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P Calabresi

Publications and source records attributed to P Calabresi.

At least 199 records · Page 11Linked to original sources
PubMed1989

Met- and leu-enkephalins inhibit rat cortical neurons intracellularly recorded in vivo while morphine excites them: evidence for naloxone-sensitive and naloxone-insensitive effects.

The action of enkephalin-analogues (D-ala2-D-leu5-enkephalin and D-ala2-D-met-enkephalin) and morphine, iontophoretically applied, was tested on rat cortical neurons intracellularly recorded "in vivo". Inhibition of cellular excitability of 60% of the tested cells followed the iontophoretic administration of opioid peptides. 50% of the inhibited cells were also hyperpolarized. The amplitude of membrane hyperpolarization was related to the value of the membrane potential. In 13 out of the 30 inhibited cells the change in membrane input resistance was measured; the input resistance was decreased by 30%. In 8 cells, hyperpolarized by the opioid peptides, the depolarizing postsynaptic potentials, evoked by cortical stimulation, were also reduced in amplitude. Naloxone, iontophoretically applied, reversed and/or prevented the peptide responses. On the same neurons, morphine induced a bursting pattern of spiking activity and increased the membrane input resistance: this action was naloxone-insensitive. The reported results suggest that opioid peptides and morphine activate, respectively, naloxone-sensitive and naloxone-insensitive mechanisms on the same cortical neurons, leading to different and, in some respect, opposite effects on the neuronal activity.

Animals↗
PubMed1989

Selective depression of synaptic transmission by tetanus toxin: a comparative study on hippocampal and neostriatal slices.

Tetanus toxin reduces the release of neurotransmitters in several brain areas. We have studied the effects of this toxin on the intrinsic and synaptic activity of CA1 hippocampal neurons and of neostriatal cells in the rat by utilizing intracellular and extracellular recordings from slice preparations. Tetanus toxin (10 micrograms/ml) applied by bath produced an increase of the field potentials evoked by the orthodromic stimulation of the CA1 region coupled with the disappearance of the inhibitory period following the first conditioning stimulus. Orthodromically and antidromically activated postsynaptic hyperpolarizing potentials were also decreased and spontaneous bursting activity was observed following the application of tetanus toxin. At this concentration the toxin did not alter excitability in neostriatal cells and in these neurons even 30-50 micrograms/ml of the toxin produced only a slight increase of excitability. Higher concentrations (100 micrograms/ml) of tetanus toxin reduced the excitatory synaptic transmission in the hippocampus as well as in the neostriatum. The toxin (10-100 micrograms/ml) did not alter membrane potential, input resistance or directly evoked firing in both these structures. We conclude that, although the toxin's mechanisms of action in the neostriatum are similar to those operating in the hippocampus (i.e. decrease of inhibitory and/or excitatory inputs), the local synaptic circuits produce differential electrophysiological effects in these two structures.

Action Potentials↗
PubMed1989

The mechanism of amphetamine-induced inhibition of rat substantia nigra compacta neurones investigated with intracellular recording in vitro.

1. The effects of (+)-amphetamine (1-300 microM) applied by superfusion, on substantia nigra zona compacta neurones were studied in slices of the rat mesencephalon with intracellular recording techniques (current and voltage clamp mode). 2. Amphetamine inhibited the action potential discharge, hyperpolarized the cells and increased the membrane conductance. Under voltage clamp it produced an outward current. 3. The amphetamine outward current reversed at potentials negative to -100 mV (2.5 mM extracellular potassium) and was reduced by barium, (1 mM) suggesting an increased potassium conductance. 4. In slices treated with tetrodotoxin and calcium-free solution and added cobalt, amphetamine was still effective. 5. (-)-Sulpiride, (1 microM) a D2 antagonist, blocked the effects of both amphetamine and dopamine. 6. In slices treated for more than 3 h with 30 microM alpha-methyl-DL-tyrosine, an agent known to block the synthesis of dopamine, the action of amphetamine was attenuated, while dopamine was still effective. 7. Responses to applied dopamine were potentiated by cocaine (10 microM) but unaffected by amphetamine (1-3 microM). 8. It is suggested that the inhibition of substantia nigra compacta neurones by amphetamine is mainly due to the release of endogenous dopamine.

Amphetamine↗
PubMed1989

Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording.

