The absolute bioavailability of clodronate from two different oral doses.

Clodronate (disodium clodronate tetrahydrate) is a bisphosphonate used in the treatment of hypercalcemia and osteolysis due to malignancy. Like all bisphosphonates, clodronate has low and variable oral bioavailability. The purpose of this study was to examine the absolute bioavailability of clodronate from two different oral doses. Thirty-one healthy young volunteers participated in this open, randomized, three-period, single-dose, cross-over study. The absolute bioavailability was calculated from the area under the serum clodronate-time curve in 48 h (AUC(0-48 h)) after administration of 800 or 1600 mg (Bonefos 400 mg capsules) of oral clodronate, or 30 mg (Bonefos 60 mg/mL infusion concentrate) of intravenous clodronate. The maximum concentration of clodronate in serum (C(max)), the time to maximum concentration (t(max)), the elimination half-life (t(1/2)), and the cumulative amount of clodronate excreted into urine in 48 h (Ae(0-48 h)) were also determined. The geometric mean of the absolute bioavailability of 800 mg of clodronate was 1.9% and that of 1600 mg 2.1%. The difference in the absolute bioavailability of these two doses was statistically nonsignificant. All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study.

Timing of food intake has a marked effect on the bioavailability of clodronate.

Because of the low and variable bioavailability of bisphosphonates and the huge effect of food on their gastrointestinal absorption, it is of utmost importance to know the optimal timing of drug intake in relation to food intake. We investigated the effect of time on the bioavailability of clodronate when the drug was administered 2, 1, or 0.5 h before breakfast, with breakfast, or 2 h after breakfast (in the middle of a 4-h fast). The study was conducted as a single-center, open, balanced, randomized, crossover pharmacokinetic study in 31 healthy subjects aged 21 to 34 years. The volunteers participated in five different sessions with 800 mg of oral clodronate, and these sessions were separated by washout phases, each for at least 1 week. The primary pharmacokinetic variables were the area under the serum concentration time curve in 24 h (AUC(0-24)) for clodronate and the maximal concentration of clodronate in serum (C(max)). Clodronate was absorbed rather similarly when taken in the morning on an empty stomach 2, 1, or 0.5 h before breakfast, but because the best absorption occurred (as expected) when the drug was taken 2 h before breakfast, this scheme served as the reference treatment. As evaluated by area under the serum concentration time curves, the dose-breakfast interval of 1 h scarcely reduced absorption from the reference treatment level (relative absorption 91%, p = 1.0). Compared with the reference treatment, clodronate was absorbed with 69% efficacy (p = 0.65) when breakfast followed only 0.5 h later. The dose-breakfast intervals of 0.5 and 1 h did not differ significantly from each other (p = 0.85). Absorption was, however, only 34% (p < 0.0001) of the optimum when the drug was taken 2 h after breakfast, and only 10% of optimal when clodronate was taken with breakfast (p < 0.0001). In conclusion, it can be recommended to take Bonefos capsules in the morning on an empty stomach at least 0.5 h before breakfast.

Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers.

