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PubMed1998

Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. II. Evidence from selective inactivation of cell bodies and axon initial segments.

The results presented in the companion paper showed that extracellular electrical stimulation of the gray matter directly activates axons, but not cell bodies. The second set of experiments presented here was designed to separate the contribution of the axon initial segments and cell bodies from that of the axonal branches to the pool of presynaptic neuronal elements activated by electrical stimulation. For that purpose, N-methyl-D-aspartate (NMDA) iontophoresis was used to induce a selective inactivation of the cell body and of the adjoining portion of the axon by depolarization block, without affecting axonal branches that lack NMDA receptors. After NMDA iontophoresis, the neurons located near the iontophoresis electrode became unable to generate action potentials in an irreversible manner. When the NMDA-induced depolarization block was performed at the site of electrical stimulation, an unexpected increase in the amplitude of the orthodromic responses was observed. Several control experiments suggested that the field potential increase was due to changes of the local environment in the vicinity of the iontophoresis pipette, which led to an increased excitability of the axons. After the period of superexcitability, the orthodromic responses displayed an amplitude that was 15-20% lower than that observed before the NMDA-induced depolarization block, even though cell bodies and axon initial segment at the site of stimulation could not be activated by electrical stimulation. This result shows a low contribution for axon initial segments to the pool of neuronal elements activated by the electrical stimulation. Altogether, these experiments demonstrate that the postsynaptic responses obtained after electrical stimulation of the cortical gray matter result almost exclusively from the activation of axonal branches. Since the neocortex is organised as a network of local and long-range reciprocal connections, great attention must be paid to the interpretation of data obtained with electrical stimulation.

Animals↗

PubMed2004

Pharmacokinetics of acyclovir in rabbit skin after i.v.-bolus, ointment, and iontophoretic administrations.

The aim of this study was to characterize and compare the pharmacokinetics of acyclovir (ACV) in skin and plasma after iontophoresis, i.v.-bolus, and ointment administrations in rabbit. On five occasions, each separated by at least 1-week washout, rabbits received a 10 mg/kg dose of ACV as i.v.-bolus, ACV iontophoresis for 1 h at different current densities (100, 200, 300 microA/cm2) or a commercially available ointment for two hours. Blood samples were collected serially up to 6 h. Skin ACV concentrations were monitored via microdialysis using linear microdialysis probes (1 cm window). Cathodic iontophoresis was performed using commercially available patches (10 cm2 contact area). Following i.v.-bolus, C(max) in skin occurred with a delay of 38 +/- 4 min compared with plasma. No quantifiable concentration of ACV was detected in the skin on passive drug delivery. Following iontophoresis, skin exposure to ACV was 40, 22, and 11% of that following i.v.-bolus. Conversely, systemic exposure to ACV was negligible and plasma concentrations were below the limit of quantification at any time-point. In skin dialysate, C(max), AUC, and half-life increased with current density. During ointment application, ACV in dermis was detectable only for the first 30 min thereafter ACV skin concentrations were below the LOQ (30 ng/ml).

Acyclovir↗

PubMed2006

Combination strategies for enhancing transdermal absorption of sumatriptan through skin.

The aim of the present work was to characterize in vitro sumatriptan transdermal absorption through human skin and to investigate the effect of chemical enhancers and iontophoresis applied both individually and in combination. A secondary objective was to compare the results obtained with those in porcine skin under the same conditions, in order to characterize the relationship between the two skin models and validate the porcine model for further research use. Transdermal flux of sumatriptan was determined in different situations: (a) after pre-treatment of human skin with ethanol, Azone (1-dodecyl-azacycloheptan-2-one), polyethylene glycol 600 and R-(+)-limonene, (b) under iontophoresis application (0.25 and 0.50 mA/cm(2)) and (c) combining chemical pre-treatment and iontophoresis at 0.50 mA/cm(2) current density. All the strategies applied enhance sumatriptan transdermal absorption. A linear relationship between the fluxes in the two skin models in the different conditions assayed can be established. The combination of both strategies, Azone and iontophoresis, proved to be the most effective of the techniques for enhancing the transdermal absorption of sumatriptan. The flux obtained with porcine skin in vitro is approximately double that obtained in human skin.

Adjuvants, Pharmaceutic↗

PubMed2005

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment.

