuvant chemotherapy using AC-P sequential regime is effective in breast cancer with tolerable side effects and excellent treatment compliance in the study population.Keywords: Neoadjuvant chemotherapy, breast cancer, clinical response, compliance, limited resource

Rabies post-exposure prophylactic vaccination for returning travelers to Japan

BackgroundRabies post-exposure prophylaxis (PEP) in Japan is administered using 6 subcutaneous doses (on days 0, 3, 7, 14, 30, and 90), which is not in line with international recommendations of 4 or 5 intramuscular doses. For reducing dose frequency, we evaluate the immunogenicity of PEP with a regimen of 6 subcutaneous doses. MethodThis prospective single-center cross-sectional study was performed between September 2013 and December 2014. We included patients underwent rabies PEP by purified chick embryo-cultured rabies vaccine Kaketsuken (PCEC-K) at our clinic, and excluded patients with a history of pre-exposure prophylaxis or PEP using rabies immunoglobulin. The rabies virus-neutralizing antibody tests were performed at the first visit to our office (doses 1–4) and at the fifth and sixth doses. ResultsData were available for 43 of 59 enrolled patients. Thirty-two patients did not start PEP within 48 h after exposure to animals. The seroprotection rates (≥0.5 IU/mL) were 90.7% and 75.7%, at days 30 and 90, respectively. Despite receiving a fifth dose, 85.3% of the patients exhibited decreasing antibody titers during days 30–90 (p < 0.001). ConclusionsThe seroprotection rates of PCEC-K induced subcutaneously were insufficient to prevent rabies at day 30 and 90.

Safety, Tolerability, and Pharmacokinetic Characteristics ofa Novel Nonopioid Analgesic, VVZ-149 Injections in Healthy Volunteers: A First-in-Class, First-in-Human Study.

VVZ-149, a dual antagonist of GlyT2 and 5HT2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25-8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ-149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23- to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single- or multiple-dose administration of VVZ-149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies.

Postmortem redistribution of olanzapine following intramuscular administration of olanzapine pamoate in dogs

The potential for postmortem redistribution of olanzapine was investigated in beagle dogs. Olanzapine pamoate monohydrate was administered once every 14 days by intramuscular injection for 3 months to fed male dogs (n=15) at a dose of 20mg/kg olanzapine (equivalent to 46mg/kg olanzapine pamoate monohydrate). Blood samples were collected after the fifth (Day 57) and sixth (Day 71) doses to determine olanzapine and N-oxide olanzapine concentrations. On Day 71 at 72h postdose, dogs were euthanized and placed on their backs without additional manipulation and held for postmortem blood, urine, and tissue collection at room temperature for up to 168h postdose (96h after euthanasia). Concentrations of olanzapine and N-oxide olanzapine were determined by liquid chromatography–mass spectroscopy/mass spectroscopy (LC–MS/MS). Postmortem olanzapine concentrations in blood increased up to seven-fold compared to the last quantified antemortem blood concentration. Olanzapine concentrations in vein tissue samples (surrogates for peripheral blood) also increased, whereas other tissue concentrations, such as myocardium, lung, liver, and kidney decreased over the postmortem period. An increase in blood concentration of olanzapine after death was observed in all but one animal, suggesting that postmortem redistribution may occur in dogs following biweekly intramuscular administration of olanzapine pamoate monohydrate. The rise in olanzapine concentrations in blood after death in this study may potentially be attributed to diffusion from multiple tissues to blood and, to a lesser extent, reduction of the N-oxide olanzapine metabolite back to olanzapine. However, the generalizability of these results to humans cannot be confirmed by the present study.

Performance of a Divided-Load Intravenous Vancomycin Dosing Strategy for Critically Ill Patients

