Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin

The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys(6)]LH-RH linked to 2-pyrrolino-doxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2-pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys(6)]LH-RH or conjugated to the carrier [D-Lys(6)]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN-207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-207, the tumors regressed from an initial volume of 8.35 +/- 1.7 cm(3) to 4.47 +/- 0.8 cm(3), while tumors in the control group measured 17.84 +/- 2.2 cm(3). The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm(3). After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 +/- 0.51 cm(3), whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 +/- 1.4 cm(3) and 6.74 +/- 1 cm(3), respectively), as compared to 15.6 +/- 2.2 cm(3) for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer.     

The effect of chronic administration of a synthetic LH-RH analogue intranasally in cryptorchid boys

Eighteen boys with either unilateral or bilateral cryptorchidism were treated with a synthetic LH-RH analogue ("D-Leu 6, Des-Gly-10 LH-RH ethylamide") intranasally. The peptide was dissolved in aqueous solution (25 micrograms in 0,2 ml) and administered in the form of nasal drops. The patients were divided in two groups: in group A, 50 micrograms of the synthetic LH-RH analogue were administered intranasally every 48 h for 36 days; in group B same dose was given every 24 h. Additionally, in 4 cases a LH-RH test prior the trial was performed with the same peptide. The nasal administration resulted in a fivefold increase of LH and of FSH plasma concentration in 30 min and in 60 min, respectively. The endocrine profiles for T, LH and FSH were studied in each group over the treatment period and in group B (same dose was given every 24 h) a significant decrease of the LH and FSH plasma levels could be found. The clinical effect of treatment was same in the both groups. In the whole material 44% had either unilateral or bilateral descent of the testis after the therapy.     

Behavioural change in injecting drug users: evaluation of an HIV/AIDS education programme

The results obtained from the training and follow-up of 189 IDUs who participated in a programme consisting of an audiovisual presentation, pre-/post-testing and individual counselling are presented. Syringe sharing decreased from 35% at initial contact to 12% after 6 months. Sexual behaviour proved more resistant to change. However, condom use in at-risk situations increased from 49% to 70%. IDUs under continuous methadone treatment were less likely to engage high risk drug injecting practices than the other IDUs. Results indicate that an educational programme addressed toward risk reduction may determine relevant behavioural change among IDUs.     

Hockey Games and the Incidence of ST-Elevation Myocardial Infarction

Background

The association between diagnosed acute ST-elevation myocardial infarction (STEMI) and hockey games in the Canadian population is unknown.

How should we approach parental refusals of opioids on behalf of children in the perioperative setting? A practical approach based on ethical theory

In the midst of the current opioid epidemic, we have encountered more parents who are concerned about the use of opioids in the perioperative setting. Some parents have completely refused the use of opioids on behalf of their children. How should we approach this treatment refusal? This article describes ethical theory related to the refusal of treatment by parents on behalf of their children, and when it is justified to override parental decisions. We propose a decision‐making framework that focuses on improving communication and considering alternatives. Assessment of harm to the child from avoiding opioids, as well as potential harms from overriding parental autonomy must be undertaken prior to considering overriding parents.     

Actions of MPTP and MPP+ on synaptic transmission in guinea-pig hippocampal slices

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes a Parkinson's disease-like syndrome in man, monkeys, and mice. We studied the effects of MPTP and its metabolite, MPP+, on neuronal properties and synaptic transmission in isolated slices of guinea-pig hippocampus using intra- and extracellular recording methods. Addition of MPTP to the superfusate (50 to 100 microM) produced the following effects: Excitatory postsynaptic potentials and extracellularly recorded population spikes, evoked by stimulation of the Schaffer collaterals were increased in amplitude during the application period (30 min). Within 30 min of washing in normal solution, synaptic transmission was blocked, although axonal population action potentials could still be elicited. The block of synaptic transmission was prevented by prior incubation in pargyline, an inhibitor of monoamine oxidase. The membrane potential and resistance of single pyramidal neurons were virtually unaffected; action potentials elicited by depolarizing intracellular current pulses were also unchanged. MPP+ (50 microM) blocked synaptic transmission during the application period by a pargyline-in-sensitive mechanism. These results suggest that MPP+ blocks synaptic transmission in the hippocampus at a presynaptic site. This effect may be relevant for the acute action of MPTP and may provide some insight into its chronic action on nigrostriatal neurons.