Review of the side-effect profile of buspirone.

In 984 patients with generalized anxiety disorder who received buspirone in double-blind studies, the incidence of drowsiness (9 percent) did not differ significantly from that (10 percent) reported in 334 patients who received placebo. A probability value of p less than or equal to 0.10 was the criterion for significance. The incidence of drowsiness in buspirone-treated patients was significantly less than that in each of the groups receiving diazepam (32 percent), clorazepate (26 percent), lorazepam (58 percent), or alprazolam (43 percent). The side effects that did occur significantly more frequently in the buspirone group than in the placebo group were dizziness (9 percent versus 2 percent), headache (7 percent versus 2 percent), nervousness (4 percent versus 1 percent), light-headedness (4 percent versus less than 1 percent), diarrhea (3 percent versus less than 1 percent), paresthesia (2 percent versus less than 1 percent), excitation (2 percent versus less than 1 percent), and sweating/clamminess (1 percent versus 0 percent). The severities of these effects were predominantly rated as only mild or moderate. Fatigue occurred less frequently in buspirone-treated patients than in those receiving any of the benzodiazepines, and weakness occurred more frequently in diazepam-treated patients. Depression occurred less frequently in buspirone-treated patients than in those receiving clorazepate, diazepam, or lorazepam. Impotence occurred only in clorazepate- and lorazepam-treated patients. Decreased libido occurred more frequently in diazepam-treated patients, whereas increased libido was more frequent in clorazepate-treated patients. Nausea was reported more frequently in buspirone-treated patients than in those receiving clorazepate, diazepam, or alprazolam; diarrhea occurred more frequently in the buspirone group than in the diazepam group. The mean daily doses of the various treatments were buspirone, 20 mg; diazepam, 20 mg; clorazepate, 24 mg; lorazepam, 3 mg; and alprazolam, 1.5 mg. In an open-field study in West Germany involving 5,414 patients, gastrointestinal-related complaints were the most frequently reported side effects.

Effects of primidone, phenobarbital and phenylethylmalonamide in the stimulated frog neuromuscular junction.

The effects of primidone (1.0 mM), phenobarbital (0.2 mM) and phenylethylmalonamide (PEMA) (1.0 mM) on nerve-stimulated transmitter release (quantal content) were determined for extracellular Ca++ concentrations ([Ca++]0) from 0.4 to 0.8 mM at 1.0 Hz nerve stimulation frequency. At these [Ca++]0, the relationship between the log of quantal content vs. the log of [Ca++]0 is linear. Both primidone and phenobarbital increased quantal content to 171% of controls. These drugs, however, caused parallel shifts of the log-log plot of quantal content vs. [Ca++]0 to the left. Thus, drug effects were not modified by varying [Ca++]0. These drugs were also examined on frequency facilitation. During frequency facilitation, the relationship between the log of quantal content vs. nerve-stimulation frequency (0.5-8.0 Hz) is linear. Both primidone and phenobarbital caused parallel shifts of this plot to the left. These drug effects, therefore, were not modified by nerve stimulation frequency. PEMA did not affect quantal content in either series of experiments. Finally, the sciatic nerve was not stimulated and spontaneous transmitter release was measured. Under these conditions, phenobarbital increased transmitter release in high external K+ (7.5 mM) (1.8 mM Ca++, no Mg++) and in normal K+ (2.5 mM) (1.8 mM Ca++, no Mg++) to the same magnitude (130% of control) in contrast to the reported effects of primidone and PEMA. In conclusion, the effects of primidone, phenobarbital and PEMA were different in the stimulated frog neuromuscular junction.

Primidone but not phenylethylmalonamide, a major metabolite, increases nerve-evoked transmitter release at the frog neuromuscular junction.

The fundamental responses of primidone and phenylethylmalonamide (PEMA), a major metabolite, were investigated electrophysiologically at the frog (Rana pipiens) neuromuscular junction. Concentrations of 0.2 to 1.,0 mM of each drug were used. Primidone significantly increased nerve-evoked transmitter release in a dose-dependent manner up to 186% of control at 1.0 mM concentration, whereas PEMA had no significant effect. In a separate set of experiments in which the sciatic nerve was not stimulated, primidone significantly increased transmitter release in high external K+ (7.5 mM) (no Mg++), but had no significant effect in normal K+ (2.5 mM (no Mg++). The effect of primidone in high K+ diminished in the presence of Mg++ or of decreased Ca++; PEMA also increased the frequency of MEPPs in high K+, but this effect was not sustained and diminished slowly to control values over a period of 50 min. In addition to its predominant presynaptic action, primidone also decreased MEPP amplitude to 79% of control compatible with the relatively small postjunctional depressant action, whereas PEMA had no effect. Propylene glycol, the solvent used for primidone, did not alter the effects of the drug. In conclusion, primidone but not PEMA has a predominant presynaptic action resulting in a dose-dependent increase in nerve-stimulated transmitter release and EPP amplitude.

