Ibogaine for treating drug dependence. What is a safe dose?

The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient's treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients.

Acrolein: a potent modulator of lung macrophage arachidonic acid metabolism.

Resting rat pulmonary alveolar macrophages exposed to acrolein were stimulated to synthesize and release thromboxane B2 and prostaglandin E2 in a dose-dependent manner. Zymosan-activated pulmonary alveolar macrophages released approximately twice as much prostaglandin E2 as thromboxane B2, whereas acrolein-activated pulmonary alveolar macrophages released 4-5 times less prostaglandin E2 than thromboxane B2. In the zymosan-stimulated pulmonary alveolar macrophages, acrolein also induced a reversal in the relative amounts of prostaglandin E2 and thromboxane B2 synthesized and released into the culture medium. This reversal was achieved by a dose-dependent reduction in prostaglandin E2 synthesis. Although phagocytosis was also inhibited in a dose-dependent manner, the reduction in prostaglandin E2 appeared to be partially independent of particle ingestion since thromboxane B2 synthesis was not affected by low doses of acrolein. In fact, high doses induced a slight enhancement in thromboxane B2 synthesis. These results suggest that acrolein selectively inhibited the enzyme, prostaglandin endoperoxide E isomerase, necessary for the conversion of the endoperoxide to prostaglandin E2. Sulfhydryl reagents such as N-ethylmaleimide and 5,5'-dithiobis (2-nitrobenzoic acid) mimicked acrolein's effects, and reduced glutathione afforded protection against the effects of acrolein. These results indicated the possible involvement of acrolein's sulfhydryl reactivity in the inhibition of the isomerase enzyme. Propionaldehyde had no effect on macrophage arachidonic acid metabolism whereas crotonaldehyde mimicked the effects of acrolein. Pulmonary macrophages were unable to reverse the acrolein effects on arachidonate metabolite synthesis after 6 h in an acrolein-free environment. These data indicated the necessity of the unsaturated carbon bond for the acrolein effects on arachidonic acid metabolism and the relative irreversibility of acrolein's reaction with the macrophage.

Successful management of Mycoplasma hominis septic arthritis involving a cementless prosthesis.

PIP: Prompt identification of the infectious agent and antibiotic treatment are essential to the prevention of mortality or serious morbidity in patients with septic arthritis. Of concern is the increasing incidence of Mycoplasma hominis saprophytes as a cause of joint infections given the problems in isolating these microbes. The case of a 32-year-old black woman with a 9-year history of systemic lupus erythematous who presented with an M hominis-related septic arthritis involving hip and knee joint protheses offers guidelines on the predisposing factors and characteristic clinical and laboratory findings in such cases. The literature indicates that hypogammaglobulinemia, immunocompromise, postpartum or postabortion fever, and urinary tract manipulation are the risk factors most commonly associated with mycoplasmal septic arthritis. Typical laboratory results include a synovial fluid white blood cell count exceeding 80,000/mm3, a synovial fluid smear greater than 95% neutrophils, negative Gram's stain of synovial fluid smear, positive acridine-orange stain, and slow or absent growth in standard culture media. M hominis infections respond to tetracyclines, lincomycin, and clindamycin, but are resistant to erythromycin. Risk factors in the patient described here included longterm corticosteroid treatment, prior urinary tract infection, and an abortion 2 months prior to presentation for which antibiotic prophylaxis was not administered. The results of synovial tissue, bone, and irrigation fluid cultures were initially negative, but more sophisticated testing ("fried egg" morphology) isolated M hominis. This microorganism was also isolated in endometrial tissue cultures, and retained products of conception are considered the most likely source of the patient's joint infection. A 10-week course of tetracycline eliminated the infection.^ieng

Beam shaping for microwave waveguide hyperthermia applicators.