1. Intracellular recordings were made from presumed dopamine-containing neurones in the ventral tegmental area (VTA) in rat brain slices. 2. Nicotine (10-100 microM) and acetylcholine (ACh) depolarized the neurones. The depolarization caused by ACh was typically biphasic; both components were increased by neostigmine (0.1-10 microM), but only the slower component was blocked by scopolamine (1-10 microM). 3. The nicotinic action of ACh, studied in the presence of neostigmine and scopolamine, persisted in the presence of tetrodotoxin (1 microM) and cobalt (2-5 mM). 4. ACh or carbachol (30 microM) caused inward currents in neurones voltage-clamped near the resting potential. These currents reversed polarity at around -4 mV, were blocked by hexamethonium (1-100 microM) in a voltage-dependent manner, and showed desensitization with prolonged or repeated agonist applications. 5. Depolarizations caused by ACh and carbachol were reduced in slices pretreated with kappa-bungarotoxin, but were not changed by alpha-bungarotoxin. 6. These responses to ACh and nicotine resemble those previously described on autonomic ganglion cells. The direct action on VTA neurones may contribute to the positive reinforcement associated with nicotine consumption.

Acetylcholine↗
PubMed1989

Oral 5-fluorouracil in psoriasis: pharmacokinetic-pharmacodynamic relationships.

Previous studies have suggested oral 5-fluorouracil (5-FU) is unpredictably and erratically absorbed. We studied oral pharmacokinetics of 5-FU in 16 patients (aged 34-71 years) with severe recalcitrant psoriasis. Each patient received repeated single oral doses of 5-FU, each separated by 1 week. Doses were ascending (300, 600, 900, 1,200 mg/m2), and after the first 3 patients, doses were started at 600 mg/m2 and increased. Multiple blood samples were obtained after each 5-FU dose and plasma 5-FU concentration determined by HPLC. Response was determined by clinical assessment of skin thickening, redness, and scaling on upper and lower body and quantified as percent improvement. Among all patients total dose and total area under the plasma 5-FU concentration-time curve (AUC) was significantly related (r = 0.65; p less than 0.01). In contrast no relationship between either total 5-FU dose and response (r = -0.07) or AUC and response (r = -0.08) was identified. With each individual patient, total 5-FU dose and response were well correlated in 11 of 14 patients (r = 0.96, 0.92, 0.92, 0.97, 0.78, 0.85, 0.71, 0.89, 0.96, 0.76, 0.94) and less well related in 3 of 14 (r = 0.57, 0.51, 0.15). Similarly, cumulative 5-FU AUC and response were well correlated in 11 of 14 patients (r = 0.91, 0.84, 0.83, 0.91, 0.77, 0.86, 0.75, 0.93, 0.99, 0.74, 0.89) and less well related in the same 3 patients (r = 0.61, 0.40, 0.03). The relationship of the 5-FU dose and AUC was nonlinear with normalized dose: AUC 1.0 at the lowest dose for each patient, at 1.5 dose AUC was 3.4 times baseline, at 2.0 dose AUC was 5.3 times baseline, and at 3.0 dose AUC was 36 times baseline. In patients with recalcitrant psoriasis 5-FU is consistently absorbed into the systemic circulation with extent of absorption increased with increasing dose in a nonlinear manner. Evaluation of both total 5-FU dose and total 5-FU AUC indicates a clear within-patient dose and AUC:response relationship.

Administration, Oral↗
PubMed1988

Potassium ions play a role in the glycine-induced inhibition of rat substantia nigra zona compacta neurones.

Glycine directly inhibits the firing, it hyperpolarizes and/or depolarizes the dopaminergic neurones and increases the membrane conductance. In voltage clamp experiments (near resting potential) either outward and/or inward currents were produced. These actions were present in tetrodotoxin and in 0-calcium-cobalt-treated slices and were antagonized by strychnine. The hyperpolarization depended on the extracellular concentration of potassium and was prevented by cesium diffusion into the cell. Thus potassium ions participate in the glycine mediated inhibition of the firing of substantia nigra zona compacta cells.

Action Potentials↗
PubMed1988

Cell culture of the mucinous variant of human colorectal carcinoma.

Two cell lines, RW-2982 and RW-7213, have been established for the first time from the mucinous variant of human colorectal carcinoma, which is a distinctive and important subtype that has a worse prognosis than the more common nonmucogenic large bowel carcinoma. Methods of establishment and observations made during 7 and 3 years, respectively, of continuous culture are described. These cell lines required 4-9 months of adaptation to tissue culture conditions before noticeable growth occurred. Both cell lines have the following unique properties: (a) growth in vitro as delicate branching three-dimensional tumor particles within a wide gel of insoluble, often translucent mucus (proteoglycan); (b) production of large quantities of carcinoembryonic antigen; (c) ability to survive or adapt to growth in media free of serum, hormones, growth factors, and all protein; and (d) tumorigenicity in multiple sites in nude mice, including liver, with especially rapid growth in the peritoneal cavity as gelatinous material that is nonadherent and noninvasive and thus resembles pseudomyxoma peritonei. Unlike other reported colorectal cell lines, these mucus-coated particulate cell lines will not readily grow as monolayers and grow much more slowly with a doubling time of 2 weeks or more. A serially transplantable tumor from the RW-7213 surgical specimen has also been maintained in nude mice since August 8, 1984. This tumor retains properties of the original specimen. Observations made on the tumor biology of mucogenic colorectal carcinoma using these cell lines are discussed.

