Polymer encapsulation of anticancer silver-N-heterocyclic carbene complexes.

Amphiphilic block copolymers have been developed for the encapsulation of organometallic drugs. silver-N-heterocyclic carbene complexes have shown significant promise as anticancer and antibacterial compounds, and have been studied as the payload in these carriers. Simple modification of the N-heterocyclic carbene ligand structure enables solubility properties and interaction with the polymer to be tuned.

Treatment of T-cell prolymphocytic leukemia with human CD52 antibody.

PURPOSE: T-prolymphocytic leukemia (T-PLL) is an aggressive malignancy of mature T cells refractory to conventional chemotherapy, with a median survival duration of 7.5 months. We report here promising results with the use of a genetically reshaped human CD52 antibody, CAMPATH-1H. PATIENTS AND METHODS: Fifteen patients with T-PLL, most of whom had received the purine analog deoxycoformycin (DCF), were treated with CAMPATH-1H. Results were compared with those of 25 patients treated with DCF. RESULTS: Major responses occurred in 11 patients (73%) treated with CAMPATH-1H compared with 40% with DCF. Complete remissions (CRs) were documented in nine (60%) of the CAMPATH-1H cases and only three (12%) were obtained with DCF. CRs with CAMPATH-1H were durable, and re-treatment with the antibody resulted in second CRs in three relapsed patients. Two of them were successfully autografted with peripheral-blood and bone marrow stem cells collected during the first CR. Apart from first-dose reactions, infusions of CAMPATH-1H were well tolerated. However, two responding patients developed severe bone marrow aplasia that was fatal in one; the second remained moderately pancytopenic 21 weeks after stopping CAMPATH-1H therapy. The cause of this adverse effect is unknown. CONCLUSION: CAMPATH-1H is an effective agent in T-PLL and represents a significant improvement over other types of therapy. However, CAMPATH-1H alone is not sufficient for long-term remissions, and the role of autologous stem-cell transplantation needs further investigation.

Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis.

Transformation of CLL into a large cell lymphoma has an incidence of 3-5%. We have studied 101 cases of CLL treated with fludarabine over a 10-year period (1990-2000) and observed a 12% incidence of transformation. In six of 12 patients, transformation was documented within 4 months following treatment with fludarabine. Pathological material, available in nine cases, was investigated for latent EBV by staining for LMP-1 by immunohistochemistry and EBERs-1 and 2 by in situ hybridisation. LMP-1 and EBERs were demonstrated in three of the nine samples. In two cases there was a different pattern of immunoglobulin gene rearrangement in the transformed cells assessed by PCR (FR3 fragment) compared to the original CLL clone. One of these two cases showed evidence of latent EBV. The other seven cases, of which two were EBV positive, showed identical pattern of Ig gene rearrangement in both the CLL and the transformed cells. We suggest that the relatively high incidence of transformation in this series may be due to immunosuppression mainly related to fludarabine, although other agents and prior therapies may have also contributed.

High dose methyl prednisolone in refractory chronic lymphocytic leukaemia.

We treated 14 patients with advanced, resistant chronic lymphocytic leukaemia (CLL) including three with >10% prolymphocytes (CLL/PL) with high dose methyl prednisolone (HDMP). All patients had stage C CLL or bulky stage B disease. There were 11 males and 3 females with a median age of 58.5 years (range: 49-69). Six out of eleven CLL patients had a partial response as defined by the NCI guidelines, no patient had a complete remission. The mean duration of PR was 19.6 months with a median of 8 months (range 6-78). Seven patients have died including the 5 non-responders. None of the 3 patients with CLL/PL had a measurable response. Previous treatments included chlorambucil, fludarabine, deoxycoformycin, anthracycline containing regimens such as CHOP and Campath-1H. HDMP was given at a dose of 1 g/m2 for five days, at monthly intervals for one to seven courses depending on the response. H2 antagonists and antimicrobial prophylaxis were given concurrently. Acyclovir prophylaxis was given if there was a recent history of herpes infection. HDMP was generally well tolerated. Side effects included fluid retention, hyperglycaemia, bradycardia (1 patient), herpes simplex (1), and pneumonia (1) in a patient with a previous history of recurrent chest infection and pneumonia. These results suggest that HDMP may be beneficial in the treatment of refractory CLL but is of no value in CLL/PL.