PURPOSE: Hyperthermia treatments commonly use single element microwave waveguide applicators. The microwave beam patterns produced by these applicators are often non-uniform. As a result, hot spots are formed in the heated tissue and therapeutic temperatures are reached in only small areas of the treatment field. We have constructed new coupling boluses that improve the heating patterns of external microwave applicators. METHODS: The microwave beam transmitted through the bolus is modified by microwave absorbing saline/gelatin pads. The pads can be designed to result in a uniform heating pattern over a large area or alternatively, complex heating patterns can be generated for specific clinical applications. An analysis of the effect of bolus design parameters on microwave absorption patterns is presented. The heating patterns of the MA-100 and MA-120 microwave waveguide applicators have been measured in muscle and fat phantom materials with both the manufacturer's boluses and the new boluses. RESULTS: In the case of the MA-100, the area above the 70% heating level measured in a muscle phantom was increased by a factor of 2.3 by an absorbing pad bolus. Similarly, the heating area of the MA-120 was increased by a factor of 2.6 by an absorbing pad bolus. The boluses were tested in a clinical setting by measuring tissue temperature profiles in patients under different bolus arrangements. The area over which therapeutic temperature was achieved was increased considerably when the absorbing bolus was used. A second bolus was designed for the MA-120 to produce a ring heating pattern for the treatment of a breast cancer patient who had developed recurrences at the periphery of a skin graft. The heating pattern produced in a muscle phantom is compared with tissue temperature profiles measured during the hyperthermia treatment of this patient. CONCLUSIONS: Microwave absorbing filters using saline pads significantly improve the heating patterns of microwave waveguide hyperthermia applicators. This improvement was confirmed in clinical application where much greater areas of homogeneous heating were observed. The technology was extended to produce complex heating patterns for special clinical applications.

Chiral stereoisomeric molecules in the treatment of arthritis.

Pharmacokinetic and pharmacodynamic properties of drugs and their ultimate therapeutic effects are often significantly influenced by interactions between the geometry of host receptors, host enzymes, and the three-dimensional structure of drugs. Drug molecules that are mirror images of each other are chiral stereoisomers, and such chiral isomer compounds are commonly used as therapeutic agents by rheumatologists either as racemates (mixtures of chiral isomers) or as pure stereoisomers. Understanding and using such stereoisomeric drugs may lead to lower risks of drug toxicity, better therapeutic indices, and newer approaches for the treatment of articular disorders. A review of the properties of these special isomers is presented, and their therapeutic advantages are discussed.

Detection of hypoxic fractions in murine tumors by comet assay: comparison with other techniques.

The alkaline comet assay was used to detect the hypoxic fractions of murine tumors. A total of four tumor types were tested using needle aspiration biopsies taken immediately after a radiation dose of 15 Gy. Initial studies confirmed that the normalized tail moment, a parameter reflecting single-strand DNA breaks induced by the radiation, was linearly related to radiation dose. Further, it was shown that for a mixed population (1:1) of cells irradiated under air-breathing or hypoxic conditions, the histogram of normal tail moment values obtained from analyzing 400 cells in the population had a double peak which, when fitted with two Gaussian distributions, gave a good estimate of the proportion of the two subpopulations. For the four tumor types, the means of the calculated hypoxic fractions from four or five individual tumors were 0.15 +/- 0.04 for B16F1, 0.08 +/- 0.04 for KHT-LP1, 0.17 +/- 0.04 for RIF-1 and 0.14 +/- 0.01 for SCCVII. Analysis of variance showed that the hypoxic fraction in KHT-LP1 tumors is significantly lower than those of the other three tumors (P = 0.026) but that there is no significant difference in hypoxic fraction between B16F1, RIF-1 and SCCVII tumors (P = 0.574). Results from multiple samples taken from each of five RIF-1 tumors showed that the intertumor heterogeneity of hypoxic fractions was greater than that within the same tumor. The mean hypoxic fraction obtained using the comet assay for the four tumor types was compared with the hypoxic fraction determined by the clonogenic assay, or median pO2 values, or [3H]misonidazole binding in the same tumor types.(ABSTRACT TRUNCATED AT 250 WORDS)

Design of parallel plate ion chambers for buildup measurements in megavoltage photon beams.

Dose measurements in the buildup region of megavoltage photon beams are most commonly made using parallel plate ion chambers having fixed electrode separation. Fixed-separation chambers generally do not read correctly under such beam conditions because of the contribution to the chamber signal of electrons from the side walls. In this work it is shown that the side wall error can be very large and published correction formulas are not accurate for all beam conditions and chamber geometries. The principal focus of this study has been to determine the design features of a fixed-separation chamber that has negligible side wall error. The approach has been to study, in beams of 60Co, 6 MV, and 18 MV, the response of a specially built ion chamber in which several chamber parameters could be independently varied. The study has shown that the side wall error is primarily dependent on the ratio of the electrode separation to the wall diameter as well as on the wall density and wall angle. Based on these findings the design of a fixed-separation chamber is described which reads to within about 1% of the correct dose. Guidelines are also provided for assessing the suitability of current commercial fixed-separation ion chambers for buildup measurements.

