Measurement of muon capture on the proton to 1% precision and determination of the pseudoscalar coupling gP.

The MuCap experiment at the Paul Scherrer Institute has measured the rate Λ(S) of muon capture from the singlet state of the muonic hydrogen atom to a precision of 1%. A muon beam was stopped in a time projection chamber filled with 10-bar, ultrapure hydrogen gas. Cylindrical wire chambers and a segmented scintillator barrel detected electrons from muon decay. Λ(S) is determined from the difference between the µ(-) disappearance rate in hydrogen and the free muon decay rate. The result is based on the analysis of 1.2 × 10(10) µ(-) decays, from which we extract the capture rate Λ(S) = (714.9 ± 5.4(stat) ± 5.1(syst)) s(-1) and derive the proton's pseudoscalar coupling g(P)(q(0)(2) = -0.88 m(µ)(2)) = 8.06 ± 0.55.

Measurement of the positive muon lifetime and determination of the Fermi constant to part-per-million precision.

We report a measurement of the positive muon lifetime to a precision of 1.0 ppm; it is the most precise particle lifetime ever measured. The experiment used a time-structured, low-energy muon beam and a segmented plastic scintillator array to record more than 2×10(12) decays. Two different stopping target configurations were employed in independent data-taking periods. The combined results give τ(µ(+)) (MuLan)=2 196 980.3(2.2) ps, more than 15 times as precise as any previous experiment. The muon lifetime gives the most precise value for the Fermi constant: G(F) (MuLan)=1.166 378 8(7)×10(-5) GeV(-2) (0.6 ppm). It is also used to extract the µ(-)p singlet capture rate, which determines the proton's weak induced pseudoscalar coupling g(P).

Improved measurement of the positive-muon lifetime and determination of the Fermi constant.

The mean life of the positive muon has been measured to a precision of 11 ppm using a low-energy, pulsed muon beam stopped in a ferromagnetic target, which was surrounded by a scintillator detector array. The result, tau(micro)=2.197 013(24) micros, is in excellent agreement with the previous world average. The new world average tau(micro)=2.197 019(21) micros determines the Fermi constant G(F)=1.166 371(6)x10(-5) GeV-2 (5 ppm). Additionally, the precision measurement of the positive-muon lifetime is needed to determine the nucleon pseudoscalar coupling g(P).

Measurement of the muon capture rate in hydrogen gas and determination of the proton's pseudoscalar coupling gP.

The rate of nuclear muon capture by the proton has been measured using a new technique based on a time projection chamber operating in ultraclean, deuterium-depleted hydrogen gas, which is key to avoiding uncertainties from muonic molecule formation. The capture rate from the hyperfine singlet ground state of the microp atom was obtained from the difference between the micro(-) disappearance rate in hydrogen and the world average for the micro(+) decay rate, yielding Lambda(S)=725.0+/-17.4 s(-1), from which the induced pseudoscalar coupling of the nucleon, g(P)(q(2)=-0.88m(2)(micro))=7.3+/-1.1, is extracted.

Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening.

This study describes the natural course of vincristine-induced peripheral neuropathy in patients with lymphoma (n = 114) receiving vincristine in two different dose intensities. Neuropathic changes were observed in both dose intensity groups, but the higher dose intensity group reported significantly more symptoms during therapy, whereas neurologic signs were significantly more prominent after a cumulative dose of 12 mg vincristine. Furthermore, off-therapy worsening of symptoms (24%) and signs (30%) occurred unexpectedly.

Lack of neuroprotection by an ACTH (4-9) analogue. A randomized trial in patients treated with vincristine for Hodgkin's or non-Hodgkin's lymphoma.

PURPOSE: This randomized, double-blind, placebo-controlled study evaluates the effect of the corticotropin (4-9) analogue Org 2766 on the neuropathy-free interval in patients receiving vincristine (VCR) containing chemotherapy for Hodgkin's or non-Hodgkin's lymphoma. PATIENTS AND METHODS: In a longitudinal design, 150 patients were evaluated by interview, neurological examination, and neurophysiological techniques. Patients with an expected cumulative VCR dose of at least 8 mg received a single dose of Org 2766 or placebo before and after each intravenous VCR injection and 3-4 weeks after cessation of VCR. The final patient assessment was performed 1 month after discontinuation of study medication. The neuropathy-free interval as the major end point of this study was defined as the first occurrence of bilateral paresthesias and expressed as the administered cumulative VCR dose. This bi-center study represents the largest cohort of patients monitored for the effect of an ACTH-analogue on VCR neurotoxicity. RESULTS: A total of 147 patients were included in the final analysis. No significant differences were observed between the placebo and actively treated group for the major and secondary endpoints. CONCLUSION: Contrary to a single previous pilot study in patients receiving VCR-based chemotherapy, in our study the ACTH (4-9) analogue Org 2766 did not provide protection from VCR-induced neuropathy.