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 microA/cm2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6+/-0.8% to 13.2+/-1.4%) and of the steady state input rate (from 75.3+/-6.6 to 98.3+/-12.1 nmol/cm2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.

Administration, Cutaneous↗

PubMed2006

Low-frequency oscillations of the laser Doppler perfusion signal in human skin.

Spectral analysis of the laser Doppler flow (LDF) signal in the frequency interval from 0.0095-2.0 Hz reveals blood flow oscillations with frequencies around 1.0, 0.3, 0.1, 0.04 and 0.01 Hz. The heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, the neurogenic activity of the vessel wall and the vascular endothelium influence these oscillations, respectively. The first aim of this study was to investigate if a slow oscillatory component could be detected in the frequency area below 0.0095 Hz of the human cutaneous blood perfusion signal. Unstimulated basal blood skin perfusion and enhanced perfusion during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were measured in healthy male volunteers and the wavelet transform was computed. A low-frequency oscillation between 0.005 and 0.0095 Hz was found both during basal conditions and during iontophoresis with ACh and SNP. Iontophoresis with ACh increased the normalized amplitude to a greater extent than SNP (P = 0.001) indicating modulation by the vascular endothelium. To gain further insight into the mechanisms for this endothelium dependency, we inhibited nitric oxide (NO) synthesis with N(G)-monomethyl-L-arginine (L-NMMA) and prostaglandin (PG) synthesis by aspirin. L-NMMA did not affect the increased response to ACh vs. SNP iontophoresis in the 0.005-0.0095-Hz interval (P = 0.006) but abolished the difference in the 0.0095-0.021-Hz interval (P = 0.97). Aspirin did not affect the difference in response to ACh and SNP in either of the two frequency intervals. Thus, other endothelial mechanisms, such as endothelium-derived hyperpolarizing factor (EDHF), might be involved in the regulation of this sixth frequency interval (0.005-0.0095 Hz).

Acetylcholine↗

PubMed1998

Spatial extension of sudomotor axon reflex sweating in human skin.

Acetylcholine (ACh) applied to human skin is known to elicit a sweat response, which consists of a direct muscarinergic (M3) activation of sweat glands and a nicotinic axon reflex response from sudomotor terminals. To visualize the extent of axon reflex sweating after ACh-iontophoresis, iodine starch staining was used. Iontophoresis was performed under occlusion at the peroneal aspects of the lower leg and the center of the foot dorsum of healthy volunteers (n = 10). Ten minutes after stimulation, the area of dark blue staining was recorded by a video camera. Control experiments were performed with saline, histamine, pilocarpine and nicotine iontophoresis. The stained area was measured and the maximum and minimum distance of its boundary from the edge of the iontophoresis probe was determined (maximum/minimum radius). Sizes of stained areas and maximum radii were significantly greater on the lower leg compared to the foot (P < 0.01). The median sizes of the stained areas on the leg were 14.6 cm2 and on the foot dorsum 8.0 cm2. The respective median maximum radii were 3.1 cm on the leg and 2.3 cm on the foot dorsum (median minimum, leg 1.1 cm, foot 0.8 cm). These results match microneurographic findings of innervation territories of sympathetic efferent units. Area sizes of stained skin showed a close correlation between both stimulation sites (R = 0.96, P < 0.01), i.e. the sizes of sweat responses on leg and foot show a constant relation (foot/leg = 0.57) in spite of their great interindividual variability. This novel technique of establishing sweat responses provides information on the size of sudomotor innervation territories and may be useful for clinical studies in patients with suspected impairment of sympathetic functions.

Acetylcholine↗

PubMed1999

Noradrenaline provokes axon reflex hyperaemia in the skin of the human forearm.

High doses of noradrenaline increase the sensitivity of skin to heat, presumably by sensitizing nociceptive afferent fibres. Since activation of these fibres increases local blood flow by an axon reflex mechanism, noradrenaline might simultaneously evoke adrenoceptor-mediated vasoconstriction and axon reflex vasodilatation. To investigate this possibility, noradrenaline was introduced into the skin of the human forearm by iontophoresis, and changes in blood flow were monitored in nearby skin. Increases in blood flow were greater near the site of noradrenaline iontophoresis than near the site of saline iontophoresis. Since the response was limited in its distribution to a few centimeters from the site of iontophoresis, hyperaemia was most likely due to a local mechanism rather than a spinal or supraspinal reflex. In addition, pretreatment of the skin with a local anaesthetic cream inhibited the increase in flow, indicating that the response was mediated neurally. These findings suggest that activation of nociceptive afferents by noradrenaline provokes axon reflex hyperaemia.