Current guidelines recommend vancomycin trough concentrations 15 to 20 µg/mL in complicated infections and all trough concentrations above 10 µg/mL. We assessed the performance of a novel divided-load protocol designed to attain target trough concentrations within 24 hours of initiation and prevent doses given at concentrations above the target range, in critically ill patients. The protocol was evaluated in 79 critically ill patients through retrospective medical record review. Vancomycin serum concentrations were drawn before the third dose after initiation and after any dosing change. Steady-state concentrations were drawn before the fifth or sixth doses. Vancomycin concentrations before the second dose were predicted using a nonparametric expectation maximization algorithm. Sixty-nine of 79 patients received scheduled doses, and 62 (90%) of the scheduled-dose patients attained therapeutic target concentrations 12 to 24 hours after therapy initiation. Eight scheduled-dose patients weighed > 150% of ideal body weight (IBW) and were significantly more likely to exhibit supratherapeutic trough concentrations before the fifth or sixth doses (P = .0004) compared with patients weighing ≤150% of IBW. Ten of 79 patients (8 dialysis dependent and 2 experiencing acute kidney injury) were dosed in response to measured serum drug concentrations drawn according to the divided-load protocol. All the 8 dialysis-dependent patients (100%) attained therapeutic concentrations 12 hours after therapy initiation. The divided-load vancomycin dosing strategy achieved measured trough concentrations 15 to 20 µg/mL for most critically ill patients within 24 hours of initial dosing, without allowing doses given during supratherapeutic concentrations.

Increase in efficacy of cancer radiotherapy by combination with whole-body low dose irradiation

Purpose:Design of cancer radiotherapy protocol to reduce radiation dose and increase treatment efficacy in Lewis lung cancer (LLC) model.Methods: C57BL/6J mice subcutaneously implanted with LLC were treated by conventional radiotherapy (2Gy × 6) combined with LDWBI (low dose whole-body irradiation; the second, third, fifth and sixth local doses of 2Gy each substituted by LDWBI with 0.075Gy) and/or gene therapy (intratumor injection of pEgr-IL-18-B7.1 plasmid 24 h before the first and fourth local doses). Immunologic mechanisms were explored.Results: Cancer control was most significantly improved in the group receiving local radiotherapy combined with LDWBI and gene therapy as shown by prolongation of mean survival time by 60.4%, reduction in average tumor weight by 70.8%, decrease in pulmonary metastasis by 66.9% and decrease in intratumor angiogenesis by 64.8% as compared to local radiotherapy alone (p < 0.05). These changes in tumor growth and progression were accompanied with up-regulation of host immunity manifested by stimulated NK (natural killer) and CTL (cytotoxic T lymphocyte) activity, IFN (interferon)-gamma and TNF (tumor necrosis factor)-alpha secretion, PKC (protein kinase C)-theta activation and LAMP (lysosomal associated membrane protein)-1 expression.Conclusion: Combination of conventional radiotherapy with LDWBI and gene transfer could reduce total radiation dose by 2/3 and at the same time improve treatment efficacy of cancer accompanied with up-regulated host anticancer immunity.

Effect of hyperimmunization with an Escherichia coli J5 bacterin in adult lactating dairy cows

To determine the effect of hyperimmunization with an Escherichia coli J5 bacterin on serum IgG2 concentration, incidence of clinical mastitis, and rate of survival to the end of the lactation period (ie, day 305) in adult lactating dairy cattle. Randomized controlled trial. 1,012 Holstein cows in their second lactation and greater. All cows were given 3 doses of the J5 bacterin; cows in the hyperimmunization group were given an additional 3 doses during the first 3 months of lactation. Blood was collected from a small sample of cows to determine anti-J5 IgG2 concentrations. Cows in the hyperimmunization group had higher mean serum anti-J5 IgG2 concentrations than did control cows 28 days after administration of the fourth, fifth, and sixth doses of the J5 bacterin. However, mean serum anti-J5 concentrations during the subsequent lactation were not significantly different between groups. The proportions of cows that developed clinical mastitis were not significantly different between groups. However, control cows were more likely to have severe clinical mastitis than were cows in the hyperimmunization group. The percentage of control cows that remained in the herd to day 305 was significantly lower than the percentage of cows in the hyperimmunization group that did. Results suggested that hyperimmunization of mature lactating dairy cattle was associated with increased serum anti-J5 IgG2 concentrations and decreased incidence of severe clinical mastitis, but did not alter survival rate of cows that developed severe clinical mastitis.

Study of the serological response after vaccination against tick-borne encephalitis in Sweden

The antibody response to vaccination against tick-borne encephalitis (TBE) with FSME-Immun™ Inject (Immuno AG/Baxter) was studied in 535 persons, mainly adults, attending a vaccination centre in Stockholm, Sweden. Emphasis was laid on long-term follow-up. Antibody activity was measured by three different serological test systems: a commercial ELISA kit, a hemagglutination inhibition (HI) test and a neutralization test (RFFIT). The neutralization test proved to be the most sensitive assay for the detection of the vaccine response, which was demonstrable in the majority of vaccinees (>90% after three and >98% after four and five vaccinations, respectively). ELISA and HI were less sensitive for antibody measurement during primary immunization. Neutralizing antibody activity persisted prior to the third dose in 77% of the vaccinees and prior to the fourth to sixth doses in 89–95% of the vaccinees. ELISA activity, but no neutralizing activity, was found in some individuals. Based on our data and previous experience of vaccine failures after two doses, a more condensed three-dose vaccination schedule may be advantageous and ought to be tested. The persistence of neutralizing antibodies justifies further studies of the antibody responses after the fourth dose for periods beyond the recommended 3-year booster intervals.

