A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

The mechanics of landing when stepping down in unilateral lower-limb amputees.

BACKGROUND: The ability to successfully negotiate stairs and steps is an important factor for functional independence. While work has been undertaken to understand the biomechanics of gait in lower-limb amputees, little is known about how amputees negotiate stairs and steps. This study aimed to determine the mechanics of landing in unilateral lower-limb amputees when stepping down to a new level. A secondary aim was to assess the effects of using a shank-mounted shock-absorbing device (Tele-Torsion Pylon) on the mechanics of landing. METHODS: Ten unilateral amputees (five transfemoral and five transtibial) and eight able-bodied controls performed single steps down to a new level (73 and 219 mm). Trials were repeated in amputees with the Tele-Torsion Pylon active and inactive. The mechanics of landing were evaluated by analysing peak limb longitudinal force, maximal limb shortening, lower extremity stiffness, and knee joint angular displacement during the initial contact period, and limb and ankle angle at the instant of ground-contact. Data were collected using a Vicon 3D motion analysis system and two force platforms. FINDINGS: Amputees landed on a straightened and near vertical limb. This limb position was maintained in transfemoral amputees, whereas in transtibial amputees knee flexion occurred. As a result lower extremity stiffness was significantly greater in transfemoral amputees compared to transtibial amputees and able-bodied controls (P<0.001). The Tele-Torsion Pylon had little effect on the mechanics of landing in transtibial amputees, but brought about a reduction in lower extremity stiffness in transfemoral amputees (P<0.05). INTERPRETATION: Amputees used a stepping strategy that ensured the direction of the ground reaction force vector was kept anterior of the knee joint centre. Using a Tele-Torsion Pylon may improve the mechanics of landing during downward stepping in transfemoral amputees.

The gait initiation process in unilateral lower-limb amputees when stepping up and stepping down to a new level.

BACKGROUND: Unilateral lower-limb amputees lead with their intact limb when stepping up and with their prosthesis when stepping down; the gait initiation process for the different stepping directions has not previously been investigated. METHODS: Ten unilateral amputees (5 transfemoral and 5 transtibial) and 8 able-bodied controls performed single steps up and single steps down to a new level (73 and 219 mm). Duration, a-p and m-l centre of mass and centre of pressure peak displacements and centre of mass peak velocity of the anticipatory postural adjustment and step execution phase were evaluated for each stepping direction by analysing data collected using a Vicon 3D motion analysis system. FINDINGS: There were significant differences (in the phase duration, peak a-p and m-l centre of pressure displacement and peak a-p and m-l centre of mass velocity at heel-off and at foot-contact) between both amputee sub-groups and controls (P<0.05), but not between amputee sub-groups. These group differences were mainly a result of amputees adopting a different gait initiation strategy for each stepping direction. INTERPRETATION: Findings indicate the gait initiation process utilised by lower-limb amputees was dependent on the direction of stepping and more particularly by which limb the amputee led with; this suggests that the balance and postural control of gait initiation is not governed by a fixed motor program, and thus that becoming an amputee will require time and training to develop alternative neuromuscular control and coordination strategies. These findings should be considered when developing training/rehabilitation programs.

Morphine and ibuprofen compared using the cold pressor test.

The analgesic efficacy of single doses of oral morphine sulphate solution (10 mg) and ibuprofen 600 mg was compared in 12 volunteers using a double-blind, double-dummy, placebo-controlled design on the cold pressor experimental pain model. Measurement of pain intensity was made before medication and then at 30, 60, 90, 120 and 180 min; blood samples were taken at these times for measurement of morphine and glucuronide metabolites by radioimmunoassay. Sessions were at least 5 days apart. Correlations were sought between analgesic effect and plasma concentrations of either morphine or morphine-6-glucuronide. Morphine produced significant reduction in both peak pain intensity and area under the pain intensity curve compared with placebo; the threshold time was significantly increased by morphine compared with placebo. Ibuprofen was statistically indistinguishable from placebo on all three measures of analgesia. Analgesic effect and plasma concentrations of morphine showed significant correlation (P = 0.053). The study confirmed reports of the opiate sensitivity of the cold pressor model, and the apparent insensitivity of the model to non-steroidal anti-inflammatory drugs.