Adolescent↗

PubMed2001

In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species.

Transdermal iontophoresis would be a promising method for the systemic delivery of water soluble and ionic drugs of relatively high molecular size, including peptides. In the present study, the effect of biological parameters such as age of the animal and species variation (rat, rabbit, mouse, guinea pig and human) on the transdermal iontophoretic transport was studied using timolol maleate (TM) as a model drug. The iontophoretic transport of TM across the skins obtained from the rats of different age groups was found to be similar. The results of the present study suggest that the age of the animal (Wistar rats: 1-8 months) did not appear to influence the transdermal iontophoretic transport of TM significantly. The amount of TM transported during iontophoresis (2 h) was significantly different among the different skin species. But the total amount of TM transported up to 24 h (2 h iontophoresis+22 h post-iontophoretic passive diffusion) was not significantly different among the different species studied. The present study provides further evidence that iontophoresis technique reduces the interspecies differences in the transdermal permeation of drugs, which is normally observed in passive diffusion of drugs. However, it must be noted that excised skins have been used in the present study to investigate the role of age and species variation on the iontophoretic transport of TM. The influence of these parameters under in vivo conditions might be different considering the physiological differences in different species and in the animals of different age groups.

Administration, Cutaneous↗

PubMed2002

Reverse iontophoretic monitoring in premature neonates: feasibility and potential.

Premature neonates represent a fragile patient population, often subjected to intensive clinical care and multiple drug therapy, which must be monitored carefully and continuously. The difficult and painful nature of repetitive blood sampling, particularly in this population, has provided considerable impetus for the development of noninvasive methods for monitoring blood analytes. Reverse iontophoresis, a relatively new technology already used for the transdermal monitoring of blood glucose levels in adults, may be particularly well-suited to exploit the unique properties of preterm neonatal skin. The underdevelopment of the premature infant's epidermis, and more specifically the stratum corneum (SC), results in an increased permeability to molecular transport. In this study, we have investigated the feasibility of reverse iontophoretic monitoring of two model drugs, caffeine and theophylline, which are often administered to premature neonates. To this purpose, tape-stripped porcine skin in vitro, which has been previously demonstrated to be an excellent model for premature neonatal skin, was employed. Reverse iontophoresis across intact membranes enabled a quantifiable extraction of both drugs predominantly at the cathode compartment. The mechanism of extraction of these essentially neutral drugs (caffeine and theophylline being uncharged at pH 7.4) was electroosmosis. However, when the SC was removed by progressive tape-stripping, the amounts of drugs extracted by reverse iontophoresis were equivalent to those obtained by passive diffusion. In these circumstances, therefore, the benefit and usefulness of the applied electric field had been lost. In summary, the absence of an at least partially functional skin barrier obviates, in the case of neutral molecules, the control (and directional transport) offered by iontophoresis; in contrast, for ionized species, where the principal iontophoretic transport mechanism is electromigration, the approach should be valid.

Animals↗

PubMed2002

Iontophoretic delivery of apomorphine: from in-vitro modelling to the Parkinson patient.

Apomorphine is a mixed dopamine D1/D2 receptor agonist which is potentially useful in the treatment of Parkinson's disease. The delivery of apomorphine is however complicated because it is not absorbed orally and other delivery routes with the exception of the intravenous route seem to fail. The most interesting route for controlled delivery of apomorphine is transdermal iontophoresis because this could enable the Parkinson patient to directly control the needed amount of apomorphine by increasing or decreasing the drug input in order to achieve optimal drug therapy ('on-demand') with a minimum of toxic side effects. The typical features of Parkinson's disease could be used to monitor the needed drug input and even more elegantly by means of suitable chip sensors which are able to directly measure bradykinesia, akinesia and/or tremor and to regulate in such a way the drug input. Such a chip-controlled iontophoretic system would be the first closed-loop system monitoring not pharmacokinetic data (blood levels) but more importantly externally measurable pharmacodynamic effects of Parkinson's disease. This scenario is more feasible as skin irritation and toxicity studies have proven that iontophoresis is a safe route of treatment. This review describes the basics of iontophoresis and the development of a transdermal iontophoretic delivery system on the basis of integrated pharmacokinetic/pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. Transdermal iontophoretic transport of apomorphine was studied both in vitro with human stratum corneum using a newly developed iontophoretic continuous flow-through transport cell and in vivo in a first exploratory study in patients with Parkinson's disease. These studies showed that the delivery of apomorphine is feasible and furthermore the rate of delivery can be controlled by variation of the current densities. Additionally the pretreatment of the skin either with a mono-surfactant or a vesicular suspension of elastic liquid-state vesicles may be useful to further increase the apomorphine flux across the skin in combination with iontophoresis.