In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4-9) analogue Org 2766.

The use of the cytostatic agent vincristine (VCR) is limited by the occurrence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubules and reacts with tubulin to form paracrystals. The potential of a neurotrophic ACTH(4-9) analogue, Org 2766, to counteract peripheral neuropathy caused by cytostatic agents is being investigated. In the present ultrastructural study, modulatory effects of Org 2766 on VCR-induced neurotoxicity were studied in vivo in neurons of the pond snail Lymnaea stagnalis, which has been shown previously to be a suitable test system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 microM), 68.4 +/- 34.7 paracrystals were counted per cross-section of the cerebral commissure and the number of microtubules in the axons had been lowered to 46% of the control level. After a survival period of two weeks all paracrystals had disappeared. By that time, no recovery of the axonal microtubular system could be observed. However, post-treatment with Org 2766 (10(-6) M) on day 6 after VCR treatment had induced a significant increase in the number of microtubules (+55%) on day 7. This beneficial effect lasted for the rest of the experimental period (14 days). These results suggest that post-treatment with Org 2766, i.e. after VCR clearance, can induce long-lasting beneficial effects on VCR-induced neurotoxicity in vivo.

Ultrastructural neuropathologic effects of Taxol on neurons of the freshwater snail Lymnaea stagnalis.

Cerebral ganglia of the freshwater snail Lymnaea stagnalis were incubated in vitro in 10 microM Taxol for 8 and 24 h. Cremophor EL (0.1%) was used as a diluant. The tissue was processed for electron microscopy. Various ultrastructural parameters were assessed quantitatively. Cremophor EL appeared to seriously affect the cell somata of the multipeptidergic caudodorsal cells. In the Cremophor-controls the mean area of Golgi zones, the percentage dense material (neuropeptides) in these zones, the number of large electron dense granules (these are involved in neuropeptide processing) and the mean nuclear heterochromatin clump size, were significantly smaller than in the Ringer-controls, whereas the number of lipid droplets was higher. All these parameters, except for the lipid droplets, were not different in the Cremophor-controls and the Taxol-treated specimens. After 24 h treatment, but not after 8 h, Cremophor EL furthermore induced an increase in the number of axonal microtubules. It is argued that the results might signify activation of the neurons by Cremophor EL. Taxol induced a significant increase in the number of microtubules in axons and cell somata. Furthermore an increase in the number of Golgi zones was observed, suggesting activated neuropeptide synthesis. In all groups immunostaining with antibodies to neuropeptides produced by the caudodorsal cells was normal. Release of neuropeptide (exocytosis) from axon endings was elevated after Taxol treatment, and exceptionally high in specimens cotreated with Taxol and Org 2766 (incubation time 22 h). The effect of Org 2766 and Taxol on the number of microtubules was cumulative.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the ACTH(4-9) analogue, ORG 2766, on vincristine cytotoxicity in two human lymphoma cell lines, U937 and U715.

The use of cytotoxic drug vincristine (VCR) is limited by the occurrence of peripheral neuropathy. A neurotrophic ACTH(4-9) analogue, ORG 2766, is being studied for its protective effect. Possible modulatory effects of ORG 2766 on tumour cell growth and interference with the cytotoxic efficacy of VCR were studied in two human lymphoma cell lines, U937 and U715. The effects of ORG 2766 on cell growth and survival and on VCR-mediated cytotoxicity were investigated using two MTT-based assays to study direct cytotoxic effects and to assess residual growth after pretreatment. Treatment with ORG 2766 alone had no effect on cell growth and survival. Neither did this drug affect VCR cytotoxicity. However, after 96 h pretreatment with ORG 2766 and a culture period of 7 days, a reduction in residual growth and a potentiation of VCR-induced inhibition of growth capacity was observed in U715 cells, and to some extent also in U937 cells. It is concluded that ORG 2766 has no stimulatory effects on tumour growth and does not negatively interfere with VCR-mediated cytotoxicity. Rather it enhances the cytostatic effect of VCR. It is suggested that ORG 2766 can safely be used in clinical trials investigating the ability of ORG 2766 to counteract VCR-induced neurotoxicity.

