Synthesis utilizing insoluble polymers: new reactions and small molecules.

It can be argued that solid-phase organic chemistry is the preferred method of preparing screening libraries for lead compound discovery and lead optimization within the pharmaceutical industry. Solid-phase peptide chemistry is the most reliable and general of the synthetic methods available today; however, the purities of products are inadequate for the needs of the current market and the screening departments of pharmaceutical companies. Recent synthetic advances in solid-phase organic chemistry have started to increase the range of chemistry that can be used to prepare 'drug-like' small molecules in library format.

Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

The value of shoulder distension arthrography with intraarticular injection of steroid and local anaesthetic: a follow-up study.

A series of 51 patients, seen in Leicester, with "frozen shoulder", and referred for arthrographic examination, were assessed both before and after distension arthrography, using air and a low-osmolar contrast media combined with a steroid and local anaesthetic injection. 38 attended for further assessment at up to 6 months later. 16 patients were found to have a rotator cuff tear. There was no significant change in the mean range of active movement in the patients with rotator cuff tears, but symptomatic improvement ensued in 44% of cases. In those found to have no rotator cuff tear, and external rotation of less than 35 degrees, a significant improvement in range of movement was seen. While those with less limitation of external rotation showed no change in their range of movement, they did experience symptomatic improvement in 73% of cases. We conclude that shoulder distension arthrography, with steroid and local anaesthetic injection, may be of symptomatic benefit in patients with frozen shoulder and without a rotator cuff tear, while only those with external rotation of less than 35 degrees are likely to improve their range of motion.

The aetiology of solitary hot spots in the ribs on planar bone scans.

The aim of this study was to determine the aetiology of solitary hot spots in the ribs found at bone scintigraphy in patients with known extraskeletal malignancy. A group of 34 patients whose bone scans showed a solitary hot spot in a rib were identified retrospectively over a 4-year period. They all had a known extraskeletal malignancy. Aetiology of the rib hot spot was established in 26 patients based on a review of clinical features, radiographic findings and clinical follow-up. In eight cases it remained indeterminate. In 14 (41%) cases, the rib lesion was malignant in origin, 9 were due to metastasis and 5 due to direct spread from intrapulmonary malignancy. In 12 (35%) cases, it was benign. In the remaining 8 (24%) cases, the aetiology was indeterminate. In the subgroup of 14 hot spots confined to the anterior rib end, 5 (36%) were due to malignancy, 4 (28%) were benign and 5 (36%) were indeterminate. We conclude that solitary hot spots in the ribs of patients with known extraskeletal malignancy undergoing bone scintigraphy are frequently (41%) malignant in origin. This also applies when the hot spot is in the anterior rib end (36% malignant). Thus, such hot spots are far more sinister than previously reported and require careful clinical and radiographic evaluation.

Low and minimal flow inhalational anaesthesia.

PURPOSE: To describe the pharmacokinetic behaviour and practical aspects of low (0.5-1 l.min-1) and minimal (0.25-0.5 l.min-1) flow anaesthesia. METHODS: A Medline search located articles on low flow anaesthesia, and computer simulated anaesthetic uptake models are used. PRINCIPAL FINDINGS: Most, 85-90%, of anaesthetists use high fresh gas flow rates during inhalational anaesthesia. Low/minimal flow anaesthesia with a circle circuit may avoid the need for in-circuit humidifiers, raise the temperature of inspired gases by up to 6 degrees C, reduce cost by about 25% by reduction of fresh gas flows to 1.5 l.min-1, and reduce environmental pollution with scavenged gas. Knowledge of volatile anaesthetic pharmacokinetic behaviour facilitates the use of minimal/low flow rates. Small amounts of nitrogen or minute amounts of methane, acetone, carbon monoxide, and inert gases in the circuit are of no concern, but the degradation of desflurane (to carbon monoxide by dry absorbent) and sevoflurane (to compound A by using a fresh gas flow of > 2 l.min-1) must be avoided. With modern gas monitoring technology, safety should be no more of a concern than with high flow techniques. CONCLUSION: The use of fresh gas flow rates of < 1 l.min-1 for maintenance of anaesthesia has many advantages, and should be encouraged for inhalational anaesthesia with most modern volatile anaesthetics.

Continuous spinal anesthesia: the Canadian perspective.

BACKGROUND AND OBJECTIVES: Until the arrival of microcatheters, continuous spinal anesthesia was mainly restricted to elderly and high-risk patients. The introduction of microcatheters enabled the technique to be used in a wider range of patients. This paper describes the experiences of anesthetists in Canada with these catheters, and the changes in their practice since their withdrawal. METHODS: Anesthetists (those known to have experience with continuous spinal anesthesia, or to be regional anesthesia enthusiasts) across Canada were surveyed by telephone or mail. RESULTS: Of a total of 36 respondents, 25 had tried continuous spinal anesthesia with microcatheters. The majority had experience of only a few cases but a few reported larger series of hundreds of cases, Numerous technical difficulties with catheter insertion occurred, and problems with catheter breakage and neurologic deficit were reported. Some of these problems were reported to the Health Protection Branch, and, as a result of these reports and problems experienced in the United States, microcatheters were recalled in Canada soon after the FDA safety alert in the United States. CONCLUSIONS: Various techniques are being used instead of continuous spinal anesthesia with microcatheters, and only a few anesthetists favored their return.