Adenocarcinoma, Mucinous↗
PubMed1988

Phase I trial of the combination of 6-methylmercaptopurine riboside and 5-fluorouracil.

6-Methylmercaptopurine riboside (MMPR) and 5-fluorouracil (5-FU) were administered sequentially to 12 patients in a phase I clinical trial. Toxicities included mild nausea and vomiting, as well as reversible leukopenia and thrombocytopenia. Maximal accumulation of 6-methylmercaptopurine ribonucleoside 5'-monophosphate (MMPR-P), the active metabolite of MMPR, in patients' erythrocytes occurred between 2 and 6 h after the administration of MMPR and the degree of accumulation was dose-related. At 96 h after MMPR administration, MMPR-P was still detectable in patients' erythrocytes. Although no clinical responses were documented, a modified dosage schedule of these drugs should be pursued based on the pharmacokinetic data obtained.

Aged↗
PubMed1988

Depletion of catecholamines reveals inhibitory effects of bromocryptine and lysuride on neostriatal neurones recorded intracellularly in vitro.

Intracellular recordings were obtained from slices of striata from naive and catecholamine-depleted rats. Depletion of catecholamines was obtained by: (i) acute treatment with reserpine (5 mg/kg i.p., 12 hr before sacrifice); (ii) chronic treatment with reserpine (2-3 mg/kg i.p. die for 5 days) and (iii) electrolytic lesion of the homolateral substantia nigra. The ergots, bromocryptine and lysuride (0.1-1 microM), D2 dopamine agonists, did not have detectable effects on the striatal cells of naive animals, but produced a dose-dependent decrease of the excitatory synaptic potentials evoked intrastriatally and recorded from slices depleted of DA; this inhibitory effect was not coupled to changes in membrane potential and input resistance. Lysuride was more potent than bromocryptine. In 78% of the cells recorded, these ergots also produced a decrease in the intrinsic membrane excitability. The inhibitory effects of the ergots were antagonized by the D2 antagonist sulpiride (1 microM), but not by the D1 antagonist SCH 23390 (1 microM). It is concluded that treatments causing depletion of catecholamines, by up-regulating striatal D2 receptors, reveal inhibitory effects of bromocryptine and lysuride.

Animals↗
PubMed1988

Endogenous dopamine and dopaminergic agonists modulate synaptic excitation in neostriatum: intracellular studies from naive and catecholamine-depleted rats.

Intracellular recordings from slices of rat neostriatum were utilized to study the effects of endogenous dopamine and of exogenous dopaminergic agonists on the excitatory synaptic potentials evoked by the local stimulation of the slice. D-Amphetamine (0.1-5 microM), as well as dopamine, produced a dose-dependent decrease of the excitatory synaptic potentials. This effect was blocked by membrane hyperpolarization. The blockade of potassium channels by intracellular cesium or by extracellular 4-aminopyridine (0.5-1 mM) did not block the voltage-dependent effect of dopamine. The effects of D-amphetamine were antagonized by (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7 -ol (SCH 23390) (0.1-1 microM), an antagonist for D1 dopaminergic receptors, but not by sulpiride (0.1-1 microM), an antagonist for D2 receptors. Pretreatment of the animals with alpha-methyl-p-tyrosine (200 mg/kg) or with reserpine (5 mg/kg) blocked the amphetamine-induced effect on the synaptic potentials. In reserpinized animals, the hyperpolarization of the membrane potential did not block the dopamine-induced decrease of the synaptic excitation. After reserpine pretreatment bromocryptine and lysuride, D2 agonists which in control conditions were ineffective, also mimicked the effects of dopamine. In reserpinized rats, the inhibitory effects of the dopaminergic agonists were antagonized by sulpiride, but not by SCH 23390. We conclude that in naive animals endogenous dopamine mimics the voltage-dependent reduction of synaptic excitation produced by D1 activation, while in catecholamine-depleted rats dopamine lacks its voltage-dependent effect and interacts with "supersensitive" D2 receptors.

4-Aminopyridine↗
PubMed1988

Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin.

Clinical, pharmacologic, and immunologic effects of 2'-deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologic neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered.