BACKGROUND: Quercetin is a flavonoid with a wide range of biological activities. It mainly occurs in plants as glycosides, such as rutin (quercetin rutinoside) in tea. Quercetin and rutin are used in many countries as vasoprotectants and are ingredients of numerous multivitamin preparations and herbal remedies. OBJECTIVES: The primary objective was to characterise and compare the absorption and the pharmacokinetics of quercetin from quercetin aglycone and rutin. A secondary objective was to investigate which forms of quercetin are present in plasma. METHODS: In this double blind, diet-controlled, two-period cross-over study, 16 healthy volunteers received three different doses of quercetin and rutin orally. The doses corresponded to 8 mg, 20 mg and 50 mg quercetin aglycone. Blood samples were obtained between 0 h and 32 h post-dose. RESULTS: The overall kinetic behaviour of quercetin differed remarkably after ingestion of quercetin aglycone or rutin. The mean area under the plasma concentration-time curve from 0 h to 32 h [AUC(0-32)] and maximum plasma concentration (Cmax) values of the two treatments were similar. However, time to reach Cmax (tmax) was significantly shorter after the quercetin aglycone treatment than after the rutin treatment (1.9, 2.7 and 4.8 versus 6.5, 7.4 and 7.5 h, for doses 1, 2 and 3, respectively). Also, the absorption of quercetin from quercetin aglycone was predictable and inter-individual variation was small. In contrast, after ingestion of rutin, inter-individual variations in AUC(0-32) and Cmax values were considerable and seemed to be associated with gender and use of oral contraceptives. Quercetin and rutin were found in plasma as glucuronides and/or sulfates of quercetin and as unconjugated quercetin aglycone, but no rutin was detected. CONCLUSIONS: In clinical trials, studying the effects of quercetin from rutin, bioavailability must be taken into consideration and plasma quercetin concentrations monitored. Whether our results apply to other glycosidic drugs as well, especially other rutosides, should be investigated.

I.v. diclofenac and ketorolac for pain after thoracoscopic surgery.

We studied intensity of pain, cumulative morphine consumption, ventilatory and renal function, and haemostasis in patients undergoing video-assisted thoracoscopic surgery and receiving a 2-day i.v. infusion of diclofenac, ketorolac or saline. Plasma concentrations of the two NSAID were also measured. The study was randomized, double-blind and placebo-controlled, with 10 patients in each group. Patients experienced mainly moderate pain. Mean consumption of i.v. morphine during the first day after operation was 57 (SEM 11) mg in the placebo group. Diclofenac and ketorolac were equally effective in reducing total morphine consumption (61% and 52%, respectively). Adverse events were similar and minor. Greater variability in plasma concentrations of ketorolac were detected compared with diclofenac.

Chronic pain after thoracic surgery: a follow-up study.

BACKGROUND: The incidence of long-term post-thoracotomy pain is reported to be up to 67%. A relationship between the severity of acute postoperative pain and the development of chronic post-thoracotomy pain has been suggested. METHODS: Patients scheduled for elective thoracotomy were interviewed before and one week after surgery to find out if they had pain before surgery and how much pain they experienced postoperatively. The amount of analgesics the patients were given were registered during the first 5 postoperative days. The patients were interviewed by letter 3, 6 and 12 months after surgery to find out if they still had pain due to surgery and to what extent this pain interfered with their daily activities. RESULTS: One hundred and ten patients entered the study. Information about the complete study period was obtained from 67 patients. The incidence of chronic post-thoracotomy pain was 80% at 3 months, 75% at 6 months and 61% one year after surgery. The incidence of severe pain was 3-5%. Chronic post-thoracotomy pain interfered with the patient's normal daily life in more than half of the patients. High consumption of analgesics during the first postoperative week was associated with a higher risk of chronic post-thoracotomy pain. CONCLUSION: A significant proportion of patients undergoing thoracotomies will suffer from chronic pain. Surgeons and anaesthetists should be aware of this fact and they should look for effective means of preventing and treating this pain syndrome.

Intrathecal morphine for post-sternotomy pain in patients with myasthenia gravis: effects on respiratory function.