Two cases of untoward sequelae associated with thiopentone.

Two cases of adverse sequelae associated with the use of 2.5% thiopentone are reported: one involved extensive local venous thrombosis at the site of the injection causing great distress to the patient; the other involved a histaminoid reaction in a patient who, like others who have been reported with this type of reaction, had a history of allergy.

Side effects of doxapram infusion.

Four cases are reported where patients reacted with severe restlessness, violence or hallucinations at low doses of doxapram infusion. A possible association with hepatic dysfunction is discussed. These reactions persisted long after the cessation of doxapram infusion and the various treatments used are described.

Reversal of epidural morphine-induced respiratory depression and pruritus with nalbuphine.

The effect of nalbuphine on the respiratory depression, pruritus and analgesia induced by epidural morphine was determined in a randomized, prospective, double-blind, placebo-controlled fashion. Twenty ASA physical status I women received 0.1 mg.kg-1 epidural morphine at induction of general anaesthesia for elective total abdominal hysterectomy. Group 1 (n = 14) received 0.3 mg.kg-1 nalbuphine intravenously six hours after the epidural morphine administration. Group 2 (n = 6) received saline. Prior to agent administration, six patients from the nalbuphine group and four patients from the saline group had respiratory depression indicated by a PaCO2 greater than 45 mmHg. After nalbuphine administration the PaCO2 (mean +/- SE) decreased from 49.5 +/- 1.2 mmHg to 42.5 +/- 0.7 mmHg (p less than 0.005) while there was no significant change after saline administration. Nine of the 14 patients receiving nalbuphine appeared to become more sedated, despite an improvement in ventilation. Pruritus was antagonized by 0.1 mg.kg-1 nalbuphine (p less than 0.006). There was no reversal of analgesia after administration of 0.3 mg.kg-1 nalbuphine.

Tissue reaction of morphine applied to the epidural space of dogs.

Epidural morphine has found increasing popularity in clinical trials for the relief of chronic and postoperative pain relief. This study was conducted to determine if there was any adverse tissue reaction when morphine was applied to the epidural space of dogs. Sixteen dogs were given 0.07 mg X kg-1 of morphine in a volume of 2 cc of normal saline into the epidural space. Gross and microscopic studies of the epidural space, dura, and spinal cord did not show any adverse tissue reaction.

Solid phase synthesis of functionalized biaryl ethers: versatile scaffolds for combinatorial chemistry.

4-Fluoro-3-nitrobenzoic acid attached to a solid support was shown to react under mild conditions with a wide range of functionalized phenols to yield, after cleavage, the corresponding biaryl ethers in excellent purity. In a similar fashion, biaryl thioethers could be obtained. Further elaboration of immobilized biaryl ethers demonstrates the potential for combinatorial library generation.

Continuous intercostal blockade after cardiac surgery.

The provision of analgesia using continuous bilateral intercostal blockade was compared with that provided by conventional i.v. narcotics for the first 48 h after cardiac surgery. The subjective quality of analgesia was significantly superior with the regional technique. However, pulmonary function tests, gas exchange, lung volume, and radiological and clinical evidence of pulmonary complications were not improved. The failure to reduce morbidity and the potential for complications such as pneumothorax, makes it difficult to recommend the regional analgesia technique in this situation.

Prevention of epidural morphine-induced respiratory depression with intravenous nalbuphine infusion in post-thoracotomy patients.

The efficacy of nalbuphine, an agonist/antagonist opioid, in preventing respiratory depression from epidural morphine analgesia after thoracotomy, was assessed in a randomized double-blind placebo controlled trial. After a standardized general anaesthetic and 0.15 mg.kg-1 of epidural morphine, patients received a bolus and then a 24 h infusion of nalbuphine (200 micrograms.kg-1 + 50 micrograms.kg-1.hr-1, 100 micrograms.kg-1 + 25 micrograms.kg-1.hr-1, or 50 micrograms.kg-1 + 12.5 micrograms.kg-1.hr-1) or placebo. Blood gases, analgesia, sedation, side effects, and blood nalbuphine concentrations were assessed every two hours for the next 24 h. Fifty-three per cent of placebo-treated patients had a PaCO2 greater than 50 mmHg and 89 per cent of these received naloxone. A 200 micrograms.kg-1 bolus of nalbuphine followed by a 50 micrograms.kg-1.hr-1 infusion achieved a mean steady state blood level of 38.2 ng.ml-1 and prevented CO2 retention greater than 50 mmHg in all but two patients, neither of whom required naloxone. There was no difference in the incidence of side effects among groups, and analgesia appeared to be unaffected by nalbuphine.