Administration, Cutaneous↗

PubMed1998

The involvement of metabotropic glutamate receptors in sensory transmission in dorsal horn of the rat spinal cord.

The role of metabotropic glutamate receptors in the processing of somatosensory information was studied in dorsal horn neurons of the rat spinal cord. Activation of metabotropic glutamate receptors by local iontophoresis of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid resulted in an increased response of dorsal horn neurons to ionotropic glutamate receptor agonists (N-methyl-D-aspartate and kainic acid) applied by iontophoresis. Greater amounts of 1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid, ejected at high iontophoresis currents, directly excited dorsal horn neurons. Application of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid also led to a significant increase in responses to innocuous (brush, pressure) but not in responses to noxious (pinch, squeeze) mechanical stimulation. The excitatory effects of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid were selectively blocked by (S)-4-carboxy-3-hydroxyphenyl-glycine, an antinociceptive phenylglycine derivative which is a selective group 1 metabotropic glutamate receptor antagonist, confirming the involvement of these receptors. In wide dynamic range neurons, wind-up, the progressive potentiation of C-fibre-evoked responses during a train of stimuli, was increased by iontophoretic application of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid or decreased by iontophoresis of (S)-4-carboxy-3-hydroxyphenyl-glycine without significant change in the C-fibre input. The results suggest an interaction between metabotropic and ionotropic glutamate receptors in spinal dorsal horn neurons. Metabotropic glutamate receptors proved to be involved in the frequency-dependent potentiation of C-fibre responses possibly via modulation of ionotropic glutamate receptors. The long-lasting effects of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid on wind-up and on responses to peripheral mechanical stimuli strongly support the view that metabotropic glutamate receptors in these neurons may play a significant role in spinal synaptic plasticity, and therefore, may contribute to the central sensitization during mechanical hyperalgesia.

Animals↗

PubMed2000

Enhanced transdermal delivery of tetracaine by electroporation.

The effect of electroporation on the transport of tetracaine through skin in vitro was studied using side-by-side compartment diffusion cells method. After achieving steady state by passive diffusion, fluxes of tetracaine achieved with passive diffusion, electroporative pulse and iontophoresis were compared. Electroporation (square-wave pulse, voltage 130 V, pulse time 0.4 s, pulse frequency 40 pulses min(-1)) or iontophoresis (0.2.mA cm(-2), lasting for 4 h) increased the transport of tetracaine through skin. The flux of tetracaine at 0.25 h after electroporation (pulse number 400) was 54.6+/-6.0 microg.cm(-2).h(-1), that after iontophoresis was 17.4+/-5.8 microg.cm(-2).h(-1) and that after passive diffusion was 8.2+/-0.5 microg.cm(-2).h(-1). In addition, the fluxes of tetracaine increased with the increasing of pulse number. From these results, it is clear that electroporation is effective in enhancing transdermal delivery of tetracaine and its function is better than iontophoresis.

Administration, Cutaneous↗

PubMed2003

Poloxamer gel as vehicle for transdermal iontophoretic delivery of arginine vasopressin: evaluation of in vivo performance in rats.