Orofacial granulomatosis: a diagnostic problem for the unwary and a management dilemma. Case reports.

Orofacial granulomatosis is a condition that may be difficult to diagnose for those unfamiliar with the entity. This paper describes two cases and addresses the presentation, pathogenesis and treatment. The clinical recognition of this condition is important as is the subsequent investigation by an appropriate specialist. Management of patients needs to take into account the results of further investigations, the patient's expectations, and the severity of the condition.

The 'redefinition of death' debate: western concepts and western bioethics.

Biomedicine is a global enterprise constructed upon the belief in the universality of scientific truths. However, despite huge scientific advances over recent decades it has not been able to formulate a specific and universal definition of death: In fact, in its attempt to redefine death, the concept of death appears to have become immersed in ever increasing vagueness and ambiguity. Even more worrisome is that bioethics, in the form of principlism, is also endeavouring to become a global enterprise by claiming neutrality. It appears that the discourse within both disciplines have similarly manipulated the boundaries of death to include the "dying". This paper argues that the redefinition of death debate in biomedicine reveals a concept of personhood which is profoundly western in origin and which is in accordance to the concept adhered to within principlism. Biomedicine and bioethics do not appear to acknowledge the limitations of their own world view and hence lack an understanding of their applicability and appropriateness in diverse social and cultural contexts; a situation which adds credence to claims as to the hegemonic and imperialistic nature of all such global enterprises.

Vinorelbine: a new antineoplastic drug for the treatment of non-small-cell lung cancer.

OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, and dosage and administration guidelines for vinorelbine in the treatment of non-small-cell lung cancer (NSCLC). DATA SOURCES: A MEDLINE search (1989-1995) using the terms vinorelbine and Navelbine was conducted. Additional unpublished data were provided by Glaxo Wellcome Drug Information. STUDY SELECTION AND DATA EXTRACTION: The articles chosen for inclusion all appeared in peer-reviewed journals. Pertinent abstracts, as judged by the authors, were also included. DATA SYNTHESIS: Vinorelbine is a new semisynthetic vinca alkaloid approved by the Food and Drug Administration for the first-line treatment of patients with advanced NSCLC. The drug demonstrated a broad spectrum of antitumor activity in preclinical studies and produced dose-limiting neutropenia in Phase I trials. In Phase II studies, an overall response rate of approximately 30% was reported with single-agent vinorelbine. Furthermore, in large, multicenter, randomized Phase III trials, treatment with vinorelbine alone and in combination with cisplatin resulted in improved survival compared with controls. The drug was well tolerated, with granulocytopenia being the most commonly reported adverse effect. However, the incidence of fever and hospitalization associated with this granulocytopenia was exceptionally low. The recommended dose is 30 mg/m2 weekly administered by intravenous injection or infusion. CONCLUSIONS: As no specific chemotherapy regimen has previously been regarded as standard therapy for advanced NSCLC, vinorelbine is a promising new treatment for this patient population. It has been shown in several randomized, controlled trials to increase survival without compromising quality of life.

Some effects of nerve stimulation andhemicholinium on quantal transmitter release at the mammalian neuromuscular junction.

1. Rat phrenic nerve-diaphragm preparations have been used to assess some effects of prolonged nerve stimulation on transmitter release.2. The amplitude of the end-plate potentials evoked by prolonged repetitive nerve stimulation fell gradually during stimulation. Most of this fall was due to a reduction in the number of transmitter quanta released by each nerve impulse; however there was also a small reduction in the muscle cell depolarization produced by each quantum of transmitter.3. Repetitive nerve stimulation also produced a small reduction in the amplitude of the miniature end-plate potentials. Recovery of amplitude occurred within about 7-8 min of ceasing stimulation.4. A much greater reduction in miniature end-plate potential amplitude accompanied prolonged nerve stimulation if hemicholinium was present in the bathing solution.5. Estimates of the ;readily available transmitter' (Elmqvist & Quastel, 1965b) were made at intervals following prolonged nerve stimulation. Readily available transmitter was reduced, and recovered over approximately 15 min.6. The relationship of these changes to the changes in nerve terminal synaptic vesicle numbers and volumes induced by similar prolonged nerve stimulation (Jones & Kwanbunbumpen, 1970) is discussed.