Structural requirements for the inhibition of human monocyte carboxylesterase by organophosphorus compounds.

Human blood monocyte carboxylesterase (CBE) is inhibited by a variety of organophosphorus compounds including arylphosphates and arylphosphites and some alkylphosphites. Triphenyl phosphate and triphenyl phosphite with Ki values of 8 x 10(-9) M and 4.8 x 10(-8) M, respectively, are the most potent inhibitors of this enzyme evaluated by this study. The arylphosphates vary in their capacity to inhibit carboxylesterase activity. Diphenyl phosphate with its strong negative charge is not a potent inhibitor (Ki = 1 x 10(-4) M), whereas if its negative charge is neutralized, as in diphenyl methyl phosphate, its capacity to inhibit carboxylesterase is significantly increased. Compounds with increased bulk, such as trinaphthyl phosphate, only inhibit the enzyme at concentrations of 10(-5) M or greater. Arylphosphites have inhibitory capacities similar to the arylphosphates. Alkylphosphites (tributyl phosphite/triethyl phosphite) inhibit carboxylesterase activity, whereas alkylphosphates (tributyl phosphate/triethyl phosphate) have no inhibitory effect. Arylphosphines and arylphosphine oxides do not inhibit carboxylesterase activity. This study demonstrates that organophosphates and organophosphites are relatively effective inhibitors of human monocyte CBE activity with the exception of the alkylphosphates which have no inhibitory activity. We conclude that molecular bulk and charge have a significant role in determining the potency of organophosphorus inhibitors of monocyte CBE. The observed variations in the degree of esterase inhibition by organophosphorus compounds as well as the differences in the pathological expression of neuropathic disorders associated with such chemicals suggest that different esterase enzymes derived from the family of esterase genes may mediate the different neuropathies observed with organophosphorus exposures. Such data also provide the rationale for the kinetic analyses of esterases and the design of non-toxic organophosphorus compounds with low or no monocyte CBE inhibitory capacity to reduce the potential of these commonly used chemicals for human toxicity.

Regulation of bradykinin-induced cyclic amp response by quinacrine and prostaglandin E2 and F2 alpha in human synovial fibroblasts.

Bradykinin induces an increment in intracellular cyclic AMP concentrations of human synovial fibroblasts and evokes the release of [3H]arachidonic acid and [3H]-E prostaglandins from human synovial fibroblasts pre-labeled in their phospholipids. Both these bradykinin-induced reactions are inhibited by quinacrine, an inhibitor of phospholipase A activity. The cyclic AMP response of human synovial fibroblasts to bradykinin is potentiated by prostaglandin E2 and inhibited by prostaglandin F2 alpha. These data emphasize the critical role of the prostaglandin system in reactions induced by bradykinin and suggest mechansims by which inflammatory reactions due to bradykinin may be modulated.

Classification of back muscle impairment based on the surface electromyographic signal.

A surface electromyographic (EMG) procedure for classifying muscle impairments in persons with low back pain (LBP) is described. The procedure was studied using a device, the Back Analysis System (BAS), to acquire and process EMG signals from six bilateral muscle sites during sustained isometric contractions designed to progressively fatigue the lower back. Back muscle impairment was determined on the basis of the different ways in which the EMG median frequency parameters change as a function of contraction duration and muscle site. The article describes a series of studies that have been useful in developing an automated procedure for identifying back muscle impairment by comparing individual test results to a normative database. To date, the research results have produced multivariate discriminant functions that have identified two muscle impairment categories associated with deconditioning and imbalances secondary to LBP. We have found that the functions can distinguish individuals with and without LBP with an accuracy of approximately 90%. Other studies are described in which the technique is applied to monitoring changes in muscle performance capability that occur following rehabilitation for LBP. Many of our findings here are also compared to the results of independent studies by others using similar procedures. The need for further research and development of the technique to improve its clinical applicability is also described.

