Continuous Intrathecal Infusion of a Solution Containing Two Drugs: Calculation Methods

The calculation of the parameters of the pump is complicated for a mixture of two drugs in continuous intrathecal therapy with implantable and programmable pumps. It is important to determine the best proportion of drug solutions to obtain the desired clinical results and also to adapt their proportion to obtain the maximal volume of solution so that the time between two fillings is maximized. This paper proposes mathematical formulas that make easier and faster the calculation of the flow of the pump, the volume of each drug solution to be added to the pump, the concentration of each drug in the mixture, and the duration of the infusion. These values are determined from the desired quantity of each drug to be infused in 24 h, the concentration of each drug solution, and the volume of the reservoir. The calculated values cannot be directly applied because the syringes used to measure the volume of each drug solution have limited accuracy. It is necessary to round the volume of each drug solution and to hold their sum equal to the total volume of the reservoir. All the parameters are then recalculated, and the physician has to choose between several combinations of volumes.     

Locating drug addicts who have dropped out of treatment.

Staff at a VA-sponsored drug treatment center followed up dropouts one year after they left the program; they were able to locate 80 per cent of those clients. The staff found several contacts useful in locating the difficult-to-find population, including the addicts' mothers, other drug programs, prisons, and the department of motor vehicles. To make it easier for researchers to tract down dropouts, the author suggests that when patients enter a program they should be required to give names, addresses, and telephone numbers of at least two friends or relatives who would know where they were. Staff should emphasize to patients that the information is for research purposes and that confidentiality will be preserved.     

Carnitine treatment for stroke in rats

Changes in the concentrations of carnitine, long-chain acylcoenzyme A, and long-chain acylcarnitine in ischemic myocardium parallel those in ischemic brain. Since carnitine treatment reverses these changes and improves function in ischemic hearts, we examined whether carnitine given to rats before focal cerebral ischemia (produced by tandem right common carotid artery and middle cerebral artery occlusion) alters infarct volume in four separate experiments. Mannitol was used to control for the osmotic effect of carnitine on brain edema in one experiment. While carnitine was found to significantly decrease infarct volume compared with saline in one experiment (p less than 0.05, Student's t test), this result could not be replicated in the subsequent three experiments. Because the positive treatment effect was not reproducible despite similar experimental conditions, the result of the first experiment was attributed to a type I error. Mannitol also showed no significant effect on infarct volume. This study emphasizes the need for concurrent controls with each group of treated animals and the need for replicating the results of a single experiment when testing for drug efficacy in animal models of focal cerebral ischemia.     

Stability of Morphine Sulfate-Clonidine and Sufentanil-Clonidine Mixtures

BackgroundSpinal analgesia is recommended for intractable cancer pain. Morphine-clonidine and sufentanil-clonidine are often used in association in intrathecal drug delivery systems, injected by intraabdominal pumps. To refill these pumps and to limit patient transport, it may be necessary to ship the mixtures in polypropylene syringes to peripheral establishments located near patient homes. The purpose of this study is to determine the stability of morphine-clonidine and sufentanil-clonidine mixtures in polypropylene syringes to ensure the best and safest transport conditions and in implantable pumps for intrathecal use.Materials and MethodsThe stability study method was conceived according to the International Council for Harmonization guidelines. For polypropylene syringes, four different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over seven days. Two storage temperatures were tested (5 ± 3 °C and 25 ± 2 °C). For implantable pumps, two different mixtures of morphine-clonidine and sufentanil-clonidine were assessed over 28 days and stored at 37 °C.ResultsFor the morphine-clonidine mixtures in polypropylene syringes, all mixtures remained stable for five days in both storage conditions (5 ± 3 °C and 25 ± 2 °C) because of relative concentrations systematically positioned between 90% and 110% (95% CIs of the mean of three samples). The two mixtures in implantable pumps remained stable for 28 days.For the sufentanil-clonidine mixtures in polypropylene syringes, cold conservation kept all the preparations stable for seven days, whereas a quick degradation was observed after only two days for ambient storage conditions. This result is similar to that with an implantable pump, in which the concentration is <90% on day 7 for low concentration mixtures.No visual modification, no significant pH modification, and no changes in turbidity assays were observed in either study.ConclusionThis study shows the stability of the morphine-clonidine mixtures in syringes stored at 5 °C for five days and in implantable pumps stored at 37 °C for 28 days. For the sufentanil-clonidine mixtures, the results show stability in syringes for seven days at 5 °C. Pump results show stability of seven days for low concentrations and 28 days for high concentrations.     

The HPA axis and cocaine reinforcement.

Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous self-administration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases. Corticosterone is necessary during acquisition; self-administration does not occur unless this stress-related hormone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can be augmented by increasing circulating levels of corticosterone, but similar treatments do not affect responding maintained by higher doses. In a similar vein, ongoing, low-dose cocaine self-administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine dose-response curve can each be attenuated by drugs that block central corticotropin-releasing hormone (CRH) receptors. Finally, corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior, demonstrating an involvement of the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction.     

Anticoagulant and membrane-degrading effects of secretory (non-pancreatic) phospholipase A2 are inhibited in plasma

Plasma concentrations of secretory (non-pancreatic) phospholipase A2 (sPLA2) may rise 1000-fold during inflammation, and this acute phase response has been related to anticoagulant effects. In the present study this hypothesis was further investigated. Prothrombinase activity was measured for model membranes mimicking the phospholipid composition of the outer membrane of resting and activated blood platelets. Using ellipsometry, membrane degradation by sPLA2 could be measured simultaneously with inhibition of thrombin production. The same technique was used to study clotting, by the sudden appearance of fibrin strands on the membrane. Results were compared with the effects of sPLA2 on the activation of washed platelets and platelets in plasma. In buffer solution, model membranes were degraded by (patho)physiological concentrations of sPLA2. Even when only partially degraded, membranes rapidly lost their prothrombinase activity, indicating preferential degradation of phosphatidylserine. Addition of diluted plasma interfered with membrane degradation, and also with inhibition of prothrombinase activity. In agreement with these observations, sPLA2 inhibited thrombin production and annexin V-binding of activated washed platelets, but had no effects on platelet activation or clotting in plasma. These findings indicate that the elevated plasma sPLA2 concentrations observed in inflammatory disease will not reduce hypercoagulability in such patients.     

Reversible and irreversible knockout of the ventroposterolateral thalamic nucleus measured by intracerebral SEP recordings in the rat brain--an aid to neuronavigation in small nuclei

Centrally active drugs are often hard to administer because of the blood brain barrier, and frequently high systemic doses are required to reach sufficient brain parenchyma concentrations, since these drugs are, additionally, diluted in the total blood volume. Moreover, topical administration via the systemic route is not possible. We here propose a technique for the local, quantitative deposition of active substances at defined intracerebral targets, e.g. the thalamic nuclei. We used a long micropipette and stereotactically advanced it to the desired coordinates under electrophysiological control. The pipette acted as both an electrode for intracerebral recordings and as a transportation means for the drug. The amplitude of intracerebral evoked potentials relayed by the thalamic nucleus to the sensorimotor cortex indicated the distance between the pipette tip and the neurons of the targeted nucleus. Data were obtained from anesthetized rats, where the micropipette was advanced towards the nucleus ventralis posterolateralis (VPL) during contralateral electrical forepaw stimulation and intracerebral recording of somatosensory evoked potentials. Within the VPL we either injected lidocaine or kainic acid, both resulting in an attenuation of the intracerebral as well as the cortical evoked potentials. This proposed tool may be useful for functional investigations of deep brain structures.     

Physicochemical Stability Study of the Morphine-Ropivacaine-Ziconotide Association in Implantable Pumps for Intrathecal Administration

PurposeThis study aimed to investigate the physicochemical stability of morphine-ropivacaine-ziconotide mixtures used in intrathecal analgesia.Materials and MethodsEight mixtures were studied to assess their stability profiles according to the initial drug concentrations used. The solutions obtained were put in implantable pumps and stored at 37 °C over a period of 60 days. Assays were performed using ultra high-pressure liquid chromatography. Turbidity and pH were also measured throughout the study.ResultsResults confirmed excellent physicochemical stability for morphine and ropivacaine. Concerning ziconotide, three of the eight mixtures did not show any sign of chemical instability: average concentrations remained constant throughout the 60 days. A decrease of the concentration was observed for the five other mixtures. Moreover, the appearance of a degradation product linked to oxidation confirmed the ziconotide degradation.ConclusionsAll these results are in favor of a physicochemical stable preparation for three of the mixture profiles when stored in implantable pumps at 37 °C up to 60 days. For the five others, the efficacy should decrease over time owing to the degradation of ziconotide. The decrease in kinetics of the ziconotide concentration depends on the mixing profile. One possibility is to adapt the filling intervals according to the profile of the mixture. Finally, the results show the period of stability ensuring maximum analgesic efficacy for the eight mixture profiles studied.     

