Solubility and Stability of Baclofen 3 mg/mL Intrathecal Formulation and Its Compatibility With Implantable Programmable Intrathecal Infusion Systems.

BACKGROUND: Commercial baclofen formulations used with infusion pumps are available at therapeutic concentrations of 0.5-2.0 mg/mL. However, patients who receive higher daily doses of baclofen may benefit from products with greater baclofen concentrations since their refill frequency would be reduced (up to a maximum of 180 days). We evaluated baclofen solubility, baclofen 3 mg/mL intrathecal (IT) formulation stability, and chemical and physical compatibility with Medtronic SynchroMed® II and Codman Medstream® programmable IT infusion pumps. METHODS: For solubility evaluations, baclofen powder was dissolved into isotonic saline and tested at 5°C, 25°C, and 40°C. To demonstrate drug product stability, both physical and chemical stability attributes of baclofen 3 mg/mL in prefilled syringes were evaluated over 36 months with storage at 25°C. For a simulated in-use stability (compatibility) study, a 3 mg/mL baclofen IT formulation was placed in SynchroMed II and Codman Medstream pumps at 37ºC for study durations, and evaluated at different flow rates. Pump effluent was collected at various times and analyzed by high-performance liquid chromatography for baclofen content. On completion of the in-use stability study, pumps exposed to baclofen 3 mg/mL were dissected and visually evaluated for signs of deterioration. RESULTS: Baclofen solubility was found to be 3.2 mg/mL at 5°C, 3.6 mg/mL at 25°C, and 3.9 mg/mL at 40°C. During the 36-month stability study of prefilled syringes stored at 25°C, baclofen content remained unchanged and no precipitation was observed. The simulated in-use pump study performed at 37ºC showed that a baclofen 3 mg/mL IT formulation was stable at different flow rates and throughout different expected residence times for both pump models. Components from both pumps exhibited no noticeable deterioration after exposure to the 3 mg/mL formulation. CONCLUSION: Baclofen 3 mg/mL IT formulation was stable during long-term storage at 25°C and remained stable under conditions matching those encountered in clinical practice (37°C).

Male adaptations to minimize sexual cannibalism during reproduction in the funnel-web spider Hololena curta.

Males of many spider species risk being attacked and cannibalized while searching for, courting, and mating with conspecific females. However, there are exceptions. We show that the funnel-web spider, Hololena curta, has 3 adaptations that minimize risk to males during courtship and mating, and enhance reproductive success. First, males detected chemical or tactile signals associated with webs of virgin females, and differentiated them from webs of mated females, enabling males to increase encounter rates with virgin females and avoid aggressive mated females. Second, males produced stereotyped vibrational signals during courting which induced female quiescence and suppressed female aggression. Third, when touched by males, sexually receptive females entered a cataleptic state, allowing males to safely approach and copulate. Because males can mate multiple times and the sex ratio in natural populations of H. curta is female biased, overall reproductive output is likely increased by males of this species avoiding sexual cannibalism.

A new species of the spider genus Eridantes Crosby & Bishop from the southwestern United States and mainland Mexico with a revised diagnosis of the genus (Araneae, Linyphiidae, Erigoninae).

A new Eridantes Crosby & Bishop (1933) species, E. diodontos n. sp., discovered in the United States in the state of Arizona and in Mexico in the state and city of San Luis Potosí, is described and illustrated. Both males and females are very similar to the respective sexes of the type species, E. erigonoides (Emerton 1882), but can be distinguished by the higher cephalic lobe, position of the prosomal pit, and the form of the palpal tibia in the male and by the convolution of the m-shaped carinae of the epigynum in the female. Comparative illustrations of the male bulb of E. erigonoides and a distribution map of the three known species are also provided. Pending formal taxonomic revision of Eridantes, a revised diagnosis and a brief description of the genus are presented based on examination of specimens of the type species and of the new species described here. The mesal rather than ectal position of the paracymbium and the broadly divided dorsal and ventral sclerites of the largely membranous radix are proposed synapomorphies that distinguish Eridantes from all similar genera.

Restraint stress modulates virus specific adaptive immunity during acute Theiler's virus infection.

Multiple sclerosis (MS) is a devastating CNS disease of unknown origin. Multiple factors including genetic background, infection, and psychological stress affect the onset or progression of MS. Theiler's murine encephalomyelitis virus (TMEV) infection is an animal model of MS in which aberrant immunity leads to viral persistence and subsequently results in demyelination that resembles MS. Here, we examined how stress during acute TMEV infection altered virus-specific cell mediated responses. Using immunodominant viral peptides specific for either CD4(+) or CD8(+) T cells, we found that stress reduced IFN-gamma producing virus-specific CD4(+) and CD8(+) T cells in the spleen and CD8(+) T cells CNS. Cytokine production by cells isolated from the CNS or spleens following stimulation with virus or viral peptides, indicated that stress decreased both type 1 and type 2 responses. Glucocorticoids were implicated in the decreased T cell function as the effects of stress were partially reversed by concurrent RU486 administration but mimicked by dexamethasone. As T cells mediate viral clearance in this model, our data support the hypothesis that stress-induced immunosuppression may provide a mechanism for enhanced viral persistence within the CNS.

Glucocorticoid exposure alters the pathogenesis of Theiler's murine encephalomyelitis virus during acute infection.

Previous research has shown that chronic restraint stress exacerbates Theiler's virus infection, a murine model for CNS inflammation and multiple sclerosis. The current set of experiments was designed to evaluate the potential role of glucocorticoids in the deleterious effects of restraint stress on acute CNS inflammatory disease. Exposure to chronic restraint stress resulted in elevated levels of corticosterone as well as increased clinical scores and weight loss (Experiment 1). In addition, corticosterone administration alone exacerbated behavioral signs of TMEV-induced sickness (i.e. decreased body weight, increased symptoms of encephalitis, and increased mortality) and reduced inflammation in the CNS (Experiment 2). Infected subjects receiving exogenous corticosterone showed exacerbation of acute phase measures of sickness and severe mortality as well as decreased viral clearance from CNS (Experiment 3). These findings indicate that corticosterone exposure alone is sufficient to exacerbate acute CNS inflammatory disease.

Social stress alters the severity and onset of the chronic phase of Theiler's virus infection.

Social stress alters the acute phase of Theiler's virus infection (TMEV), a model of multiple sclerosis. Stress applied prior to infection had deleterious disease outcomes, while stress applied concurrent with infection was protective. The current study examined multiple behavioral (motor impairment, open field activity) and immunological measures (IL-6, antibodies to virus and myelin proteins) in both the acute and chronic phases of TMEV. It was found that stress applied prior to infection exacerbated disease outcomes, while concurrent application was protective in both disease phases.