The pharmacokinetics and tolerability of oseltamivir suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis

Oseltamivir dose reduction is recommended for patients with end-stage renal disease (ESRD). However, dosing recommendations are not available for treatment or prophylaxis of influenza in these patients. This study assessed the pharmacokinetics and tolerability of oseltamivir in ESRD patients undergoing maintenance haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In this open-label, multiple-dose study, patients received 30 mg oral oseltamivir suspension over 6.5 weeks. This dose was predicted to be suitable for ESRD patients based on a 2-compartment model. HD patients received 9 doses given 1 h after the completion of alternate HD sessions (three times a week). CAPD patients received 6 doses given once weekly after a dialysate exchange. The primary parameters were peak plasma concentration (C(max)) and the area under the curve (AUC) for oseltamivir and oseltamivir carboxylate. In HD patients, the C(max) for oseltamivir carboxylate after single and repeated dosing were 943 and 1120 ng/ml, respectively. The mean AUC(0-42) was 31 600 ng h/ml for days 1-5 and 38 200 ng h/ml for days 38-43. Similarly, in CAPD patients, mean C(max) after the first and sixth doses were 885 and 849 ng/ml, respectively. The mean AUC(0-48) values for days 1-6 and days 36-43 were 33 400 and 32 400 ng h/ml, respectively. Oseltamivir was well-tolerated in both the patient groups. A 30 mg dose of oseltamivir given once weekly in CAPD or after alternate sessions in HD patients provides sufficient exposure to oseltamivir carboxylate to allow safe and effective anti-influenza treatment and prophylaxis.

A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer

Vascular endothelial growth factor promotes angiogenesis, an important mediator of growth and metastasis in human breast cancer. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is under investigation as an anti-angiogenic agent. This phase I/II trial evaluated the safety and efficacy of bevacizumab in patients with previously treated metastatic breast cancer. Seventy-five patients were treated with escalating doses of bevacizumab ranging from 3 mg/kg to 20 mg/kg administered intravenously every other week. Tumor response was assessed before the sixth (70 days) and 12th (154 days) doses. Safety was evaluated during every cycle. Eighteen patients were treated at 3 mg/kg, 41 at 10 mg/kg, and 16 at 20 mg/kg. Four patients discontinued study treatment because of an adverse event. Hypertension was reported as an adverse event in 17 patients (22%). The overall response rate was 9.3% (confirmed response rate, 6.7%). The median duration of confirmed response was 5.5 months (range, 2.3 to 13.7 months). At the final tumor assessment on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response. The optimal dose of bevacizumab in this trial was 10 mg/kg every other week and toxicity was acceptable. These data support the initiation of trials in metastatic breast cancer combining bevacizumab with chemotherapy.

Toxicity and Toxicokinetics of a Phosphorothioate Oligonucleotide Against the c-mycOncogene in Cynomolgus Monkeys