A Method for Reducing the Pocket Complications of the Internal Infusion Pumps in Pediatric Patients: A Case Report

Internal infusion pumps are increasingly used as a safe method to deliver drugs in adult patients. However, a formal contraindication of this mode of therapy is the presence of a imbalance between the pump volume and the size of the abdominal wall as occurs in pediatric populations. We describe a method of implantation of an intrathecal infusion pump for baclofen therapy in a 10‐year‐old patient with cerebral palsy. Before the pump implantation we inserted a subcutaneous expander with a reservoir that was filled with saline solution every week. After three sessions, a pocket similar in size to an internal infusion pump was obtained. The result was a pump pocket with soft shaping and no edges that would not generate pressure sores or tissue tension after the pump insertion. This method could extend the use of internal infusion pumps in pediatric populations.     

A newly designed salt bridge cap-type, a variable, and non-invasive EEG lead electrode and the analytical power spectrum]

A newly devised, variable EEG cap-style electrode that has an electrical salt bridge with 2% agarose gel and 5% NaCl solution was developed. The number of electrodes can be increased as required. The weight of 15 electrodes is about 100g. The electrode is simple, fast and in a one-touch form for measuring the EEG. An EEG using this electrode system was recorded in a healthy man in a sitting position on a chair, at rest, and with eyes closed. The power spectrum showed different patterns for the power at different concentrations of aqueous solution in the matrix of the salt bridge. The power changed to a pattern of J-type with 20% NaCl solution, to a pattern of U-type with 5% NaCl solution, and to a pattern of L-type with 0.9% NaCl solution, respectively. The matrix of the salt bridge that has a concentration higher than 0.9% NaCl, is a hypertonic solution for the isotonic body liquid. One person felt pain in half of the part of the experiment when a 20% NaCl hypertonic solution was applied to the scalp, so a 20% NaCl solution of the salt bridge was used in experiments concerning osmosis. When a salt bridge of 5% NaCl solution was used, the same results of the wave measurement was obtained 10 times. It was a value close to the expected measurement so it has a high probability of being correct. At this time the power spectrum shows a U-type pattern consistently.     

Early environmental stress and biological vulnerability to drug abuse.

It has long been believed that stress and drug abuse are related. Studies using animal models have repeatedly demonstrated that stressed animals more readily self-administer alcohol or other drugs. Similarly, human patients consistently report in clinical interviews that stress is one reason for taking drugs. There are also studies that document neurophysiological, neuroanatomical, neurochemical, and physiological changes to animals and humans who are stressed. Many of these changes occur within biological systems that are also affected by psychoactive drugs. Early response to stress also modifies neurodevelopment in permanent ways, and these neuroadaptations occur within the same neuronal systems which comprise the drug-reward circuit. But absent are studies in humans that link early stress and modifications of neurodevelopment with increased vulnerability to drug abuse. This article provides a glimpse of research relating stress to alteration of brain functions and to drug abuse, and points to the work of others in this volume for more details. We hope this attempt to understand how early stress affects the developing brain and increases vulnerability to drug abuse will lead to a new program of research in this emerging area.     

Neuroendocrinological Effects of L-Threo-3, 4-Dihydroxyphenylserine (DOPS), a Putative Norepinephrine Precursor, on Healthy Volunteers

Abstract: The effect of L-threo-3, 4-dihydroxyphenylserine (DOPS) on plasma Cortisol, prolactin, thyrotropin-stimulating hormone (TSH) and growth hormone concentrations was studied in nine healthy male volunteers. The drug was administered orally (300 mg or 600 mg DOPS) using a multiple crossover placebo-controlled study design. Plasma hormone concentrations were measured at 30 minute intervals for 3 hours after dosing. Plasma DOPS peak concentrations were observed between 2 and 3 hours after dosing. DOPS, however, had no effect on plasma hormone concentrations and this may be attributed to the known low brain permeability of DOPS in healthy subjects.     

Neuroendocrinological effects of L-threo-3, 4-dihydroxyphenylserine (DOPS), a putative norepinephrine precursor, on healthy volunteers

The effect of L-threo-3, 4-dihydroxyphenylserine (DOPS) on plasma cortisol, prolactin, thyrotropin-stimulating hormone (TSH) and growth hormone concentrations was studied in nine healthy male volunteers. The drug was administered orally (300 mg or 600 mg DOPS) using a multiple crossover placebo-controlled study design. Plasma hormone concentrations were measured at 30 minute intervals for 3 hours after dosing. Plasma DOPS peak concentrations were observed between 2 and 3 hours after dosing. DOPS, however, had no effect on plasma hormone concentrations and this may be attributed to the known low brain permeability of DOPS in healthy subjects.     

