First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model.

The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E(H); mean +/- S.E.M.), and the given doses of verapamil did not affect the E(H) (0.13 +/- 0.04, 0.16 +/- 0.03, and 0.12 +/- 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E(H) for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E(H) values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.     

Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.     

Mechanisms of action of intracerebral neural implants: studies on nigral and striatal grafts to the lesioned striatum

The ability of intracerebrally implanted grafts of neural tissues to promote functional recovery in brain-damaged recipient animals has raised the question of how such implants exert their functional effects. Non-specific, diffuse release of active compounds may be sufficient to restore defective neurotransmission in a denervated brain region, for example, or to provide trophic support for the survival and regeneration of damaged host neurons. The positive therapeutic effects of adrenal medullary grafts, recently reported in patients with Parkinson's disease, are likely to reflect such nonspecific hormonal or neurohumoral mechanisms. Morphological and electrophysiological studies, on the other hand, have shown that grafted fetal neurons can establish extensive efferent synaptic connections with previously denervated or neuron-depleted host brain regions and become at least partially integrated into the host neuronal circuitry. In the damaged nigrostriatal system, grafts of fetal nigral or striatal neurons can restore normal synaptic transmitter release and can also participate in a partial reconstruction of functional neural circuits in the host brain. This indicates that the potential of intracerebral grafts to induce or improve behavioral recovery in brain-damaged recipients rests on the multitude of trophic, neurohumoral and synaptic mechanisms that may allow the implanted tissue to promote host brain function and repair.     

Muscle membrane polarisation after provocative tests, and after cooling: the normal CMAP changes to be expected.

OBJECTIVE: To know the range of changes of compound muscle action potentials (CMAPs) in the muscles innervated by the ulnar nerve after diverse provocative tests, 14 healthy patients were studied with the same protocol. METHODS: CMAPs were measured at rest, just after a short exercise test (SET), during short 5 and 10c/s repetitive nerve stimulation (RNS) trains, at approximately 32 and approximately 20 degrees C. RESULTS: At 32 degrees C, the SET induced a significant but transient enlargement of the CMAPs (amplitude increased by 8.3%, duration decreased by 9%) that was only partially reproduced by RNS trains, except for a significant shortening of the CMAPs at 10c/s. At 20 degrees C without exercise, CMAPs increased significantly by approximately 30% in amplitude, duration and area, and after the SET the inverse of what has been seen at 32 degrees C was observed (amplitude decreased by 1.7% and duration increased by 9%). RNS at 20 degrees C produced a marked interpatient heterogeneity except for a significant shortening of the CMAPs at 10c/s. In one pure autonomic failure patient, the infusion of norepinephrine induced potentiation of the responses at rest and a decrease in the expected changes after provocative tests. CONCLUSIONS: CMAP amplitude and duration are significantly modified just after the SET at 32 degrees C, at rest at 20 degrees C and after RNS at 10c/s but not at 5c/s. Although providing indirect evidence, these findings indicate that provocative tests make the muscle membrane hyperexcitable by the way of a direct influence on the electrical events and by an indirect local catecholamine spillover.     

Survival and immunogenicity of dissociated allogeneic fetal neural dopamine-rich grafts when implanted into the brains of adult mice

