Physicochemical properties, in vitro release and in vivo evaluation of tramadol hydrochloride rectal suppository and rectal gel.

Background: Tramadol is a centrally acting analgesic drug. Rectal administration of tramadol is useful in the treatment of post-operative pain or malignant pain in cases where it cannot be administered orally. In Thailand, tramadol is available only as a capsule for oral use and as a solution for injection. Objective: Develop tramadol hydrochloride rectal suppositories and rectal gel preparations. Methods: Tramadol rectal suppository and rectal gel were prepared. Physicochemical properties (viscosity, gel strength, mucoadhesive force) and the in vitro release of tramadol hydrochloride were investigated from different bases (Witepsol H15, polyethylene glycol, poloxamer, and hydroxyethylcellulose). The analgesic activity of rectal tramadol hydrochloride using the hot plate test was evaluated in rats. Results: Tramadol hydrochloride rectal gel using poloxamer was more mucoadhesive to the rectal mucous membrane than was the gel with the hydroxyethylcellulose base. Tramadol hydrochloride was released rapidly in vitro from both the Witepsol H15 and polyethylene glycol bases. It was completely released from the polyethylene glycol suppository base within 15 minutes. The amount of tramadol hydrochloride release from the Witepsol H15 suppository base was about 93% at 120 minutes. When using poloxamer or hydroxyethylcellulose as a rectal base, about 90% of the tramadol hydrochloride was released from both bases within 15 minutes and completely released within 30 minutes. Administration of a tramadol hydrochloride suppository in rats exhibited a more pronounced analgesic effect with the polyethylene glycol base than with the Witepsol H15-based suppositories. The rectal gel had a less pronounced analgesic effect when made with the hydroxyethylcellulose base than with the poloxamer base. Conclusion: Tramadol hydrochloride suppositories and rectal gels with different bases showed rapid and almost complete drug release from the bases, prolonging the latency of a nociceptive response in in vivo experiments.

Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labor.

OBJECTIVE: To compare the safety and tocolytic efficacy of oral nifedipine with intravenous terbutaline for the management of threatened preterm labor. MATERIAL AND METHOD: Pregnant women between 24 and 36 completed weeks of single gestation with preterm labor were randomized to either oral nifedipine (n=20) or intravenous terbutaline (n=20) treatment. Nifedipine (immediate released capsule) 10 mg was crushed and swallowed, 10 mg every 20 minutes was allowed if necessary with a maximum 40 mg in the first hour. After that 20 mg nifedipine every 4 hours was given, up to 72 hours. Terbutaline was initially infused with the rate 10 g/min with an increment 5 microg/min every 10 minutes if required, until 25 microg/min was reached. Once the contractions had stopped for 2-6 hours, the patients were switched to subcutaneous injection with 0.25 mg terbutaline every 4 hours for 24 hours. The main safety outcome was the changes in maternal diastolic blood pressure from baseline and 1 hour after starting the treatment (deltaDBP(1hr)). Secondary outcomes were the efficacy to delay delivery > or =48 hours and 7 days, the adverse events and the birth outcomes. RESULTS: deltaDBP(1hr) was greater in the terbutaline group than that in the nifedipine group with no statistically significant difference. Hypotension (defined as BP < or = 90/60 mmHg) was found in one patient of the nifedipine group and two patients of the terbutaline group. Seventeen and 14 patients in the nifedipine group and 15 and 12 patients in the terbutaline group had delayed delivery > or =48 hours and 7 days, respectively. Mothers in the nifedipine group experienced fewer side effects than those in the terbutaline group. Maternal heart rate, at I hour after starting the treatment, increased significantly higher in the terbutaline group than in the nifedipine group. Birth outcomes were measured in all nifedipine group patients, but in only 16 of the terbutaline group patients. Six mothers in each group delivered after 37 weeks. Intraventricular hemorrhage (IVH) occurred in three babies (gestational aged 25, 29 and 37 weeks) born to mothers treated with terbutaline. In one baby, IVH related to trauma resulted from the delivery procedure. CONCLUSION: The safety and efficacy of nifedipine compares with that of terbutaline for treatment of preterm labor.

Appropriateness of therapeutic drug monitoring for lithium.