A 2-week toxicity and toxicokinetic study of a 15-mer phosphorothioate oligonucleotide, INX-3280, against the c-myc oncogene was performed in cynomolgus monkeys. As this oligonucleotide readily adopts an aggregate structure, a quadruplex, which may be associated with adverse physiologic effects, this study was performed using INX-3280 that had been converted to its monomeric form. Animals received intravenous (i.v.) infusions of monomeric INX-3280 three times per week for 2 weeks at doses of 3 or 15 mg/kg per administration. The monkeys were examined for clinical signs: changes in hematology, serum chemistry, coagulation, and urinalysis parameters; complement activation; macroscopic findings at necropsy; and histopathologic alterations. In addition, the toxicokinetics of INX-3280 were evaluated, using a validated HPLC assay, after the first and last (sixth) doses. No treatment-related clinical signs of any adverse effects were observed, and there were no test article-related changes in hematology, serum chemistry, or complement activation parameters. The only alteration in clinical pathology parameters was a minor (30%) prolongation of the activated partial thromboplastin time (aPTT), reflecting slight inhibition of the intrinsic coagulation pathway, which was less than that reported with other oligonucleotides given at similar doses. Treatment-related histopathologic alterations consisted of characteristic accumulation of basophilic material in the cytoplasm of tubular epithelial cells in the kidney, resident macrophages in the lymph nodes, and Kupffer cells in the liver. These changes were graded as minimal in all cases. The basophilic material is believed to reflect accumulation of the oligonucleotide or metabolites or both. The pharmacokinetic parameters of INX-3280 were identical on the first and sixth administrations and were similar to those reported for other phosphorothioate oligonucleotides. Maximum concentration (Cmax) values for INX-3280 (101-119 microg/ml) were in excess of the threshold plasma concentrations reported to trigger complement activation by phosphorothioate oligonucleotides. It is concluded that the safety profile of monomeric INX-3280 in cynomolgus monkeys is quite favorable relative to the known effects of other phosphorothioate oligonucleotides, particularly with respect to the blood level-related toxicities of this class of compounds, including complement activation and inhibition of coagulation. This study found no toxicities that were expected to be clinically significant.

Initial report on intraves1cal administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder

Objectives This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. Methods Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. Results Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. Conclusions AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

Experience with vecuronium during long-lasting surgery.

Our knowledge of the possible cumulative properties of vecuronium is limited. Previous studies have shown a tendency towards an increased duration of effect, a slightly prolonged recovery time, as well as an increased variation in duration of effect. We have studied 15 patients scheduled for middle-ear surgery. During i.v. N2O-O2 anaesthesia the twitch response of the adductor pollicis muscle was recorded after supramaximal stimulation of the ulnar nerve at the wrist. Prior to tracheal intubation a bolus dose of vecuronium was given (0.08 mg/kg body weight). During surgery supplementary doses of 0.02 mg/kg body weight were given at a train-of-four (TOF) ratio of 0.25. The duration of effect (DUR-IT-25) and recovery time from a TOF ratio of 0.10 to 0.25 (Recovery-IT-10-25) were recorded. When comparing 10 iteration doses, the mean DUR-IT-25 in the 15 patients studied showed only minor variations (n.s.). Each patient had a near constant interval between the iteration doses; however, a noteworthy variation between individuals was found. Recovery-IT-10-25 was 250 +/- 80 (mean +/- s.d.) 240 +/- 80 and 260 +/- 80 s comparing the second, sixth and tenth iteration doses, respectively. In conclusion, the duration of effect varied considerably between patients. Each patient showed, however, a near constant iteration interval and a recovery time with only small variations. This indicates that cumulation is unlikely to exist following repetitive administration of vecuronium of 0.02 mg/kg body weight.

A Pharmacokinetic Explanation for Increasing Recovery Time Following Larger or Repeated Doses of Nondepolarizing Muscle Relaxants

The authors used pharmacokinetic and pharmacodynamic modeling to explain the time course of neuromuscular blockade following single or multiple doses of three nondepolarizing muscle relaxants. Published and unpublished pharmacokinetic and pharmacodynamic data for 13 normal subjects were used to simulate the duration of neuromuscular blockade (time from administration of the muscle relaxant to 25% recovery of control twitch tension) following six successive doses of atracurium (150-400 micrograms/kg initially, followed by 100 micrograms/kg), vecuronium, or pancuronium (30-80 micrograms/kg initially, followed by 20 micrograms/kg). With atracurium, duration of action was similar for the second and sixth doses, regardless of the initial dose. With vecuronium (initial doses of 30-80 micrograms/kg) and pancuronium (initial doses of 30-60 micrograms/kg), duration of action was longer after the sixth dose than after the second; with larger initial doses of pancuronium (70 and 80 micrograms/kg), duration of action was similar following the second and sixth doses. The authors also determined two recovery times (time for twitch tension to recover from 5-25% and from 25-75% of control value) for varying single doses of atracurium, vecuronium, or pancuronium. When the dose of atracurium was increased from 200 to 400 micrograms/kg, neither recovery time increased. When the dose of vecuronium was increased from 40 to 80 micrograms/kg, 5-25% recovery time increased from 6.0 +/- 2.5 min to 8.8 +/- 4.0 min (mean +/- SD) and 25-75% recovery time increased from 8.7 +/- 4.3 min to 12.6 +/- 4.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)