The present study describes the formulation and evaluation for pharmacokinetic and pharmacodynamic activity of arginine vasopressin (AVP), a nanopeptide with antidiuretic activity on being delivered by transdermal iontophoresis. Poloxamer 407 was used to form stable gels that did not reduce the release of AVP. The release rate from the gel followed Higuchi kinetics indicating that the dominant mechanism of release is diffusion. Iontophoresis alone and in combination with chemical enhancers was used to augment the transdermal permeation of AVP. The results of both pharmacokinetic and pharmacodynamic studies emphasize the dimension of 'rapid onset' achieved by iontophoresis. The correlation between pharmacokinetic data and pharmacodynamic activity was only qualitative. Histopathological studies revealed that skin toxicity caused by either iontophoresis or chemical enhancers when used alone could be reduced by using a combination of both the techniques in tandem.

Administration, Cutaneous↗

PubMed2004

Compartmental modeling of transdermal iontophoretic transport: I. In vitro model derivation and application.

PURPOSE: The objective of this study was to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vitro. METHODS: Two structurally different compartmental models describing the in vitro transport during iontophoresis and one compartmental model describing the in vitro transport in post-iontophoretic period are proposed. These models are based on the mass transfer from the donor compartment to the acceptor compartment via the skin as an intermediate compartment. In these models, transdermal iontophoretic transport is characterized by 5 parameters: 1) kinetic lag time (tL), 2) steady-state flux during iontophoresis (Jss), 3) skin release rate constant (K(R)), 4) the first-order rate constant of the iontophoretic driving force from the skin to the acceptor compartment (I1), and 5) passive flux in the post-iontophoretic period (Jpas). The developed models were applied to data on the iontophoretic transport in human stratum corneum in vitro of R-apomorphine after pretreatment with phosphate buffered saline pH 7.4 (PBS) and after pretreatment with surfactant (SFC), as well as the iontophoretic transport of 0.5 mg ml(-1) rotigotine at pH 5 (RTG). RESULTS: All of the proposed models could be fitted to the transport data of PBS, SFC, and RTG groups both during the iontophoresis and in the post-iontophoretic period. The incorporation of parameter I1 failed to improve the fitting performance of the model. This might indicate a negligible contribution of iontophoretic driving force to the mass transfer in the direction from the skin to the acceptor compartment, although it plays an important role in loading the skin with the drug. The estimated values of Jss of PBS, SFC, and RTG were identical (p > 0.05) to the values obtained with the diffusion lag time method. Moreover, time required to achieve steady-state flux can be estimated based on the parameter tL and the reciprocal value of parameter K(R). In addition, accumulation of drug molecules in the skin is reflected in a reduction of the value of the K(R) parameter. CONCLUSIONS: The developed in vitro models demonstrated their strength and consistency to describe the drug transport during and post-iontophoresis.

Administration, Cutaneous↗

PubMed1998

Skin electroporation causes molecular transport across the stratum corneum through localized transport regions.

High voltage pulsing of human skin (approximately 100 V across the skin, 1 ms pulses) has been hypothesized to cause electroporation of the stratum corneum, and to cause large fluxes of drugs and other molecules across the skin, through newly created aqueous pathways. In contrast, iontophoresis (<0.5 mA per cm2, <1 V across the skin) has long been used in transdermal drug delivery, and is believed to involve pre-existing pathways associated with hair follicles and sweat ducts. Either high voltage pulsing or iontophoresis was applied to human, hairless rat, or black rat snake skin. Hairless rat skin contains more hair follicles than human skin, and snake skin does not contain any hair follicles. All three types of skin had comparable electrical resistances at low voltages; however, the iontophoretic transport of charged fluorescent molecules was significant for human and hairless rat skin, but no transport occured across snake skin, indicating that hair follicles and sweat ducts play a major role in iontophoresis. Electroporation caused large molecular transport for all three types of skin, and involved spontaneously forming localized transport regions, not associated with appendages. These experiments thus provide further support for the hypothesis that high voltage pulsing causes electroporation in the stratum corneum, and that this transport mechanism is fundamentally different from iontophoresis.

Animals↗

PubMed1997

An investigation into variability in microvascular skin blood flow and the responses to transdermal delivery of acetylcholine at different sites in the forearm and hand.

