Potential for patient harm from intrathecal administration of preserved solutions.

Intrathecal drug administration is an important component of the management of malignancy and symptom control. This route of administration reduces systemic adverse effects, but can increase the risk of local adverse effects such as arachnoiditis. It is accepted practice that any spinal injection should not contain any preservatives (such as benzyl alcohol and parabens-containing compounds). The intrathecal administration of solutions preserved with benzyl alcohol has been shown in case studies to increase the risk of adverse neurological events. Available data do not support the safety of intrathecal injection of products preserved with parabens; rather, they demonstrate a need for further investigation. Steps should be taken to ensure that preservative-free products are used. Staff involved with the preparation and administration of intrathecal preparations need to be educated about the risks associated with preservatives in this setting.

Biological aspects of suicide: circadian disorganization.

Disturbances in the circadian rhythmicity of biological functions have been reported in various mental disorders. Four lines of research--hormonal, electroencephalographic, cerebral spinal fluid, and circadian rhythmicity--suggest possible changes in suicidal individuals. During a study investigating the effect of a photoperiod shift on circadian rhythms, 15 male, healthy, normal subjects were used. Following a 5-day baseline period a 12-hour photoperiod shift took place and was followed by 10 days of recovery period. Multiple parameters were monitored. Two weeks following completion of the study one subject suicided. The data were examined to determine whether the suicided subject differed, rhythmically, from other subjects. Summation dials describing phase changes and vector difference dials describing dynamic phase relationships of rhythm pairs showed that the rhythms of this subject were poorly synchronized internally during baseline. Total urinary output of all parameters was lower than all other subjects during baseline and more of his urinary parameters rephased incompletely during recovery. The results suggest that circadian asynchrony and an inability to respond effectively to a phase shift may characterize a presuicidal state. These results are discussed in terms of the four lines of research involving biological aspects of suicide and suggest some intriguing interactions.

Quantitation of desynchronosis.

In order to find ways of preventing or correcting the effects of desynchronosis, it is necessary to know the physiological mechanisms that are affected and to quantitatively determine their rate of recovery following a time-zone change. To best accomplish this, it is necessary not only to establish the rates of change brought about in performance and physiological systems during actual flight experiments, but to complement these observations with ground-based simulation experiments. A mathematical model was developed to quantitatively describe desynchronosis and was applied to data obtained from ground-based photoperiod shift studies using monkeys. An initial steady state, Vc, and a final steady state, Vs are postulated. The measured data vector, Vt, initially equals Vc, and finally equals Vs. The difference vector, Vts, with components A(t) and B(t), defined as the dot product and cross product of vectors Vt and Vs, is termed the desynchronosis vector. The trajectory of A(t) with time is given by: A(t) = A - e (alpha + betat), where A is the asymptote denoting complete resynchronization, alpha is proportional to the total desynchronosis on day O, and beta is the rate of resynchronization. The number of cycles required to achieve a 95% recovery, t95, is computed. This model has been applied to body temperature (BT) data from a monkey subjected to a 180 degrees phase-shift by alternating the photoperiod. The BT rhythm was initially stable and a 180 degrees reversal of phase with the new environment was eventually achieved. Estimated rephasal times were: 37% in 2.6 days; 50% in 5.6 days, and 95% in 8.4 days. Similar rates of internal and external resynchronization have been obtained from human photoperiod shift, ground-based experiments. Estimated rephasal time for BT rhythms with HR rhythms to the new photoperiod (t95) is 4.9 days.

Diurnal rhythm of the pituitary-adrenocortical response to stress: effect of constant light and constant darkness.

The existence of a biological rhythm in the response of animals to noxious stimuli and drugs is well known. However, the mechanism of this response is not well understood. This study was undertaken to describe the existence of a diurnal rhythm in the hypothalamic-pituitary-adrenocortical system before and after stress in female rats kept in controlled environmental conditions in 12L:12D, 24L:OD, or OL:24D. Plasma ACTH and plasma corticosterone concentrations were compared in unstressed animals. The time pattern in the response to stress was determined at four hourly intervals during a 24 hr period in which plasma ACTH and plasma corticosterone were measured at different time intervals. The stress response varied considerably with time of day in both magnitude and duration. The adrenals of rats exposed to constant light for 45 days atrophied, whereas the adrenals of animals kept in constant dark for the same period did not differ significantly from those of controls kept in 12L:12D. The increase in plasma ACTH in response to stress was greater both in the animals maintained in constant light and in constant dark than in the 12L:12D controls. Homeostatic mechanisms involved in these changes are discussed.

Mechanisms of action of light on circadian rhythms in the monkey.

Light is considered by many investigators to be the primary Zeitgeber for most physiologic rhythms. In order to study the effects on biorhythms of changing photoperiods and to provide information on the nature of the wave forms and the mechanisms of entrainment, unrestrained male monkeys (Cebus albifrons, Macaca nemestrina) were maintained in a sound-proofed environmental chamber. The Cebus was initially maintained on a 12L:12D schedule; it was subjected to a 180 degrees phase shift for 14 days, then returned to the original photoperiod. In two experiments (24 days; 27 days each) the same monkey was again maintained on a 12L:12D schedule which was gradually altered to a constant light environment. Deep body temperature (DBT) data were obtained with miniature radiotransmitters. Locomotor activity (LMA) was measured by strain gauges. Under the 12L:12D regimens the Macaca DBT cycles were uniform as to phase and wave form for over 60 weeks. These wave forms were analyzed by the use of periodogram and correlogram analyses and by fitting to the Volterra Integro-Differential Equation. Phase angle relationships between Zeitgeber and physiologic parameters were characterized. After the photoperiod phase shift the DBT cycle rephased in about 9 days. During the rephasing process the wave form changed. The shapes of the wave forms of DBT and activity were maintained with increasing light until an 18L:6D photoperiod was reached. The rhythms were entrained to the onset of darkness rather than lights on. Major and minor periods of LMA were detected. Hysteresis diagrams showed that DBT led the onset of major LA by 6 hr and the end of major activity by 2 hr.