Summary The survival of grafts of dissociated allogeneic fetal neural dopamine (DA) rich tissue in the striatum has been studied after transplantation between inbred strains of mice differing at defined immunogenetical loci between donor and recipient. Six to 7 weeks and 15 weeks after grafting, surviving grafted DA neurons were found in the brains of all the recipients, albeit with a large variation in numbers, located either within the striatum or within the adjacent lateral ventricle. The mean number of surviving DA neurons did not differ between the syngeneic controls and the histoincompatible donor-host combinations, and there was no difference in survival between grafts that differed at single or multiple major histocompatibility complex (MHC) loci, and those that differed at multiple non-MHC loci. The amount of inflammatory cells in the graft area did not differ between the groups, and none of the animals showed massive infiltration of inflammatory cells. The in situ immunogenicity of the grafted neural tissue after intracerebral implantation was monitored by means of Simonsen's alloimmunization test, at 6–7 weeks after transplantation, which provides a sensitive measure primarily of the cellular immunological response. Most, but not all, graft recipients showed immunization with a Spleen Index (S.I.) close to that seen in recipients of an orthotopical skin graft of the same histoincompatibility combination. In contrast to the prolonged survival of the intracerebral neural transplants, none of the skin grafts survived longer than 3 weeks, thus demonstrating the immunologically privileged status of the brain. We conclude that intracerebrally grafted allogeneic neural tissue is capable of provoking a cellular immune response. Despite host immunization, however, the dissociated fetal neural allografts survived for at least 15 weeks without any overt signs of rejection, regardless of the donor-host combination used.     

Demonstration of A-currents in pancreatic islet cells

Voltage-activated K⁺ currents resistant to TEA but blockable by 4-AP were recorded from mouse pancreatic islet cells. These currents first become observable during depolarizations to voltages more positive than –40 mV, reaching a peak amplitude of 120±34 pA at +6 mV (n=4), display rapid turn on (=3.3±1.1 ms at +6 mV) and inactivate completely within 250 ms (=65±5 at +6 mV). The current is subject to steady-state inactivation. The midpoint (V _h) of the inactivation curve (h) was observed at –72±2 mV. The properties of this current resemble those reported for the A-current in neurons.     

Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials

The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K8644-like action on Ca2+ channel gating.     

Inhibitory effects of clonidine on the allergen-induced wheal-and-flare reactions in patients with extrinsic asthma

We investigated the possibility that clonidine, an alpha 2-adrenoceptor agonist, can reduce the wheal-and-flare reactions induced by intradermal injections of allergen in patients with extrinsic asthma. Ten adult subjects with asthma with positive skin tests to one or several pollens were selected. They received, in random order and double-blind manner, clonidine (two doses, each 75 micrograms) or placebo for 3 days, and then, after a 1-week washout period, they crossed over to the other treatment for 3 days. Treatment with clonidine reduced the area of wheal-and-flare reaction induced by allergen without significantly changing the blood pressure or the plasma cortisol level. There was a drop in the histamine content of leukocytes and in the number of eosinophils in peripheral blood after allergen challenge during the placebo treatment, whereas clonidine prevented these changes. The results suggest that treatment with clonidine can reduce the inflammatory reactions induced by allergens in subjects with extrinsic asthma.     

Evaluation of the imaging properties of two generations of a CCD-based system for digital chest radiography

Two generations of a CCD-based detector system with lens-based optical coupling for digital chest radiography were evaluated in terms of presampling MTF, NPS, NEQ, DQE, linearity in response, and SNR over the detector area. Measurements were performed over a wide exposure range and at several different beam qualities. Neither the presampling MTF nor the DQE showed any general strong beam quality dependence, whereas the NPS and NEQ did when compared at specific entrance air kerma values. The exposure dependency for the DQE was found to be considerable, with the detectors showing low DQE at low exposures, and higher DQE at higher exposures. It was found that the second generation has been substantially improved compared to its predecessor regarding all the relevant parameters. The DQE(0) at an entrance air kerma of 5 microGy increased from 9% to 15%, mainly due to a better system gain (including optical coupling efficiency and matching of the energy of the emitted light photons to the sensitivity of the CCD camera). The first generation of detectors was found to have problems with bad peripheral resolution [MTF(muN/2) <0.1]. This problem was nonexistent for the second generation for which uniform resolution has been obtained [MTF(muN/2)=0.3]. A theoretical calculation of the DQE of two model systems similar to the ones evaluated was also performed, and the results were comparable to the experimentally determined data at high exposures. The model shows that both systems suffer from low optical coupling efficiency due to the large demagnification used. The main conclusion is that although the second generation has been improved, there is still a problem with low system gain leading to relatively modest DQE values, especially at low exposures.