Guidelines for the use of cannabinoid compounds in chronic pain.

OBJECTIVE: To provide clinicians with guidelines for the use of cannabinoid compounds in the treatment of chronic pain. METHODS: Publications indexed from 1990 to 2005 in the National Library of Medicine Index Medicus were searched through PubMed. A consensus concerning these guidelines was achieved by the authors through review and discussion. RESULTS: There are few clinical trials, case reports or case series concerning the use of cannabinoid compounds in the treatment of chronic pain. There are no randomized clinical trials examining the use of herbal cannabis in the treatment of chronic pain. CONCLUSIONS: A practical approach to the treatment of chronic pain with cannabinoid compounds is presented. Specific suggestions about the off-label dosing of nabilone (Cesamet, Valeant Canada limitee/Limited) and dronabinol (Marinol, Solvay Pharma Inc, Canada) in the treatment of chronic pain are provided.

Typical variability in drug dissolution testing: study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product.

To evaluate variability in drug dissolution testing 28 laboratories analyzed USP calibrators, US FDA prednisone tablets and a marketed glibenclamide tablet product. The experiments were conducted using paddle and basket methods at 50 (calibrators) and 75 (glibenclamide) rpm. The media employed were deaerated by equilibrating at 37 degrees C for 24 h and by the USP recommended method. The 95% CI values for percent drug release for the USP calibrator tablets were similar to the reported tolerances for the USP Acceptance Ranges; however, individual results from 15 of 28 laboratories suggest that the apparatus would not comply with the USP Apparatus Suitability Criteria. For FDA prednisone calibrator tablets, percent drug release using equilibrated medium was different (P=0.003) than by the USP recommended method. For the glibenclamide tablet results, a CV of 14-37% was observed, depending upon the sampling time and the type of apparatus employed. The results indicate that failure to meet the USP Dissolution Apparatus Suitability Test may not truly mean that the apparatus is 'out of compliance'. Due to the high variability in dissolution testing, in many cases the impact of formulation or manufacturing changes on drug release characteristics may not be observed, in particular with multi-point profiles.

Assessment of pharmaceutical quality of furosemide tablets from multinational markets.

This report describes results of a collaborative study in which samples of the 40-mg strength of furosemide tablets were evaluated following a common protocol based on British (BP), European (Ph. Eur.), and US Pharmacopoeial (USP) specifications. Several tests, including identification, uniformity of mass, and dissolution, were performed. In total, excluding Lasix lots, results for 162 lots obtained from 115 manufacturers or suppliers were submitted. Also, 23 laboratories identified and submitted data for 34 lots of Lasix products available in their countries. There were no reported abnormalities in the physical test requirements of the products analyzed. The summaries (n, mean, and 95% CI) of the assay results for the "standard sample" (a common sample), Lasix lots from participating countries, and for all other furosemide products, respectively, are as follows: 30, 99.8%, 96-104; 33, 100.0%, 94-106; and 162, 99.6, 94-105. About half (approximately 62%) of the reported uniformity of mass results based on tablet weights were in the range 150-175 mg/tablet. However, there appears to be notable variability in tablet weights that would result in significant differences in the ratios (0.14 to 0.40) of active ingredient to excipient. The reported disintegration times ranged from 0 (instantaneous) to 18 min, with most less than 1 min. The drug dissolution testing was conducted with phosphate buffer at pH 5.8 (USP recommended). Another test was conducted with acetate buffer at pH 4.6 (noncompendial). There appears to be remarkable similarity in overall percentage of drug release from the three types of products (standard sample, Lasix lots, and other products). Although apparently there is a very wide spread in dissolution characteristics of the products tested, the analyses of variance did not detect differences among the products tested and, to this extent, would not indicate differences in bioavailability characteristics for most of these products. It is observed that about 20-38% of the variability in dissolution testing is not product related (i.e., it is from the dissolution testing itself), while the remaining 62-80% variability is product related (manufacturing, formulation, etc). The results of this multinational collaborative study showed that most of the furosemide products available in different countries met the required pharmaceutical quality standards, including drug-release characteristics. Based on an extensive statistical analysis, the main concern from the study was that the high variability in drug dissolution testing would require wide tolerance standards (e.g., pharmacopoeial standards). This may result in lack of needed discriminating ability of the test in revealing the impacts of formulation and manufacturing changes on in vitro, and perhaps in vivo, drug-release characteristics.

Quantification of ketoprofen enantiomers in human plasma based on solid-phase extraction and enantioselective column chromatography.

