Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients.

BACKGROUND: We examined the relationship between voriconazole utilization and non-melanoma skin cancer (NMSC) development among adult lung and heart/lung transplant patients who were continuously enrolled in a large U.S. commercial health plan. METHODS: Cox proportional hazards regression models were constructed to assess both the crude and adjusted effect of voriconazole usage on NMSC development. Overall, 467 adult lung (98%) and heart/lung (2%) transplant patients (60% male) with median age of 58 years were analyzed. RESULTS: Fifty-seven (12%) patients developed NMSC over a median follow-up time of 610 days. At the crude level, patients with any (vs. none) claim for voriconazole were more likely to develop NMSC (19% vs. 12%, hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.02, 2.96, P = 0.04). However, after statistical adjustment for demographic and clinical factors, the effect was largely diminished and no longer statistically significant (HR: 1.23, 95% CI: 0.71, 2.14, P = 0.45). Results were similar when modeling average and total dose of voriconazole. Risk factors significantly related to NMSC development were being male, older age, sun exposure, history of chronic obstructive pulmonary disorder, and history of immune disorder. CONCLUSION: Results suggest that the relationship between voriconazole utilization and NMSC among lung transplant patients may be a result of confounding by indication, and that controlling for underlying patient characteristics is paramount.

De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha?

Cryoglobulinaemic mononeuritis multiplex (MNM) is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.

Synchronized GABAergic IPSPs recorded in the neocortex after blockade of synaptic transmission mediated by excitatory amino acids.

1. Intracellular and extracellular recordings were carried out in guinea pig neocortical slices to examine the effects of blockade of excitatory amino acid (EAA) synaptic transmission on population discharges elicited by 4-aminopyridine (4-AP; 50-100 microM). 2. After the introduction of 4-AP, two distinct types of rhythmic spontaneous field potentials were recorded in neocortical slices. Type I consisted of multiple spike discharges lasting 20-90 s. These events occurred at a frequency of 0.4-0.2/min. Type II were single field potential spikes (3-6 s in duration) occurring at a higher frequency (2-4/min). 3. Blockade of amino acid-mediated excitatory synaptic transmission with D-2-amino-5-phosphonovaleric acid (D-AP5; 10-30 microM) or 3-(2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP, 10 microM) and 6-cyano-7nitroquinoxaline-2,3-dione (CNQX; 10 microM) abolished the first type of 4-AP-induced field potential, whereas type II events persisted. 4. Type II field events, occurring in the presence of EAA blockers, were further characterized by paired recordings. Events recorded along an axis orthogonal to the pia surface occurred simultaneously without measurable delay. Recordings made along a plane parallel to the pia surface showed that type II discharges propagated over distances of greater than or equal to 3 mm at an estimated velocity of 7.5 mm/s. 5. Intracellular recordings show that during type II field discharges all cells exhibited phasic depolarizations or hyperpolarizations, depending on the resting membrane potential. When resting potentials were more depolarized than -68 mV, events became mostly hyperpolarizing.(ABSTRACT TRUNCATED AT 250 WORDS)

Neocortical epileptogenesis in vitro: studies with N-methyl-D-aspartate, phencyclidine, sigma and dextromethorphan receptor ligands.

Slices of rat neocortex have been used to study the role of N-methyl-D-aspartate (NMDA) receptors in the induction of epileptiform activity. The NMDA antagonist potency of a range of compounds with putative anticonvulsant activity has been compared with their ability to reduce epileptiform activity in this tissue. Epileptiform activity was induced by the omission of magnesium from the bathing medium. Competitive and noncompetitive phencyclidine-like NMDA antagonists reduced such spontaneous and stimulus-evoked epileptiform bursts and after potentials. Similar epileptiform activity induced by the addition of proconvulsant drugs, e.g. gamma-aminobutyric acidA antagonists, potassium channel blockers or carbachol was reduced by ketamine and/or D-2-amino-5-phosphonovaleric acid. In magnesium-free medium, the frequency of spontaneous bursts and the number of afterpotentials per burst were reduced in parallel. There was a good correlation (r greater than 0.9) between their potencies against NMDA depolarizations and against epileptiform bursts (MK-801 [(+)-5-methyl-10,11- dihydro-5H-dibenzvo[a,d]cyclohepten-5,10-imine] greater than thienylcyclohexylpiperidine phencyclidine greater than 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid greater than cyclazocine greater than D-2-amino-5-phosphonovaleric acid greater than dextrorphan greater than SKF10,047 (N-allylnormetazocine) greater than ketamine greater than dextromethorphan = or greater than pentazocine). Sigma and dextromethorphan receptor ligands (e.g. ditolyguanidine, carbetapentane and phenytoin), whereas inactive as NMDA antagonists, reduced epileptiform activity by decreasing the number of afterpotentials per burst with less effect on the burst frequency. The quisqualate/kainate antagonist, FG9041 (6,7-dinitro-quinoxaline-2,3-dione), only reduced spontaneous bursts at doses which also reduced NMDA. Our results imply a central role for NMDA receptors in epileptogenesis in neocortical slices.

Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro.

1. Two quinozalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N-methyl-D-aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least. 2. The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and and about 4 in the rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5. 3. At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically-evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium-containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type. 4. By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium-free medium. These burst discharges were, however, abolished by NMDA antagonists. 5. In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components. 6. Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non-NMDA receptors in the vertebrate central nervous system.

A1 adenosine receptor-mediated block of epileptiform activity induced in zero magnesium in rat neocortex in vitro.

It has been suggested that endogenous chemical substances such as adenosine, released during a seizure attack, may act as anticonvulsants in vivo. To further investigate this putative role, we have tested adenosine and stable adenosine analogues for anticonvulsant activity in vitro against ictal-like epileptiform activity induced by the removal of magnesium ions from medium superfusing wedges and slices of rat neocortex. Purinoceptor agonists attenuated such burst activity with a potency profile of L-phenylisopropyl-adenosine greater than 2-chloroadenosine greater than adenosine, suggesting that their anticonvulsant actions were mediated via the A1 adenosine receptor sub-type. Adenosine exerted no apparent effect on responses to agonists acting at glutamate receptor sub-types, implying no direct postsynaptic activity at glutamatergic synapses. Adenosine receptor antagonists, the methylxanthines (3-isobutyl-1-methylxanthine greater than theophylline) markedly enhanced established epileptiform activity and reversed the anticonvulsant action of adenosine. The selectivity of this reversal was demonstrated by the lack of effect of methylxanthines on pentobarbitone-induced inhibitions of epileptiform bursts. When added to a normal medium containing 1 mM magnesium, the methylxanthines were unable to induce long-lasting ictal-like epileptiform activity.

Validation of a neocortical slice preparation for the study of epileptiform activity.

A simple slice chamber was designed to achieve easy manipulations of temperature, ionic composition and drug concentrations. Spontaneous and evoked extracellular potentials could be recorded with glass microelectrodes from 500 micron thick slices of rat frontal neocortex. In the absence of magnesium ions in the superfusing medium or in the presence of convulsant agents, epileptiform activity was seen. The amplitude of this activity was greatest in layer II/III, each burst consisting of a long-lasting negative potential on the decay phase of which were superimposed many afterpotentials. There were multiple foci from which spontaneous epileptiform bursts spread to other ipsi- and contralateral parts of the cortex via both the grey and white matter. Although such bursts were observed between 23 and 37 degrees C, optimal recording of discrete epileptiform activity was achieved at 29 +/- 1 degrees C. Decreasing extracellular calcium or increasing extracellular concentrations of potassium enhanced burst discharges. Proconvulsant agents initiated both interictal and ictal epileptiform events. This, together with the reduction of epileptiform activity by standard anticonvulsant drugs such as carbamazepine and phenobarbitone suggested that this in vitro model may be useful for studying the pharmacology of epileptogenesis and for developing new therapeutic strategies for epilepsy.

Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands.

We have used microelectrophoretic and intravenous administration of drugs to rat spinal cord neurones in vivo and bath application to rat cortical wedges in vitro to evaluate MK-801 and other phencyclidine (PCP) receptor ligands as N-methylaspartate (NMA) antagonists, paying particular regard to the possible use-dependent nature of their action. MK-801, 0.1-0.5 mg/kg, was a selective and long-lasting NMA antagonist. We were unable to demonstrate significant use-dependent onset of antagonism of NMA by any of the drugs in vivo. Recovery, however, for MK-801 was use-dependent. In vitro there was a gradation with MK-801 being very use-dependent, followed by (PCP), cyclazocine and ketamine, the last showing little or no use-dependence. Results of experiments modulating the in vitro environment suggest that a significant difference between the in vitro and in vivo systems was temperature. Raising the temperature of the wedge chamber from 23 to 33 degrees C reduced the use-dependence of MK-801, and lowering the temperature to 13 degrees C increased the use-dependence of PCP. The mechanism of action of PCP receptor ligands is discussed in the light of these results.

Epileptiform activity induced by alkalosis in rat neocortical slices: block by antagonists of N-methyl-D-aspartate.

The effects of changing extracellular pH on epileptiform activity induced by the removal of magnesium ions from the perfusing medium were studied. The proportion of bicarbonate in the artificial cerebrospinal fluid and of CO2 in the gas mixture were altered to mimic metabolic and respiratory acid-base disturbances. Changes in pH of 0.2 unit from control produced marked effects. Epileptiform activity was enhanced by alkalosis and diminished by acidosis. In normal magnesium-containing medium metabolic alkalosis (pH greater than 7.8) induced spontaneous epileptiform activity that was blocked by selective N-methyl-D-aspartate antagonists. The relevance of these findings to acid/base changes in clinical epilepsy is discussed.