AIMS: Transdermal iontophoresis in combination with laser Doppler fluxmetry (LDF) are useful techniques for examining dermal microcirculatory responses to different vasodilators. Differences in skin and microcirculation structure could influence the recorded baseline flux, and the observed vasodilatation. To examine this we compared baseline flux and the response of microvascular blood flow to a single vasodilator, acetylcholine, at sites in the forearm and hand. METHODS: Baseline microcirculation flow was recorded by LDF in a temperature controlled laboratory. The change in flux with iontophoresis of identical doses of acetylcholine, 150 microA for 40 s, was recorded at 12 different sites in the forearm and hand in 10 female and 3 male subjects. RESULTS: Baseline flux patterns and the vasodilatation to identical periods of iontophoresis of acetylcholine were site dependent. Palmar sites showed a higher baseline flux, but no vasodilatation to iontophoresis of acetylcholine. In contrast the volar forearm, dorsal hand and finger sites showed lower site-dependent baseline flux, but did vasodilate. CONCLUSIONS: Patterns of baseline flux are specific to sites on the hand and forearm reflecting differences in underlying microvascular structure. The vasodilatation to transdermal delivery of acetylcholine is also site dependent, but differences in skin structure may be more important than the underlying microvasculature in determining the response.

Acetylcholine↗

PubMed2001

Calcium-dependent effects of melatonin inhibition of glutamatergic response in rat striatum.

The effects of melatonin, amlodipine, diltiazem (L-type Ca2+ channel blockers) and omega-conotoxin (N-type Ca2+ channel blocker) on the glutamate-dependent excitatory response of striatal neurones to sensory-motor cortex stimulation was studied in a total of 111 neurones. Iontophoresis of melatonin produced a significant attenuation of the excitatory response in 85.2% of the neurones with a latency period of 2 min. Iontophoresis of either L- or N-type Ca2+ channel blocker also produced a significant attenuation of the excitatory response in more than 50% of the recorded neurones without significant latency. The simultaneous iontophoresis of melatonin + amlodipine or melatonin + diltiazem did not increase the attenuation produced by melatonin alone. However, the attenuation of the excitatory response was significantly higher after ejecting melatonin + omega-conotoxin than after ejecting melatonin alone. The melatonin-Ca2+ relationship was further supported by iontophoresis of the Ca2+ ionophore A-23187, which suppressed the inhibitory effect of either melatonin or Ca2+ antagonists. In addition, in synaptosomes prepared from rat striatum, melatonin produced a decrease in the Ca2+ influx measured by Fura-2AM fluorescence. Binding experiments with [3H]MK-801 in membrane preparations from rat striatum showed that melatonin did not compete with the MK-801 binding sites themselves although, in the presence of Mg2+, melatonin increased the affinity of MK-801. The results suggest that decreased Ca2+ influx is involved in the inhibitory effects of melatonin on the glutamatergic activity of rat striatum.

Amlodipine↗

PubMedDate not supplied

Ocular reactivation phenotype of HSV-1 strain F(MP)E, a corticosteroid-sensitive strain.

PURPOSE: Elucidate the ocular reactivation of HSV-1 strain F(MP)E. METHODS: Rabbit corneas were infected with HSV-1 strains McKrae and F(MP)E. Latency was established and rabbits were treated with epinephrine iontophoresis or corticosteroid injection (immunosuppression). Cultured tear films were used to determine the presence of infectious virus. Eyes of immunosuppressed rabbits were also examined by slit lamp biomicroscopy. Trigeminal ganglia were co-cultured on indicator cells at time of sacrifice for detection of virus. Quantitative real-time PCR was used to detect the number of viral genome copies in the trigeminal ganglia. RESULTS: Acute infections by strains McKrae and F(MP)E were the same. Ocular reactivation of strain F(MP)E by epinephrine iontophoresis was significantly reduced compared to McKrae (P </= 0.0001), but was not significantly different from McKrae after corticosteroid injection (P > 0.29). Slit lamp examination following corticosteroid injection showed a correlation of recurrent herpetic lesions with infectious virus in tear film swabs for both McKrae and F(MP)E. Trigeminal ganglia from rabbits latently infected with each strain and each method of induced reactivation resulted in infectious virus (P >/= 0.69). Genome copies for both strains were present and were highly variable. CONCLUSIONS: HSV-1 strain F(MP)E has low reactivation following epinephrine iontophoresis compared to McKrae, but has high reactivation like McKrae in response to corticosteroids. The difference in reactivation following epinephrine iontophoresis is not due to a difference in the establishment of latency.

Adrenal Cortex Hormones↗