Comparison of the effects of trimethadione and its primary metabolite dimethadione on neuromuscular function and the effects of altered pH on the actions of dimethadione.

The effects of the anticonvulsant trimethadione (TMO) and its primary metabolite dimethadione (DMO) were investigated at the frog neuromuscular junction using intracellular recording techniques. TMO (1, 2 and 5 mM) caused dose-dependent decreases in miniature end-plate potential (MEPP) and end-plate potential (EPP) amplitudes, decreased quantal content only at the highest dose and did not affect MEPP frequency. DMO (2 and 5 mM) at the normal pH of 7.2 significantly decreased quantal content and decreased EPP amplitude at the higher concentration used. Neither MEPP amplitude nor frequency was significantly affected by DMO at pH 7.2. When 2 mM DMO was added at the same time that pH was lowered to 6.6, considerably larger decreases in EPP( amplitude and quantal content were observed. Under these conditions, DMO still did not alter MEPP amplitude but did cause about a doubling in MEPP frequency. The effects of pH 6.6 alone were also examined, but lowered pH did not account for all of the exaggerated effect of DMO in pH 6.6. Presumably, more DMO accumulates intracellularly in low pH conditions because it is a weak acid and sensitive to alterations in pH. In conclusion, both TMO and DMO cause depression of neuromuscular transmission; however, their mechanisms for depression are different, especially when therapeutically relevant concentrations are considered. TMO acts primarily by suppressing postjunctional sensitivity to acetylcholine, whereas DMO primarily decreases transmitter release from the nerve terminal.

Further comparison of the effects of physostigmine and neostigmine on frog neuromuscular transmission.

1. The effects of physostigmine and neostigmine were compared at frog neuromuscular junctions using intracellular microelectrodes. 2. Both drugs increased the amplitudes of miniature endplate potentials (MEPP) in a dose-dependent manner because of their ability to competitively inhibit cholinesterase activity. 3. In addition, physostigmine (1.0-20.0 mumol/l) decreased by approximately 20% the quantal content (determined by two methods), indicating a decrease in the amount of transmitter released upon nerve stimulation, whereas neostigmine did not alter quantal content. 4. Because the endplate potential (EPP) amplitude is a composite of pre- and post-junctional effects, the dose-response curve for neostigmine on EPP amplitude approximately paralleled that obtained on MEPP amplitude, whereas the effect of physostigmine on EPP amplitude was depressed because of its action to decrease transmitter release. 5. Upon washout of neostigmine, the increase in EPP amplitude reversed more rapidly than effects on MEPP amplitude, a difference dependent on the magnitude of quantal content and explained by an action on the postjunctional membrane. Similar results were obtained with physostigmine. 6. Neither drug significantly affected MEPP frequency although small decreases were sometimes observed. 7. These results suggest that at the frog neuromuscular junction the effects of neostigmine are explained primarily by its inhibition of cholinesterase, whereas physostigmine are explained primarily by its inhibition of cholinesterase, whereas physostigmine has an additional action on nerve terminals of decreasing nerve-stimulated release of acetylcholine.

Multiple actions of beta-bungarotoxin on acetylcholine release at amphibian motor nerve terminals.

The action of beta-bungarotoxin (beta-BuTX) on spontaneous transmitter release, as monitored by miniature endplate potential (MEPP) frequency, and nerve-stimulated release, which relates directly to endplate potential (EPP) amplitude, was studied at frog sciatic nerve-sartorius muscle junctions. Three phases were found for both spontaneous and evoked release: a transient decrease followed by an increase and a later decrease leading to complete failure. The initial inhibitory phase for both spontaneous and neurally-evoked release occurred at the same time and was independent of stimulation frequency. Both the excitatory and late inhibitory phases for both types of release had a more rapid onset when stimulation frequency was increased, with the effects on evoked release occurring more rapidly than the effects on spontaneous release. Even though EPP amplitude decreased to low levels while MEPP frequency was still high, EPPs did not completely fail until the MEPPs had also declined to very low levels. In elevated K+ solutions, the number of quanta released after toxin application was only about half that released during the control experiment. During the terminal part of the late inhibitory phase of beta-BuTX action on MEPP frequency, no effect or only small transient increases were observed after La3+ administration, elevated [K+]0, or increased osmotic pressure. The present study suggests that depolarization of nerve terminals by the toxin is responsible for initiation of the excitatory phases of both types of release followed by inhibition of nerve-evoked release, and then depletion of vesicular transmitter accounts for the eventual disappearance of both MEPPs and EPPs.