A comparison of lumbar epidural and intravenous fentanyl infusions for post-thoracotomy analgesia.

This double-blind randomised study compared the analgesic efficacy, respiratory effects, side effects, and pharmacokinetic disposition of 24 hr lumbar epidural and intravenous infusions of the same dosage regimen of fentanyl (1.5 micrograms.kg-1 bolus then 1 microgram.kg-1.hr-1 infusion) in 50 patients after thoracotomy. Patients received either epidural fentanyl and intravenous normal saline, or epidural normal saline and intravenous fentanyl, for postoperative analgesia, after a standard low-dose alfentanil and isoflurane general anaesthetic. Visual analogue pain scores were lower in the epidural group (P < 0.05) only at two hours postoperatively, and there was no difference in the amount of supplementary morphine self-administered by patient-controlled analgesic pump. A mainly spinal analgesic effect probably occurred in the first few hours since fentanyl was not detectable in the plasma of patients in the epidural group until two hours after bolus injection; its concentration was less at that time than after intravenous injection (P < 0.05). Thereafter there was no difference in the plasma concentration profiles between the two groups. Seven patients in the epidural group and ten patients in the intravenous group received naloxone for PaCO2 > 50 mmHg, and one patient in the intravenous group had the infusions stopped because of PaCO2 elevation and somnolence. In patients who did not receive naloxone, the epidural route produced better analgesia throughout the study period (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Multiple solid-phase synthesis of hydantoins and thiohydantoins.

A novel general protocol for the construction of hydantoins and thiohydantoins on a solid support has been developed. Using this novel methodology, the synthesis of a diverse 96-compound library has been achieved. Resin-bound dipeptides are cyclised via the formation of an intermediate isocyanate or isothiocyanate on resin as the key step in the strategy.

Novel modified tripeptide inhibitors of alpha 4 beta 7 mediated lymphoid cell adhesion to MAdCAM-1.

MAdCAM-1 specifically binds the lymphocyte integrin alpha 4 beta 7 and participates in the homing of leukocytes to intestinal mucosal sites. The LDT sequence located on the CD loop of MAdCAM-1 is an important binding site for MAdCAM-1/alpha 4 beta 7 interactions. N-Terminus acylation of the LDT motif and modification of the C-terminus carboxamide with amines led to low micromolar MAdCAM-1 inhibitors.

A double-blind, placebo-controlled trial of transdermal fentanyl after abdominal hysterectomy. Analgesic, respiratory, and pharmacokinetic effects.

BACKGROUND: A randomized, double-blind, placebo-controlled trial was conducted to assess the analgesic, pharmacokinetic, and clinical respiratory effects of 72-h application of two transdermal fentanyl (TTSF) patch sizes in patients undergoing abdominal hysterectomy. METHODS: TTSF patches releasing 50 micrograms/h (TTSF-50) or 75 micrograms/h (TTSF-75) fentanyl or placebo patches were applied to 120 women 2 h before abdominal hysterectomy under general anesthesia. Postoperatively, all patients had access to supplemental morphine using patient-controlled analgesia pumps. Each patient was attended continuously by a research nurse for 8 h on the night before surgery and for 84 h after patch application. The following data were collected: visual analog scale pain scores, supplementary analgesia, fentanyl plasma concentration (4-h intervals), continuous hemoglobin saturation (pulse oximetry), respiratory pattern (continuous respiratory inductive plethysmography), and adverse effects (nausea, vomiting, pruritus). Data analysis included analysis of variance, Kruskal-Wallis, and chi-squared. P < 0.05 was considered significant. RESULTS: There were no demographic differences among groups. Visual analog scale pain scores were significantly lower for the TTSF-75 group, and supplemental morphine was significantly decreased in the TTSF-75 group in the postanesthesia care unit and for both the TTSF-50 and the TTSF-75 group for 8-48 h postoperatively. Between 5 and 36 h, the TTSF groups had significantly increased abnormal respiratory pattern including apneic episodes (tidal volume of less than 100 ml for more than 15 s) and episodes of slow respiratory rate (less than 8 breaths/min persisting for more than 5 min) and significantly increased requirement for oxygen supplementation. Nine patients in the TTSF groups were withdrawn because of severe respiratory depression compared to none in the placebo group. No significant between-group differences were present in the incidence of nausea, vomiting, or pruritus. Although fentanyl plasma concentration was higher in the TTSF-75 group than in the TTSF-50 group, the differences were not significant. Fentanyl plasma concentration decreased significantly 48 h after patch application. CONCLUSIONS: Application of TTSF patches 2 h preoperatively is associated with moderate supplementary opioid requirements for analgesia in the early postoperative period and ongoing opioid supplementation for at least 72 h. Although good analgesia is the result of this combination therapy, it is associated with a high incidence of respiratory depression requiring intensive monitoring oxygen supplementation, removal of the TTSF patches in approximately 11% of the patients and opioid reversal with naloxone in approximately 8% of the patients.