Hermsmeyer, K; Aprigliano, O
The negative inotropic effect of a commonly used formulation of bradykinin (Sandoz BRS-640) was found to be due to chlorobutanol, a constituent of the preparation. Solutions containing up to 100 mug of crystalline bradykinin/ml had no effect on tension or action-potential shape. Chlorobutanol (500 mug/ml) caused a 30% decrease in contraction amplitude and a 20% increase in action-potential duration. Chlorobutanol lowered conduction velocity and induced conduction failure and automaticity within isolated ventricular muscle strips. Chlorobutanol affected neither positive nor negative treppe. We conclude that bradykinin has no direct action on toad, frog, or rat myocardium. However, chlorobutanol does have direct effects on myocardial cells, acting on the cell membrane and decreasing isometric tension produced by the heart.
Costantino, Henry R; Culley, Heather; Chen, Lishan; Morris, Daniel; Houston, Michael; Roth, Sharin; Phoenix, Mary Jo; Foerder, Chuck; Philo, John S; Arakawa, Tsutomu; Eidenschink, Lisa; Andersen, Niels H; Brandt, Gordon; Quay, Steven C
The similarity of an intranasal salmon calcitonin (sCT) employing chlorobutanol as preservative (Calcitonin Salmon Nasal Spray) was compared to the reference listed drug (RLD) employing benzalkonium chloride as preservative (Miacalcin Nasal Spray). Various orthogonal methods assessed peptide structuring, dynamics, and aggregation state. Mass spectrometry, amino acid analysis, and N-terminal sequencing all demonstrated similarity in primary structure. Near- and far-UV circular dichroism (CD) data supported similarity in secondary and tertiary sCT structure. Nuclear magnetic resonance studies further supported similarity of three-dimensional structure and molecular dynamics of the peptide. Other methods, such as sedimentation velocity and size exclusion chromatography, demonstrated similarity in peptide aggregation state. These latter methods, in addition to reversed phase chromatography, were also employed for monitoring stability under forced degradation, and at the end of recommended shelf storage and patient use conditions. In all cases and for all methodologies employed, similarity to the RLD was observed with respect to extent of aggregation and other degradation processes. Finally, ELISA and bioassay data demonstrated similarity in biological properties. These investigations comprehensively demonstrate physicochemical similarity of Calcitonin Salmon Nasal Spray and the RLD, and should prove a useful illustration to pharmaceutical scientists developing alternative and/or generic peptide or protein products.
... Theranates, containing strychnine, sodium, and calcium glycerophosphates, thiamine hydrochloride, alcohol..., chlorobutanol, phenol, camphor, alum, and isopropyl alcohol. (b) Zirnox Topical Lotion, containing... Gel (DESI 11562), for which notice of withdrawal of approval of the new drug application was...
Hutchings, Regina L; Singh, Surinder M; Cabello-Villegas, Javier; Mallela, Krishna M G
One-third of protein formulations are multi-dose. These require antimicrobial preservatives (APs); however, some APs have been shown to cause protein aggregation. Our previous work on a model protein cytochrome c indicated that partial protein unfolding, rather than complete unfolding, triggers aggregation. Here, we examined the relative strength of five commonly used APs on such unfolding and aggregation, and explored whether stabilizing the aggregation 'hot-spot' reduces such aggregation. All APs induced protein aggregation in the order m-cresol > phenol > benzyl alcohol > phenoxyethanol > chlorobutanol. All these enhanced the partial protein unfolding that includes a local region which was predicted to be the aggregation 'hot-spot'. The extent of destabilization correlated with the extent of aggregation. Further, we show that stabilizing the 'hot-spot' reduces aggregation induced by all five APs. These results indicate that m-cresol causes the most protein aggregation, whereas chlorobutanol causes the least protein aggregation. The same protein region acts as the 'hot-spot' for aggregation induced by different APs, implying that developing strategies to prevent protein aggregation induced by one AP will also work for others.
Kaur, Indu Pal; Lal, Shruti; Rana, Cheena; Kakkar, Shilpa; Singh, Harinder
Presence of a preservative in an ocular medication has often been considered a culprit in damaging the epithelium. However, the inclusion of a preservative is equally necessary, especially in multiple-dose containers, in order to protect against dangerous organisms accidentally gaining access during instillation. Benzalkonium chloride (BAK), chlorobutanol, chlorhexidine acetate (CHA), and phenylmercuric nitrate or acetate are some commonly used preservatives in eye preparations. New preservatives with a wide range of activity and good safety profiles have been introduced in the market, such as stabilized oxychloro complex (SOC), sofZia, and sodium perborate. In the present review, we discuss various conventional and newly proposed and patented preservative molecules for ocular use. Reasons for discontinuing traditional preservatives and the need for less-toxic molecules are discussed at length, along with newer options coming up in this area.
Paradoxical bronchospasm from benzalkonium chloride (BAC) preservative in albuterol nebulizer solution in a patient with acute severe asthma. A case report and literature review of airway effects of BAC.
George, Mathew; Joshi, Saumya Vinod; Concepcion, Emily; Lee, Haesoon
Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multi-dose dropper bottle of albuterol sulfate solution contains 50 μg BAC per/2.5 mg of albuterol, which may be below or at the lower limit of the threshold dose for bronchoconstriction. However, with repeated albuterol nebulization, the effect can be additive and cumulative, often exceeding the bronchoconstriction threshold. We report a case of a 17 years old patient, who received 32 mg of BAC via nebulization over a period of 3.5 days that probably caused persistent bronchospasm evidenced by failure to improve clinically and to increase peak expiratory flow rate (PEFR) from 125 L/min (27% of predicted value) to 300 L/min (68% of predicted value) within 2 hours of withdrawing BAC. The patient's respiratory status and PEFR improved dramatically once the nebulization solution was switched to BAC free lev-albuterol solution. The pediatric providers, particularly the emergency department physicians, intensivists and pulmonologists need to be aware of this rare albeit possible toxicity to the respiratory system caused by BAC used as a preservative in albuterol nebulizer solution.