Differential trophic effects of ORG 2766, an ACTH(4-9)/MSH(4-9) analogue, on peptidergic neurons and glial cells in the snail Lymnaea stagnalis.

Cerebral ganglia of the pond snail Lymnaea stagnalis were incubated in vitro in 10(-6) M ORG 2766 for 10 and 20 h, with or without regular refreshment of the medium. Quantitative ultrastructural study of cross sections of the cerebral commissure showed that the number of microtubules in large axons of all ORG 2766-treated groups had increased after 10 h by approximately 40%. In a separate experiment, central nervous systems were incubated in ORG 2766 for only 15 min and then kept in Ringer's for 9 h and 45 min. Maximal stimulation (40% increase of microtubules) in these specimens was also observed. The results would seem to support the hypothesis that ORG 2766 binds to a receptor and initiates a long-lasting effect. It is argued that ORG 2766 stimulates novel synthesis of tubulin rather than being involved in the assembly of microtubules. Also, glial cells were found to be activated by ORG 2766. This was concluded from the fact that the number of heterochromatin clumps and the size of the clumps in these cells had decreased and the amount of glial tissue surrounding the axons had increased (approximately 50%). In contrast to the activating effects of ORG 2766 on glial tissue, this drug did not affect nucleoli, number, and size of the heterochromatin clumps and the Golgi apparatus in the neuropeptidergic caudodorsal cells. The data indicate that ORG 2766 exerts differential trophic effects.

Org-2766, an acth(4-9)-msh(4-9) analog, modulates vincristine-induced neurotoxicity in the snail lymnaea-stagnalis.

In vincristine (VCR) chemotherapy the dose-limiting factor is neurotoxicity, a side-effect which probably is caused by the action of the drug on axonal microtubules. VCR transforms them into paracrystalline structures. ORG 2766, an ACTH(4-9)/MSH(4-9), analogue, might have protective properties against this toxicity, because of its potency to induce the formation of microtubules. Therefore, the effects were studied of co-treatment with VCR and ORG 2766 on paracrystals and on microtubules in axons of the cerebral commissure (CC) of the snail Lymnaea stagnalis. In vitro experiments were carried out, incubating cerebral ganglia including the CC, for various periods of time (5-25 h) in Ringer's solution, in ORG 2766 (10(-6) M), in VCR (10(-4) M), or in VCR+ORG 2766. Furthermore, the effects of VCR (5 h) were studied in CC, pre- and/or post-treated with ORG 2766 (10 h). In another experiment VCR was used at a concentration at which no paracrystals were formed (2x10(-6) M). In this experiment VCR-treatment (5, 15 h) was compared to pre treatment and pre- and post-treatment with ORG 2766 (10 h). The numbers of microtubules (per mu m(2) axoplasm) and paracrystals (number encountered along perpendicular axes of the CC) were counted and the size of the paracrystals was measured in cross-sections of the CC, using electron microscopy. Irrespective of the type of additional treatment, significant differences were not observed in the numbers of paracrystals (32+/-10) after VCR-treatment for 5 h. Between 5 and 10 h of incubation the number increased (to 55+/-21) and remained approximately at this level. The number of microtubules decreased during the first 5 h of VCR treatment from 128+/-16 (control) to 37+/-10, and decreased further 19+/-5 between 5 and 10 h of incubation. The size of the paracrystals of all groups treated for 5 h with either VCR or VCR+ORG 2766 were similar (x=1.7 mu m(2)) However, the paracrystals were significantly larger in all groups co-treated for longer periods (10, 15 or 20 h) with ORG 2766 (VCR: x=2.3-3.0 mu m(2); VCR+ORG 2766: x=3.0-3.4 mu m(2)). This indicates that after an initial period of formation of paracrystals, tubulin is added to the existing paracrystals. At the low VCR concentration studied no paracrystals were formed. However, the number of microtubules had decreased significantly (from 159+/-10 to 84+/-17 after 15 h treatment). Pre- as well as pre- and post-treatment with ORG 2766 resulted in microtubule numbers which were not different from control values, indicating the positive effect of ORG 2766. In the groups pre- and/or post-treated with the high concentration of ORG 2766 (especially in the pre-treated group), the remaining number of microtubules was higher than in those co-treated with VCR and ORG 2766, but lower than in the controls. Although translation of the present results into clinical terms is difficult, they suggest that pre-and/or post-treatment with ORG 2766 may have a benificial effect on VCR-induced neurotoxicity. This conclusion is based on the observation that when ORG 2766 is given before VCR administration or after VCR clearance, larger numbers of microtubules were found in the nervous tissue than after treatment with VCR alone.