Differential effects of the anticonvulsants phenobarbital, ethosuximide and carbamazepine on neuromuscular transmission.

The actions of the anticonvulsants phenobarbital, ethosuximide and carbamazepine were examined electrophysiologically at the frog neuromuscular junction. Phenobarbital reduced miniature end-plate potential (MEPP) amplitude, did not significantly affect end-plate potential amplitude and increased quantal content. Ethosuximide decreased MEPP and end-plate potential amplitudes proportionally; quantal content was unchanged. Carbamazepine decreased end-plate potential amplitude more than MEPP amplitude; quantal content was decreased. In a solution containing elevated (7.5 mM) K+, phenobarbital and carbamazepine increased MEPP frequency, whereas ethosuximide had no effect. Carbamazepine had to be dissolved in a solvent, propylene glycol, which was shown to produce small, but sometimes statistically significant, alterations in the measured parameters of neuromuscular transmission. The results show that all three of these anticonvulsants depress postjunctional sensitivity to released acetylcholine producing parallel dose-response curves for MEPP amplitude inhibition. These experiments also show that these drugs exhibit different mechanisms of action with respect to nerve-stimulated neurotransmitter release from nerve terminals at the neuromuscular junction: phenobarbital enhances acetylcholine release, ethosuximide has no effect and carbamazepine decreases transmitter release.

The increase in spontaneous transmitter release produced by beta-bungarotoxin and its modification by inorganic ions.

The excitatory phase of the biphasic action on transmitter release of the neurotoxin, beta-bungarotoxin (beta-BuTX; 0.5 microgram ml-1), was studied on miniature end-plate potentials (MEPPs) at frog sciatic nerve-sartorius muscle junctions. The most common type of excitatory response was characterized by a continuous increase in MEPP frequency that reached a plateau; a less common form was characterized by irregular episodic bursts of firing. There was a direct relationship between toxin activity and [K+]O (2.5-10.0 mM) with virtually no effect of the toxin at normal [K]O+ at the concentration of toxin used. In the absence of Mg++, there was a paradoxical inverse relationship between toxin activity and [Ca++]O (0.5-4.0 mM) at higher [K+]O. However, in the presence of 1.0 mM Mg++ the increased MEPP frequency produced by beta-BuTX was independent of [Ca++]O. The action of beta-BuTX was very sensitive to blockade by Mg++. Toxin activity was demonstrated in a Sr++-containing, Ca++-free solution, but not in a Mg++-containing, Ca++-free solution. It is probable that beta-BuTX causes a slight depolarization of the nerve terminals by a mechanism not sensitive to blockade by tetrodotoxin and that the ability of beta-BuTX to depolarize the terminals can account for the enhancement of the response by raising [K+]O and the depression of the response by Mg++. Alternatively, beta-BuTX could be producing its effects by some, as yet undefined, direct action on the release process.

Ionic basis for intracellular 14C-nicotine accumulation in slices from different rat brain areas.

The effects of ionic alterations on the accumulation, distribution and movements of 14C-nicotine in slices from rat brain striatum, hypothalamus, cortex and cerebellum were studied. The uptake of 14C-nicotone is not dependent upon Na+ present in the incubation fluid because a K+-substituted (O-Na+) solution increased the 14C-nicotine tissue space, a tris-substituted (O-Na+) solution decreased the 14C-nicotine tissue space and a sucrose-substituted (O-Na+) solution did not change the amount of 14C-nicotine taken up when compared to the 14C-nicotine tissue space obtained in a normal incubation solution. However, all three Na+-free solutions elicited a sustained decrease in 14C-nicotine efflux. The increase in 14C-nicotine space produced in a K+-substituted (O-Na+) solution was present primarily in the slower component of a two-component washout, whereas the decrease produced in a tris-substituted (O-Na+) solution produced an equal percentage decrease in the size of both components. Most of the observed effects could be attributed to a linear relationship between the logarithm of the intracellular K+ concentration and the 14C-nicotine tissue space. In conclusion, it appears that there is an intracellular binding site for nicotine and that the degree of binding is dependent upon the concentration of K+.