An HPLC method for the quantification of ketoprofen enantiomers in human plasma is described. Following extraction with a disposable C18 solid-phase extraction column, separation of ketoprofen enantiomers and I.S. (3,4-dimethoxy benzoic acid) was achieved using a chiral column [Chirex 3005; (R)-1-naphthylglycine 3,5-dinitrobenzoic acid] with the mobile phase, 0.02 M ammonium acetate in methanol, set at a flow-rate of 1.2 ml/min. Baseline separation of ketoprofen enantiomers and I.S., free from interferences, was achieved in less than 20 min. The calibration curves (n = 14) were linear over the concentration range of 0.16 to 5.00 micrograms/ml per enantiomer [mean r2 of 0.999 for both enantiomers, root mean square error were 0.015 for R(-) and 0.013 for S(+)]. The inter-day coefficient of variation for duplicate analysis of spiked samples was less than 7% and the accuracy was more than 93% over the over the concentration range of 0.2 to 4.0 micrograms/ml for individual enantiomer using 1 ml of plasma sample. This method has been applied to a pharmacokinetic study from healthy human volunteers following the administration of a ketoprofen extended release product (200 mg). This method is simple, fast and should find wide application in monitoring pharmacokinetic studies of ketoprofen.

Logarithmic transformation in bioequivalence: application with two formulations of perphenazine.

The rationale for using the logarithmic transformation on concentration-dependent pharmacokinetic parameters a priori is presented. This rationale is based on theoretical pharmacokinetic and statistical grounds, but is also applicable to the practice of physicians in dealing with variations of drug treatment within and between patients. The implications of the transformation on data analysis, specifically analysis of variance, and estimation and inference from the analysis as it pertains to bioequivalence decisions are explored. Implementation of the transformation is shown, with an example of two perphenazine formulations in a single-dose crossover study. It is concluded that the transformation has to be accepted on theoretical grounds because sample sizes are too small in bioequivalence studies and too susceptible to extreme values to state with any certainty the actual distribution of pharmacokinetic parameters or their differences within a subject.

Lithium-induced nephrotoxicity in rats following subcutaneous multiple injections and infusion using mini-osmotic pumps.

The nephrotoxicity of the anti-manic-depressive drug lithium (Li) is well recognized but the effects of fluctuation in plasma levels from different Li dosage regimens are not. Experiments were done to compare the nephrotoxicity of Li in rats treated either with subcutaneous multiple injections (SMI) or by infusion using mini-osmotic pumps (MOP) vs concurrent controls. A dose of 2 meq/kg/day of LiCl dissolved in saline was given for 8 consecutive days. During treatment, the animals were kept in individual metabolism cages and their plasma Li levels, water intake, urine volume, pH, and osmolality were monitored daily. In the SMI group, average daily plasma Li levels, 30 min post-injection and just prior to the next injection, were 2.6 and 0.34 meq/liter, respectively. The daily mean plasma Li level in the MOP group was 0.39 meq/liter. While both Li treatment groups showed evidence of toxicity not seen in the respective controls, overall differences in the nephrotoxic response between the Li regimens emerged on Days 6 to 8. Thus water consumption and urine volume were both raised with SMI and by Day 8 the urine osmolality was reduced (all p less than 0.05). The results indicate that after administering equivalent amounts of Li, SMI treatment produced a higher degree of nephrotoxicity than the MOP treatment.

Pharmacokinetics of single and chronic dose zidovudine in two HIV positive patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

The effect of continuous ambulatory peritoneal dialysis (CAPD) on zidovudine (ZDV) elimination was studied in two HIV-positive men. Serum and dialysate samples were collected after a single oral dose of 200 mg (patient 1) or 100 mg (patient 2) of ZDV, and again on at least one occasion during chronic therapy (100 mg every 8 h). Concentrations of ZDV and its glucuronide metabolite (GZDV) were measured by radioimmunoassay. ZDV serum half-lives on day 1 were 7.9 h (patient 1) and 2.6 h (patient 2). The apparent GZDV half-lives on day 1 were 19.9 h (patient 1) and 7.1 h (patient 2), with resultant accumulation of metabolite (up to 36 micrograms/ml) during chronic therapy. At 14 h following single dose, 8.2 +/- 0.4% of dose was recovered in dialysate as GZDV; ZDV accounted for less than 0.6% of dose recovered in dialysate after both single and multiple dose. After the initial dwell (tau) following single dose, peritoneal clearances of ZDV were 4.3 ml/min (tau = 4 h, patient 1) and 5.9 ml/min (tau = 5 h, patient 2), and GZDV clearances were 6.7 and 5.1 ml/min, respectively. ZDV serum protein binding was less than 10%. The small amount of unchanged ZDV removed by CAPD suggests that no supplemental doses are needed in HIV patients undergoing CAPD.

Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report.

This is a summary report of the conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies. The conference was held from December 3 to 5, 1990 in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, US Food and Drug Administration, Federation International Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. The report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: 1. To reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; 2. To determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; 3. To develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic, bioavailability and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselective determinations, were also deliberated.

Stability of diltiazem and its metabolites in plasma during storage.