Evidence that inhibitory motor neurons of the guinea-pig small intestine exhibit fast excitatory synaptic potentials mediated via P2X receptors.

Intracellular recordings were used to study the contribution of nicotinic and P2X receptors to synaptic transmission to morphologically identified myenteric neurons of guinea-pig ileum. Hexamethonium (100 microM) abolished fast excitatory synaptic potentials (EPSPs) in all orally projecting neurons, but fast EPSPs in anally projecting neurons were resistant to this antagonist. The non-cholinergic fast EPSPs were virtually abolished by suramin (100 microM). This suggests that P2X receptors are important in descending motility reflexes. However, suramin and hexamethonium together did not affect descending inhibitory reflexes when applied to the site of transmission between interneurons in this pathway. These data suggest that P2X receptors are not involved in transmission between descending interneurons, but may be important for transmission to inhibitory motor neurons.

Quantification of the pain and distress responses to castration in young lambs.

Pain and distress following castration were assessed in lambs using three indicators: behaviour, plasma cortisol and mechanical nociceptive thresholds. Three castration methods: rubber ring (RR), combined ring and Burdizzo clamp (CM) and surgery (SU) were compared. The effects of castration following local anaesthetic pre-treatment (LA) and castration performed under general anaesthetic (GA) were compared to castration performed with no anaesthetic. This gave a 4 x 3 x 3 block design i.e. 36 experimental treatments. Six lambs were allocated to each treatment i.e. 216 lambs were used in all. SU produced the greatest response, followed by RR then CM castration. LA abolished the responses to RR and CM castration but had no effect on the response to SU castration. GA did not reduce the responses to RR and SU but abolished the rise in mechanical nociceptive thresholds and markedly attenuated active pain behaviours in lambs CM castrated without anaesthesia. This suggests that the clamping procedure itself rather than post-castration pain and distress is responsible for the rise in nociceptive thresholds and active pain behaviours in CM castrated lambs.

Slow excitatory synaptic potentials evoked by distension in myenteric descending interneurones of guinea-pig ileum.

The functional significance of the slow excitatory synaptic potentials (EPSPs) in myenteric neurones is unknown. We investigated this using intracellular recording from myenteric neurones in guinea-pig ileum, in vitro. In all, 121 neurones responded with fast EPSPs to distension of the intestine oral to the recording site. In 28 of these neurones, distension also evoked depolarizations similar to the slow EPSPs evoked by electrical stimulation in the same neurones. Intracellular injection of biocytin and immunohistochemistry revealed that neurones responding to distension with slow EPSPs were descending interneurones, which were immunoreactive for nitric oxide synthase (NOS). Other neurones, including inhibitory motor neurones and interneurones lacking NOS, did not respond to distension with slow EPSPs, but many had slow EPSPs evoked electrically. Slow EPSPs evoked electrically or by distension in NOS-immunoreactive descending interneurones were resistant to blockade of NK(1) or NK(3) tachykinin receptors (SR 140333, 100 nM; SR 142801, 100 nM, respectively) and group I metabotropic glutamate receptors (PHCCC, 10-30 microM), when the antagonists were applied in the recording chamber of a two-chambered organ bath. However, slow EPSPs evoked electrically in inhibitory motor neurones were substantially depressed by SR 140333 (100 nM). Blockade of synaptic transmission in the stimulation chamber of the organ bath abolished slow EPSPs evoked by distension, indicating that they arose from activity in interneurones, and not from anally directed, intrinsic sensory neurones. Thus, distension evokes slow EPSPs in a subset of myenteric neurones, which may be important for intestinal motility.

Towards safer drug prescribing, dispensing and administration in hospitals.

A multidisciplinary workshop was held in order to identify strategies likely to produce a reduction in adverse drug events, by targeting hospital systems involved in drug prescribing, dispensing and administration. Strategies identified at the workshop included: (i) improving the education and practice development of medical and nursing staff, concerning drug therapy and safe prescribing principles; (ii) introducing and using information technology and electronic prescribing processes; (iii) implementing the Australian Pharmaceutical Advisory Council (APAC) national guidelines to achieve the continuum of quality use of medicines between hospitals and the community; (iv) enhancing the importance of medication history taking as a routine part of the admission process; (v) instituting individual patient supply as the standard method of drug distribution in hospitals; and (vi) stimulating the hospital-based clinical pharmacy workforce.