Spontaneous quantal transmitter release: a statistical analysis and some implications.

1. Miniature end-plate potentials (m.e.p.p.s) were intra- and extracellularly recorded from neuromuscular junctions in rat phrenic nerve-diaphragm preparations in vitro.2. Statistical analysis of the intervals between m.e.p.p.s showed that when the mean number of events in time t was plotted as a function of the variance of the events in time t there was a significant deviation from the straight line relationship expected for a Poisson process. Computer simulation showed that this deviation is explicable if release was generated by the random phasing of the activity of a number of releasing sites.3. There was no indication that release of one quantum influences the probability of release of remaining quanta (drag, clustering). It is suggested that m.e.p.p.s whose amplitude is larger than the mode result from the release of the contents of vesicles whose volume is also supramodal.4. The effects of depolarization of nerve terminals upon the variance-mean curve suggest an increase in the activity of sites rather than an increase in their number.5. Statistical analysis indicated at least 200 +/- 100 (mean +/- 1 S.E.) releasing sites. This number is of the same order as the number of sites of vesicle aggregation and presynaptic membrane density seen in electron micrographs of nerve terminals of this preparation.

The effects of nerve stimulation and hemicholinium on synaptic vesicles at the mammalian euromuscular junction.

1. Electron micrographs of nerve terminals in rat phrenic nerve-diaphragm preparations have been studied. This has been done before and after prolonged nerve stimulation. The effectiveness of nerve stimulation has been monitored by intracellular micro-electrode recordings from the muscle cells.2. Characteristic changes in the form and distribution of the nerve terminal mitochondria were noted after nerve stimulation.3. Synaptic vesicle numbers in the region of nerve terminal less than 1800 A from the synaptic cleft were significantly greater in tissue taken 2 and 3 min after nerve stimulation, than in unstimulated preparations.4. The long and short diameters of the synaptic vesicle profiles less than 1800 A from the synaptic cleft were measured. Analysis of the distribution of the diameters indicated synaptic vesicles to be basically spherical structures. Estimates of synaptic vesicle volume were made from the measurements. Synaptic vesicle volume was significantly reduced in tissue taken 2 and 4 min following nerve stimulation.5. If hemicholinium, a compound which inhibits acetylcholine synthesis, was present during the period of nerve stimulation, much greater reductions in synaptic vesicle volume occurred. Synaptic vesicle numbers in the region of nerve terminal less than 1800 A from the synaptic cleft were also reduced, compared with unstimulated control preparations.6. These results are regarded as support for the hypothesis that the synaptic vesicles in nerve terminals at the mammalian neuromuscular junction represent stores of the transmitter substance, acetylcholine.

Analgesia following femoral neck surgery. Lateral cutaneous nerve block as an alternative to narcotics in the elderly.

In a prospective controlled randomised trial on patients undergoing operative repair of fractured neck of femur via a lateral incision, the postoperative analgesic requirements of one group of patients who received a lateral cutaneous nerve block were compared with a second group who received no block. The former group were found to need significantly less intramuscular pethidine in the first 24 hours, and 44% required no supplementary analgesia whatsoever during this period. The time to first dose of opioid in the remainder was greatly increased. No untoward sequelae associated with the nerve block were seen.

An investigation of experimental myasthenia gravis.

Guinea-pigs were immunized with antigen prepared from calf thymus and muscle, and from guinea-pig thymus, and rats were immunized with antigen prepared from rat thymus and rat muscle. There was an increased incidence of delayed hypersensitivity and circulating thymus antibodies in the immunized guinea-pigs and an increased incidence of thymitis in the immunized guinea-pigs and rats. However, when compared with control animals, there was no electrophysiological evidence of impairment of neuromuscular transmission in the immunized animals.