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and related heart diseases. It is extensively metabolized into a host of metabolites, some of which have potent pharmacological activities. Previous work has shown that DTZ and its major metabolite N-desmethyl-DTZ (MA) were unstable and readily decomposed to deacetyl-DTZ (M1) and deacetyl N-desmethyl-DTZ (M2), respectively. This report describes the stability of DTZ and its metabolites in plasma samples stored at -20 and -70 degrees C for different periods up to 12 weeks. The results indicate that in those samples obtained from volunteers who received DTZ, no deterioration of DTZ or MA occurred up to 8 weeks, but considerable deterioration of DTZ to M1 and MA to M2 (p less than 0.01) occurred after 12 weeks. However, in samples prepared by adding DTZ and its metabolites to outdated plasma (spiked plasma), deterioration of DTZ occurred after 4-6 weeks of storage, but there were no concomitant increases in concentrations of M1 or M2. Thus, it appears that decomposition of DTZ and MA was affected by the nature of the plasma materials, but the reason for the differences in analyte stability observed between volunteers' and spiked plasma is not known. Also, it appeared that DTZ and its metabolites in plasma samples stored at -70 degrees C may be more stable than those at -20 degrees C, although further studies are required to substantiate this observation. On the basis of these results, plasma samples obtained from patients or volunteers receiving DTZ should be analyzed within 8 weeks when the samples are stored frozen at -20 degrees C.

A dose-response study of nalbuphine for post-thoracotomy epidural analgesia.

The analgesic efficacy and side-effects of epidural nalbuphine (0.075-0.3 mg.kg-1) were compared with epidural morphine 0.1 mg.kg-1 in a randomised double-blind study in post-thoracotomy patients. The drugs were administered via a lumbar epidural catheter one hour before the end of surgery. Efficacy was assessed using visual analogue pain scores and supplementary iv fentanyl requirements; respiratory function was studied with an inductive plethysmograph and arterial blood gas analysis; and plasma nalbuphine levels were measured. Pain scores and fentanyl supplementation were lowest in the morphine group (P less than 0.01). No dose-response effect was apparent in the nalbuphine dose-range studied. Respiratory depression was more common in patients receiving morphine (higher mean PaCO2P less than 0.01, more frequent apnoeas greater than 15 sec P less than 0.05, and incidence of PaCO2 greater than 50 mmHg requiring naloxone P less than 0.01). There were no differences in haemodynamic variables, sedation, or other side-effects among the groups. The pharmacokinetic profile of epidural nalbuphine was similar to that seen with rapid iv injection. The results indicate that, relative to morphine, lumbar epidural nalbuphine is an ineffective analgesic after thoracotomy. Despite the lower incidence of respiratory depression its administration by this route cannot be recommended.

Monitoring of blood levels of cyclosporine in renal and cardiac transplant recipients--comparison of HPLC to Incstar CYCLO-Trac SP RIA.

Cyclosporine in whole blood samples from renal and cardiac transplant recipients was measured by high-performance liquid chromatography (HPLC) and by CYCLO-Trac SP specific radioimmunoassay (RIA). The fresh samples assayed by RIA were remeasured in a second laboratory after storage at -20 degrees C for two to six months and good interlaboratory agreement was obtained on the 59 samples assayed (y = 0.926x + 14.8 micrograms/L, r = 0.982). The calibration curve for RIA was not influenced by fresh whole blood, hemolyzed whole blood or serum matrix from normal volunteers. However, comparison of the RIA results from patient samples with those from an HPLC procedure showed that RIA values averaged about double those measured by HPLC. The difference is attributable to differences between the blood matrix of transplant and nontransplant subjects, rather than exclusively to the apparent nonspecific nature of the antibody.

Isolation of cross-reacting compounds to Incstar Cyclo-Trac SP RIA in blood samples obtained from cardiac allograft patients on cyclosporine therapy.

To examine the specificity of the Incstar Cyclo-Trac SP RIA kit, individual blood samples from 28 cardiac allograft patients on cyclosporine A (CsA) therapy were extracted and chromatographed by HPLC. Initially, eluates from a pool of the above samples were collected at regular intervals and measured by RIA to locate possible cross-reacting compounds. Unknown cross-reacting materials were detected in a fraction (UNK) that was collected before elution of CsA. For each patient's sample, fraction UNK and the fraction containing CsA were then collected and measured by RIA. In 9 of 28 samples, cross-reactivity was detected in fraction UNK; range 11 to 36%, mean 22 +/- 7.5%. Cross-reactivity was not apparent in fraction UNK of CsA-free blood samples from normal volunteers.

Harmonization of bioavailability and bioequivalence requirements.

Requirements for bioavailability (BA) and bioequivalence (BE) of drug products have evolved in different jurisdictions according to precedents established within the framework of existing laws. Thus, while the scientific principles behind the regulation and guidelines are common, it is often difficult for countries to agree on specific standards. This presentation examines some of the similarities and differences between European Community (EC) and North American requirements and indicates areas in which consensus may be achieved as well as those issues which may be more challenging.