Intermittent spinal ischemia. A reversible cause of neurologic dysfunction and back pain.

A woman who presented with leg claudication and neurologic dysfunctions is described. Aortic obstruction was defined by aortography, with large collateral vessels observed above the obstruction extending to the femoral arteries and small collaterals extending to the spinal cord. Aorto-femoral bypass surgery resulted in resolution of the patient's symptoms. Prompt recognition and treatment of spinal cord ischemia is essential if permanent and disabling neurologic damage is to be avoided.

Immune surveillance, organophosphorus exposure, and lymphomagenesis.

Prevalence of lymphoproliferative disorders is increased in populations with various chemical exposures, including organophosphorus compounds. Lymphomas are also more common in individuals with a substantially decreased monocyte esterase activity. Organophosphorus compounds inhibit esterases associated with monocytes, natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytotoxic T lymphocytes, and these inhibitory effects impair immune surveillance and cytotoxic functions mediated by such cells. Lymphoma development is also associated with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) infections, which are regulated by cytotoxic immune responses mediated by monocytes, T cells, and NK cells. My hypothesis is that lymphomagenesis is a multistep process, and the absence or inhibition of monocyte esterase and perhaps other immune cell esterases alters esterase-dependent detoxification of a factor critical for the early steps of oncogenesis. Also, such an enzyme deficit might impair the processes that regulate the dissemination and limit the total burden of pathogens such as the lymphoma-associated herpesviruses. An added risk to any viral-mediated lymphoproliferation might be an organophosphorus-induced oncogenic genetic change.

Neutral protease activation of peritoneal macrophage prostaglandin synthesis.

We observed that the treatment of murine macrophages with proteolytic enzymes can activate the synthesis and release of arachidonic acid (ARA) metabolites. Murine peritoneal macrophage monolayers prelabeled with [14C]ARA were incubated with neutral proteases. Specific bacterial and mammalian proteases from various sources provoke the synthesis and release of prostaglandin E2 (PGE2) and other radiolabeled metabolites. However, cells treated with the neutral proteases thrombin and trypsin did not release significant amounts of PGE2. Neutral protease treatment did not decrease cell viability (> 90%) and boiled protease preparations did not activate prostaglandin synthesis. Protease-activated PGE2 synthesis was inhibited by a variety of protease inhibitors and synthetic substrates for neutral proteases. An inflammatory agent that induces macrophage neutral protease activity, 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated synthesis and release of PGE2 in a dose- and time-dependent manner. TPA-activated PGE2 synthesis was also blocked by a variety of protease inhibitors. These results suggest that neutral proteases have the capacity to activate ARA metabolism and imply that neutral proteases found in inflammatory reactions may infuence prostaglandin production.

Bioremediation of atrazine-contaminated soil by repeated applications of atrazine-degrading bacteria.

Bioaugmentation has previously been unreliable for the in situ clean-up of contaminated soils because of problems with poor survival and the rapid decline in activity of the bacterial inoculum. In an attempt to solve these problems, a 500-l batch fermenter was investigated for its ability to deliver inoculum repeatedly to contaminated soils via irrigation lines. In a field experiment, mesocosms were filled with 350 kg soil containing 100 mg kg-1 atrazine, and inoculated one, four or eight times with an atrazine-degrading bacterial consortium that was produced in the fermenter. After 12 weeks, no significant degradation of atrazine had occurred in soil that was inoculated only once; whereas, mesocosms inoculated four and eight times mineralized 38% and 72% of the atrazine respectively. Similar results were obtained in a laboratory experiment using soil contaminated with 100 mg kg-1 [14C]atrazine. After 35 days, soil that was inoculated once with 10(8) cfu ml-1 of the consortium or with the atrazine-degrading bacterium, Pseudomonas sp. strain ADP, mineralized 17% and 35% of the atrazine respectively. In comparison, microcosms inoculated every 3 days with the consortium or with Pseudomonas sp. (ADP) mineralized 64% or 90% of the atrazine over this same period. Results of these experiments suggest that repeated inoculation from an automated fermenter may provide a strategy for bioaugmentation of contaminated soil with xenobiotic-degrading bacteria.