OBJECTIVE: Evaluate the appropriateness of therapeutic drug monitoring (TDM) for lithium. MATERIAL AND METHOD: A retrospective chart review of all patients who received lithium for treatment of psychiatric disorders between January 2004 and October 2005 was done. The present study was investigated in a psychiatric hospital in Thailand Based on detailed chart review, the appropriateness of TDM utilization comprised of three aspects, i.e., the indication of TDM request, the time of blood sample taking in relation to the medication process, and the clinical applications of the reported serum lithium levels, were evaluated. The Morecambe Bay Shared Care Guideline 2003 was modified and used as criteria for evaluation. Altogether 91 serum lithium samples were measured among 60 patients. RESULT: In 66 (72.5%) of requests, clear indications for lithium TDM were recorded i.e., initiation therapy 41.8%, suspected toxicity 15.4%, patient compliance assessment 5.5%, after regimen changes 5.5%, and therapeutic failure 4.4%. Routine tests without specified indications were found in the remainder (27.5%), all were in-patients, which pointed to potentially redundant use. The time of sample taking was recorded in 37 (40.6%) of blood samples, all were taken from in-patients, after steady state had been reached. These data for out-patients were not recorded, except one noted that blood sample was drawn after the patient had not received lithium for four days. Serum lithium levels were reported in 83 (91.2%) samples. Of these, 37 (44.6%) were out of therapeutic range, and only 12 required dosage alterations. The evaluation demonstrated somewhat inappropriate use of reported lithium levels. Dose changes were done in some patients who required dosage adjustment. Among 14 toxicity-suspected patients, nine actually had serum lithium levels exceeding the therapeutic range. Of these, only one patient was subsequently switched to a reduced dose, three patients were discontinued while five patients were prescribed the pre-TDM doses. Similarly, in five toxicity-suspected patients whose serum lithium levels were below therapeutic range, lithium was discontinued in three patients and no dosage alteration, which was considerably acceptable, in two patients. The doses were increased in three out offour inadequately controlled patients whose serum lithium was lower than the therapeutic range. Overall, in only 33 (36.3%) requests was TDM performed appropriately according to the indication, sampling time and subsequent dose adjustment. CONCLUSION: The findings indicate the need to improve the utilization of TDM for lithium. Education for hospital personnel on appropriateness of serum sample collection, interpretation, and proper use of serum drug levels is encouraged. Development of a request form containing essential data, such as indication for TDM, current drug dosing regimen, time of last dose, patient compliance, test results and interpretations and clinical decision made, can help optimize TDM use and reduce unnecessary costs.

Clearance of vancomycin during high-efficiency hemodialysis.

BACKGROUND: Vancomycin is commonly used for the treatment of MRSA infections in critically ill patients with renal diseases. Vancomycin is mainly eliminated through the kidney. Its excretion is therefore substantially reduced in severe renal impaired patients. Although several studies have demonstrated that significant amounts of vancomycin are removed during High-Flux/High-Efficiency Hemo Dialysis (HF/HEHD), more data are required to optimize clinical applications. OBJECTIVE: Predict the appropriate vancomycin intradialytic dosage and dosing interval among patients receiving HEHD. MATERIAL AND METHOD: Twenty patients who were receiving HEHD with cellulose triacetate dialyzer were included to determine the vancomycin intradialytic clearance. Two patients were included twice and one patient was included three times due to reinfections. This gave rise to 24 patient-times. The study was carried out at Songklanagarind Hospital between January 2003 and March 2004. RESULTS: In a prospective opened label design, each patient received 1g vancomycin, 1 hour infusion, immediately after completion of HEHD. Six scheduled blood samples were drawn as follows: (1) 60 minutes following completion of vancomycin infusion (Cmax); (2) immediately before starting the second HEHD; (3) 2 hours after starting the second HEHD; (4) immediately after completion of the second HEHD; (5) immediately before starting the third HEHD; and (6) immediately after the third HEHD ended (Cmin). The authors measured vancomycin serum levels using HPLC technique. The serum concentrations were used to calculate all relevant pharmacokinetic parameters. The pharmacokinetic parameters (mean +/- SD) were: intradialytic clearance (CLHD) 93.4 +/- 37.1 mL/min; intradialytic elimination rate constant (k) 1.1 +/- 0.5 hr(-1); overall elimination half-life (t(1/2)) 77.1 +/- 37.8 hr; volume of distribution (Vd) 82.1 +/- 40.3 L; Cmax 25.8 +/- 8.12 mg/L (range 12.04-48.80); Cmin 6.2 +/- 3.1 mg/L; and % removal during the second HEHD 37.9 +/- 12.9. Subtherapeutic levels were found in 66.7% (16/24) and 91.6% (22/24) of patients after the second and the third HEHD, respectively. CONCLUSION: HEHD with cellulose triacetate dialyzer removes significant amount of vancomycin. Based on the authors' findings, a loading dose of 1 g, and 500 mg after every subsequent HEHD is recommended.