Perilymph sampling from the cochlear apex: a reliable method to obtain higher purity perilymph samples from scala tympani

Measurements of drug levels in the fluids of the inner ear are required to establish kinetic parameters and to determine the influence of specific local delivery protocols. For most substances, this requires cochlear fluids samples to be obtained for analysis. When auditory function is of primary interest, the drug level in the perilymph of scala tympani (ST) is most relevant, since drug in this scala has ready access to the auditory sensory cells. In many prior studies, ST perilymph samples have been obtained from the basal turn, either by aspiration through the round window membrane (RWM) or through an opening in the bony wall. A number of studies have demonstrated that such samples are likely to be contaminated with cerebrospinal fluid (CSF). CSF enters the basal turn of ST through the cochlear aqueduct when the bony capsule is perforated or when fluid is aspirated. The degree of sample contamination has, however, not been widely appreciated. Recent studies have shown that perilymph samples taken through the round window membrane are highly contaminated with CSF, with samples greater than 2microL in volume containing more CSF than perilymph. In spite of this knowledge, many groups continue to sample from the base of the cochlea, as it is a well-established method. We have developed an alternative, technically simple method to increase the proportion of ST perilymph in a fluid sample. The sample is taken from the apex of the cochlea, a site that is distant from the cochlear aqueduct. A previous problem with sampling through a perforation in the bone was that the native perilymph rapidly leaked out driven by CSF pressure and was lost to the middle ear space. We therefore developed a procedure to collect all the fluid that emerged from the perforated apex after perforation. We evaluated the method using a marker ion trimethylphenylammonium (TMPA). TMPA was applied to the perilymph of guinea pigs either by RW irrigation or by microinjection into the apical turn. The TMPA concentration of the fluid sample was compared with that measured in perilymph prior to taking the sample using a TMPA-selective microelectrode sealed into ST. Data were interpreted with a finite element model of the cochlear fluids that was used to simulate each aspect of the experiment. The correction of sample concentration back to the perilymph concentration prior to sampling can be performed based on the known ST volume (4.7microL in the guinea pig) and the sample volume. A more precise correction requires some knowledge of the profile of drug distribution along the cochlear prior to sampling. This method of sampling from the apex is technically simple and provides a larger sample volume with a greater proportion of perilymph compared to sampling through the RW.     

Oxcarbazepine does not interact with cimetidine in healthy volunteers

When cimetidine (CIM) is administered together with the anti-epileptic drug carbamazepine (CBZ), a drug interaction may cause a rise in plasma concentrations of CBZ, which can result in CBZ-related toxic symptoms. The aim of this cross-over study was to investigate whether CIM influences the disposition and kinetics of the new anti-epileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there was no difference in AUC, Cmax or tmax when OXC was administered either with or without CIM. The results of this study suggest that in the treatment of epilepsy OXC offers an important advantage over the established anti-epileptics, especially when concomitant therapy with CIM is required.     

Quantitative assessment of female sexual motivation in the rat: Hormonal control of motivation

While a good deal of information has been garnered in the last few decades regarding the neural and hormonal control of female sexual behavior, literature elucidating these mechanisms with respect to female sexual motivation has been scarce. We believe that one reason for this is the lack of a standardized paradigm that will quantify female sexual motivation while allowing for sexual interaction to occur. Here we describe a two-chambered apparatus that utilizes operant responding (nose poking) to quantify female sexual motivation. During the test, the female exhibits nose pokes to gain access to a sexually active male, with whom she is allowed to mate. Therefore, this apparatus allows for examination of sexual behavior as well as quantification of sexual motivation by assessing the number of nose pokes the female will exhibit within a fixed interval to gain access to the male.We report that hormone priming significantly increases sexual motivation in the female as indicated by the number of nose pokes she will exhibit to gain access to the male. Additionally, hormone primed females enter the male compartment after a shorter period and spend more time in direct contact with the male compared to when they are not hormone primed. In contrast, when females are not hormone primed they spend more time in view, but out of reach, of the male.This paradigm will help to advance the study of female sexual motivation, providing a method for quantifiable assessment of female sexual motivation while allowing for sexual activity to occur.     

Protective and preventive therapeutic strategies: monoamine oxidase inhibitors.