On the mechanism by which calcium and magnesium affect the spontaneous release of transmitter from mammalian motor nerve terminals.

1. The frequency of miniature end-plate potentials (m.e.p.p.s) was recorded from neuromuscular junctions in rat diaphragm phrenic nerve preparations in vitro after preparations had soaked in solutions containing Ca in concentrations between 10(-10) and 10(-2)M and a similar range of [Mg].2. Ethylenediamine tetra-acetate (EDTA) and ethyleneglycol bis (beta-aminoethyl ether) tetra-acetate (EGTA) buffers were added to prepare solutions with [Ca] and [Mg] below 10(-4)M. A computer program was used to estimate the free [Ca(2+)] in these solutions, and it was shown that the effects of Ca could be attributed to the free [Ca(2+)] in the bathing solution.3. M.e.p.p.s could still be detected without difficulty after soaking preparations for 6-8 hr in solutions containing EDTA or EGTA buffers and no added Ca. The basal frequency was unchanged upon exhibition of Ca in concentrations up to 10(-5)M and/or Mg in concentrations up to 10(-3)M.4. Ca in concentrations of and above 10(-4)M accelerated m.e.p.p. frequency from the basal level. This effect reached a maximum in [Ca] of 10 mM and raising the [Ca] above this level did not further change frequency. These effects were explained by the combination of Ca molecules with a nerve terminal receptor site. It was postulated that this combination allosterically activated the spontaneous release mechanism.5. Mg could accelerate m.e.p.p. frequency in the absence of added Ca. The interactions of Ca and Mg upon m.e.p.p. frequency indicated that Ca and Mg competed for the same sites.6. Raising the [H(+)] of the bathing medium accelerated m.e.p.p. frequency. This effect was thought to be exerted partly by combination with the same receptor sites as Ca and Mg and partly by variation of the ionization of the CaCl(2) of the bathing solution.

An examination of the effects of osmotic pressure changes upon transmitter release from mammalian motor nerve terminals.

1. When the frequency of miniature end-plate potentials (m.e.p.p.s) was measured at neuromuscular junctions in rat diaphragm nerve preparations in vitro bathed in solutions having osmolarities between 200 and 700 m-osmoles/l. it was found that m.e.p.p. frequency was transiently increased by exposure to osmotic gradients exceeding 75 m-osmoles/l., and then declined, within 1 hr, to a steady level slightly higher than the control level of frequency. Smaller osmotic gradients caused a maintained increase in m.e.p.p. frequency. E.p.p. quantal content was initially increased and later profoundly decreased upon exposure of preparations to solutions with an osmotic pressure of 500 or 600 m-osmoles/l. but was unaffected by less hypertonic solutions.2. Variation of the Ca or Mg content of the bathing solutions did not alter these effects of osmotic pressure on the early transient increase in m.e.p.p. frequency or e.p.p. quantal content but affected the late steady increase in m.e.p.p. frequency.3. The value of the transient increase in m.e.p.p. frequency was exponentially related to the osmotic gradient in the range 0-300 m-osmoles/l. with a Q(10) of 1.95 (range 11-34 degrees C). Greater osmotic gradients did not further increase m.e.p.p. frequency. Variation of the ionic strength of the bathing medium did not influence osmotic effects upon frequency.4. The discrepancy between the effects of osmotic gradients upon spontaneous and nerve-impulse induced transmitter release was explained by an occlusion of the osmotic effects by depolarization of nerve terminals. Time-course studies showed that in the presence of 20 mM-KCl the m.e.p.p. frequency increase in response to an increase in osmotic pressure was small and was followed by a reduction in frequency to below control levels while osmotic pressure changes had no immediate effect upon m.e.p.p. frequency in solutions containing 30 mM-KCl.5. It was concluded that increased osmotic gradients could release transmitter by a mechanism independent of Ca and of nerve terminal depolarization.6. It is suggested that the initial transient effects of changes of osmotic gradient upon transmitter release are related to flow of water through the nerve terminal membrane, while the later effects are related to nerve terminal volume changes.