Adenosine Deaminase↗
PubMed1987

A phase I trial of continuous infusion cisplatin.

Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein-bound plasma platinum levels. To determine the dose-limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose-limiting toxicity was found to be leukopenia: 42% of patients receiving the 5-day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high-dose regimens for response and toxicity are indicated.

Adult↗
PubMed1987

Intrinsic membrane properties of neostriatal neurons can account for their low level of spontaneous activity.

Electroresponsiveness of neostriatal neurons was studied by intracellular recording in a rat brain slice preparation maintained in standard solution or in solution containing K-channel blockers. In standard solution, the neurons fired repetitively at increasing frequencies with increasing amplitude of direct depolarization. The firing pattern was independent of the membrane potential from which firing was induced. In the presence of tetraethylammonium (20 mM), long-lasting (300-500 ms) plateau potentials could be elicited by the injection of short (5-10 ms) current pulses. Plateau potentials persisted in Na-free solution, in the presence of tetrodotoxin (1-3 microM) and if Ca in the perifusate was replaced by Ba. The plateau was blocked by Cd (500 microM). The plateaux were followed by depolarizing after-potentials. When the plateau potential failed due to fatigue, a small slow depolarization of short duration (10-30 ms) was elicited in Na-free or tetrodotoxin-containing solution, which increased in amplitude with membrane hyperpolarization. This slow depolarization was blocked by Cd, indicating that it was also mediated by Ca. By intrastriatal stimulation in the presence of 4-aminopyridine a long-lasting, voltage-dependent depolarization was triggered from the enhanced postsynaptic potential. In contrast, in the presence of tetraethylammonium, postsynaptic potentials were only slightly increased if they were compared at sizes subthreshold for the plateau potentials. It is concluded that neostriatal neurons, although being characterized as "silent" and "non-bursting", possess slow conductances for inward currents which they share with other mammalian central neurons. However, in contrast, to other central neurons, their Ca-spikes are suppressed by their K-conductances and, in contrast to oscillating neurons, low-threshold Ca-potentials are not prominent.

Animals↗
PubMed1987

Intracellular studies on the dopamine-induced firing inhibition of neostriatal neurons in vitro: evidence for D1 receptor involvement.

Intracellular recordings were obtained from rat neostriatal slices. Bath-applied dopamine (1-10 microM) produced a reversible inhibition of the action potentials evoked by direct stimulation and a decrease in the amplitude of the intrastriatally evoked depolarizing postsynaptic potentials. No change in membrane potential was detected during the application of 1-10 microM dopamine. Dopamine application also produced a decrease in anomalous rectification in the depolarizing direction. This subthreshold inward rectification was abolished by tetrodotoxin, but not by calcium-free and cadmium (0.1-1 mM)-containing solutions. The dopamine-induced decrease in excitatory postsynaptic potential amplitude was evident at resting membrane potential or at more positive levels, but was absent at hyperpolarized values of the membrane potential. Addition of bicuculline (50-500 microM) to the medium did not affect the inhibitory action of dopamine. The inhibitory action of dopamine also persisted in calcium-free and cadmium-containing solutions. The adenosine 3',5'-cyclic monophosphate analogue, 8-bromo-adenosine 3',5'-cyclic monophosphate (0.1-1 mM), mimicked the effects produced by D1 receptor activation. Bath application of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393) (1-10 microM), a selective D1 dopaminergic agonist, mimicked the effects of micromolar concentrations of dopamine. The D2 dopaminergic agonists, 4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-3,4-g-quinoline (LY 171555) and bromocriptine (both at 10 nM-10 microM), had no effects on neostriatal cells. The inhibition induced by micromolar doses of dopamine or SKF 38393 was antagonized by bath applications of R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin++ +-7-ol (SCH 23390; 0.1-10 microM), a D1-selective antagonist, but not by sulpiride (10 nM-10 microM), a D2 antagonist. We conclude that the inhibitory effect of dopamine on rat striatal neurons is postsynaptically mediated by the activation of D1 dopaminergic receptors via the reduction of a voltage-dependent tetrodotoxin-sensitive inward conductance.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Continuous-infusion cisplatin and bolus 5-fluorouracil in colorectal carcinoma.

Twenty-one evaluable patients with metastatic colorectal carcinoma were treated with a combination of continuous-infusion cisplatin (25 mg/m2/day X 3 days) and bolus 5-fluorouracil (400 mg/m2/day X 3 days). Toxicity was minimal. Seven patients (33%) responded. All responses were observed among the 16 previously untreated patients (44%) and lasted a median of 30 weeks. The results indicate the need for phase III trials of this treatment.

Adult↗