There is convincing evidence that monotherapy with 10 mg of selegiline daily substantially delays parkinsonian disability, although whether this delay is due to a symptomatic or protective mechanism remains a matter of debate. Evidence against a symptomatic effect is that the wash-out evaluation in two double-blind, placebo-controlled studies failed to detect clinical decline 1 month after discontinuing selegiline. Yet it can be argued that 1 month was not long enough to eliminate the biologic effect of the drug. Thus further studies are required to answer this question definitively. Nonetheless, because selegiline delays the requirement for levodopa therapy and appears to be relatively safe when used as monotherapy, it seems reasonable to recommend this drug as initial treatment when Parkinson's disease is first diagnosed. There is little doubt that future therapeutic and diagnostic strategies for Parkinson's disease and other neurodegenerative diseases will be profoundly influenced if this drug is unequivocally demonstrated to slow progression of Parkinson's disease. Such a finding would be a potent argument for developing biomarkers of preclinical disease because early intervention with such protective therapy might even halt the disease before symptoms develop.     

Differential effects of intermittent or continuous exposure to cocaine on the hypothalamic-pituitary-adrenal axis and c-fos expression.

Accumulating evidence indicates that acute administration of cocaine alters neuroendocrine functions. In order to ascertain the long-term effects of cocaine on the male rat's hypothalamic-pituitary-adrenal (HPA) axis, a series of experiments were performed utilizing two different paradigms of cocaine administration for 6 days. In the first paradigm, rats received daily intravenous injections of cocaine (5 mg/kg), while in the second, they were continuously exposed to the drug (5 or 100 mg/kg/day) via osmotic pumps. We measured plasma adrenocorticotropin hormone (ACTH) and corticosterone levels, as well as the brain pattern of the proto-oncogene c-fos expression in response to either mode of drug administration. Repeated, intermittent injections of cocaine caused consistent increases in ACTH and corticosterone secretion over a 30-min sampling period on days 2, 4 and 6. This paradigm of drug administration also induced considerable, short-lasting and reversible c-fos expression in the caudate putamen but not in hypothalamic regions associated with endocrine function. In contrast, we consistently failed to observe any measurable increases in ACTH or corticosterone secretion at any time during continuous exposure to the drug. Administration of cocaine by osmotic pumps also had no effect on c-fos expression in the caudate putamen, indicating that c-fos expression as well as activation of the HPA axis are dependent upon the mode and frequency in which cocaine is administered. We conclude that continuous exposure to cocaine does not appear to activate the HPA axis, while intermittent injections of the drug induce repeated increases in plasma ACTH and corticosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Infection Risk of Intrathecal Drug Infusion Pumps after Multiple Refill Procedures

The objective of this study was to evaluate the long‐term infection risk from refilling intrathecal drug delivery devices. We studied 25 patients (14 females and 11 males) with intrathecal infusion pumps placed for spasticity (23 patients) and chronic pain (two patients). In this study group there were 890 refill procedures (mean 35.6 ± 20.5; range 8–72 times) performed on an outpatient basis by four different physicians. All refill procedures were performed in a sterile and standardized fashion as suggested by the manufacturer, using manufacturer's approved kits for the refills. During the study period, five patients had recurrent infection of the urinary tract and three patients had recurrent infections of the respiratory tract. At the last pump refill of each patient, residual drug, extracted from the pump reservoir, was sent to a laboratory for aerobic and anaerobic cultures. All cultures, in all pumps, were negative for aerobic and anaerobic bacteria. We conclude that periodic refills of intrathecal implanted pumps do not seem to be a risk factor for infection if standard sterile refill procedures are performed. In this study, it was clear that comorbid infections from other parts of the body do not present as a risk for device contamination.     

A simple method for local delivery of various substances to the rat neuromuscular system

We report here a simple method for the local delivery of various substances to the neuromuscular system in developing and adult rats. This method permits continuous treatment of tissues with a compound over a period of days. Alternative drug delivery systems are unsuitable in neonates. Osmotic pumps are too large and repetitive injections damage the tissues in neonatal rats. Our delivery system provides an adaptable means by which we can directly apply substances in various concentrations in implants of differing sizes.Substances are incorporated into flexible, non-toxic silicone rubber. Strips are cut from the rubber for implantation alongside the muscle or nerve in the anaesthetised animal. The size of the strip is tailored to the length of the muscle or nerve requiring the treatment. Release of the substance from the implant occurs over a period of days and if a longer period of treatment is required, the initial strip can be replaced with a second and even a third implant.We have tested the effects of the substances applied in this manner both physiologically, by examination of muscle function, and morphologically, by muscle histology and retrograde labelling of motoneurones.We have successfully used this method for the application of various groups of substances, including neurotoxins, channel blockers (K⁺, Ca²⁺ and Cl⁻), calcium-chelating agents, protease inhibitors and ionic salts.