The present invention provides a new compositions and methods to enable the safe administration of pyridostigmine to mammalian subjects, including those with myasthenic syndromes including Myasthenia Gravis, with said compositions comprising combinations, including fixed-dose combinations, of an antagonist of the 5-hydroxytryptamine subtype-3 receptor (“5HT3-antagonist”) with an effective dose of pyridostigmine. The compositions and methods of the present invention provide for an increase in the tolerable dose of pyridostigmine over that of pyridostigmine when administered alone.