BACKGROUND: Thymectomy can induce a remission or at least an improvement in myasthenia gravis (MG) patients. After sternotomy MG patients with compromised muscle strength need an excellent postoperative pain relief. This study was designed to evaluate the efficacy of intrathecal morphine (ITM) on ventilatory function among MG patients undergoing trans-sternal thymectomy, when intravenous morphine served as control. METHODS: Twenty consecutive MG patients were randomised to receive either morphine (10 micrograms/kg) intrathecally at induction or intravenous morphine (30 micrograms/kg) with a patient-controlled analgesia (PCA) device. Anaesthesia was standardised. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), respiratory rate, oxygen saturation, arterial blood gases, pain intensity and morphine consumption were assessed during 48 hours. RESULTS: The mean age of the patients was 35 +/- 3.4 years and the mean duration of the disease 1.9 +/- 0.5 years. According to Osserman's classification 70% of the patients belonged to Class IIA and 30% to Class IIB. ITM restored ventilatory function significantly better than iv PCA morphine. FVC recovered to 60% and FEV1 to 57% of the baseline values in the ITM group compared with 32% (P < 0.05) and 37% in the PCA morphine group, respectively. Postpuncture headache occurred in 4/10 patients. CONCLUSION: Intrathecal morphine provided effective postoperative analgesia and significantly improved ventilatory function when compared with intravenous morphine.

Extradural, paravertebral and intercostal nerve blocks for post-thoracotomy pain.

Forty-five patients were allocated randomly to receive either a single intrathoracic block of four intercostal nerves, a continuous thoracic extradural infusion or a continuous paravertebral infusion of bupivacaine. Patients were allowed additional i.v. boluses of morphine via a PCA device. Segmental spread of pinprick analgesia was comparable in the groups for up to 20 h. Up to 2 h after the block, plasma concentrations of bupivacaine were greater in the intercostal group and there was large interindividual variation. There were no significant differences between the groups in pain, morphine consumption, respiratory function or adverse events. Moderate to severe respiratory depression was detected in 14 patients more than 2 h after operation.

IV diclofenac in post-thoracotomy pain.

We have studied the efficacy of a continuous i.v. infusion of diclofenac 2 mg kg-1/24 h given for 2 days after major thoracic surgery in 30 patients in a double-blind, placebo-controlled, parallel-group design. The patients were able to obtain additional pain relief as on demand morphine boluses. In the diclofenac group, the consumption of morphine was reduced by 60% during the first and by 76% during the second day after operation compared with the control group. Overall, analgesia was also superior in the diclofenac group. Arterial oxygenation was significantly greater and the arterial PCO2 increased less during the first day after operation in the diclofenac group compared with the control group. Diclofenac had no significant effect compared with placebo on blood loss or on any bleeding or platelet test. Urine output was significantly less during the first day after operation in the diclofenac group compared with the control group, but was normal on the second day after operation; plasma creatinine concentrations were unchanged. I.v. diclofenac infusion combined with opioids delivered via a patient-controlled analgesia device seems a valuable method of pain relief after thoracic surgery in patients in whom more invasive techniques, such as extradural local anaesthetics and opioids, cannot be used. However, non-steroidal anti-inflammatory drugs should be used cautiously, if at all, in patients who are at risk of acute renal failure.

Pain after thoracic surgery.

In order to evaluate postoperative pain treatment following thoracic surgery, 214 medical records of patients who were operated during 1986-1988 were examined. Nurses' comments concerning pain and the amounts of analgesics given during the 2 postoperative days were recorded. The 150 patients who were still alive in December 1989 were sent a postal questionnaire which asked about the pain and the efficacy of pain relief they had received after their operation. They were also asked if they still had pain which they connected to the thoracotomy and if any attempts had been made to treat that pain. The mean consumption of intramuscular oxycodone was 38 mg during the 1st and 33 mg during the 2nd postoperative day. The administration of nonsteroidal anti-inflammatory drugs significantly reduced the opioid consumption on the second but not on the first postoperative day. In 30% of the patients' charts there were no remarks on pain, in 10% there was a mention of no pain, in 40% pain was mentioned and in 20% the patient was reported to have severe pain. During the first postoperative week little pain was experienced by 60% of the patients, considerable pain by 35% and excruciating pain by 5% of the patients being interviewed. The postoperative pain relief was rated as good in 60% of the answers, satisfactory in 38% and poor in 2%. Persistent post-thoracotomy pain lasting for more than 6 months was reported by 44% of the patients, of whom 66% had received treatment for the pain.