Influence of pentoxifylline on fevers induced by bacterial lipopolysaccharide and tumor necrosis factor-alpha in guinea pigs

In guinea pigs intraperitoneal (i.p.) injections of 50 mg/kg pentoxifylline had no influence on abdominal temperature while higher doses of pentoxifylline caused a hypothermic response lasting for 2-3 h. Administration of 50 mg/kg pentoxifylline 1 h before intramuscular (i.m.) injections of 20 micrograms/kg bacterial lipopolysaccharide reduced the lipopolysaccharide-induced production of endogenous tumor necrosis factor-alpha (TNF-alpha) by 68%. The second phase of lipopolysaccharide-induced fever was significantly attenuated by pretreatment with 50 mg/kg pentoxifylline, a dose which had, per se, no influence on core temperature of guinea pigs. The thermal response of guinea pigs to administration of exogenous TNF-alpha was not modulated by pretreatment with pentoxifylline. Intra-arterial infusions with 5 micrograms/kg TNF-alpha, a dose which yielded the same circulating TNF bioactivity as i.m. injections of 20 micrograms/kg lipopolysaccharide, induced a biphasic febrile response. The magnitude and duration of TNF-induced fever were the same whether guinea pigs were pretreated with pentoxifylline or with 0.9% saline. The results indicate that endogenous formation of TNF-alpha may contribute to the development of fever induced by lipopolysaccharide, but is not its only mediator, since the first phase of lipopolysaccharide-induced fever was not altered by the blockade of TNF production.     

Insulin-like growth factor-I prevents development of a vincristine neuropathy in mice

Vincristine is a commonly used antitumor agent whose major dose-limiting side-effect is a mixed sensorimotor neuropathy. To assess whether insulin-like growth factor-I (IGF-I), a neurotrophic agent that supports the survival of motoneurons and enhances regeneration of motor and sensory neurons, could prevent the peripheral neuropathy produced by vincristine, mice were treated with both vincristine (1.7 mg/kg, i.p., 2 x /week) and/or IGF-I (0.3 or 1 mg/kg, s.c. daily) for 10 weeks. In mice treated with vincristine alone, there was evidence of a mixed sensorimotor neuropathy as indicated by changes in behavior, nerve conduction and histology. Caudal nerve conduction velocity was significantly slower in mice treated with vincristine alone as compared with vehicle-treated mice. Vincristine treatment alone also significantly increased hot-plate latencies and reduced gait support and stride length, but not toe spread distances. The effects of vincristine were accompanied by degeneration of sciatic nerve fibers and demyelination, indicating a peripheral neuropathy. IGF-I (1 mg/kg, s.c.) administered to vincristine-treated mice prevented the neurotoxic effects of vincristine as measured by nerve conduction, gait, response to noxious stimuli and nerve histology. At a lower dose of 0.3 mg/kg administered s.c., IGF-I partially ameliorated the neuropathy induced by vincristine as this dose only prevented the change in nerve conduction and hot-plate latencies. IGF-I administered alone had no effect on any of these parameters. These results suggest that IGF-I prevents both motor and sensory components of vincristine neuropathy and may be useful clinically in preventing the neuropathy induced by vincristine treatment.     

Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy

BACKGROUND: There is accumulating evidence that inflammatory cytokines have an important role in the pathogenesis of heart failure. Plasma concentrations of tumour necrosis factor alpha (TNF-alpha) are high in heart failure and have been correlated with the severity of symptoms. Pentoxifylline suppresses the production of TNF-alpha. This study aimed to assess the effects of pentoxifylline on left-ventricular function and functional class in patients with idiopathic dilated cardiomyopathy. METHODS: We undertook a single-centre, prospective, double-blind, randomised, placebo-controlled trial, in which 28 patients with idiopathic dilated cardiomyopathy were assigned pentoxifylline 400 mg three times daily or matching placebo. Clinical, echocardiographic, and radionuclide assessments were done at baseline and after 6 months of treatment. Primary endpoints were New York Heart Association (NYHA) functional class and left-ventricular function. FINDINGS: Baseline characteristics were similar in the two groups. Four patients died during the study period, all in the placebo group. After 6 months of treatment, the proportion of patients in NYHA functional class I or II was higher in the pentoxifylline group than in the placebo group (14/14 vs 10/14; p=0.01), and ejection fraction was higher in the pentoxifylline group than in the placebo group (mean 38.7% [SD 15.0] vs 26.8% [11.0], p=0.04). At 6 months, TNF-alpha plasma concentrations were significantly lower in the pentoxifylline-treated group than in the placebo group (2.1 [1.0] vs 6.5 [5.0] pg/mL, p=0.001). INTERPRETATION: Our results suggest that pentoxifylline improves symptoms and left-ventricular systolic function in patients with idiopathic dilated cardiomyopathy. These results must be confirmed in larger-scale trials.     

Amyloid precursor protein is synthesized by retinal ganglion cells, rapidly transported to the optic nerve plasma membrane and nerve terminals, and metabolized

We have investigated the synthesis, axonal transport, and processing of the beta-amyloid precursor protein (APP) in in vivo rabbit retinal ganglion cells. These CNS neurons connect the retina to the brain via axons that comprise the optic nerve. APP is synthesized in retinal ganglion cells and is rapidly transported into the optic nerve in small transport vesicles. It is then transferred to the axonal plasma membrane, as well as to the nerve terminals and metabolized with a t1/2 of less than 5 h. A significant accumulation of C-terminal amyloidogenic or nonamyloidogenic fragments is seen in the optic nerve 5 h after [35S]-methionine, [35S]cysteine injection, which disappears by 24 h. The major molecular mass species of APP in the optic nerve is approximately 110 kDa, and is an APP isoform that does not contain a Kunitz protease inhibitor domain. Higher molecular mass species containing this sequence are seen mostly in the retina. A protease(s) that can potentially cleave APP to generate an amyloidogenic fragment is present in the same optic nerve membrane compartment as APP.     

Laser scanning tomography of the optic nerve head in ocular hypertension and glaucoma

BACKGROUND: This study evaluated the ability of laser scanning tomography to distinguish between normal and glaucomatous optic nerve heads, and between glaucomatous subjects with and without field loss. METHODS: 57 subjects were classified into three diagnostic groups: subjects with elevated intraocular pressure, normal optic nerve heads, and normal visual fields (n = 10); subjects with glaucomatous optic neuropathy and normal visual fields (n = 30); and subjects with glaucomatous optic neuropathy and repeatable visual field abnormality (n = 17). Three 10 degrees image series were acquired on each subject using the Heidelberg retina tomograph (HRT). From the 14 HRT stereometric variables, three were selected a priori for evaluation: (1) volume above reference (neuroretinal rim volume), (2) third moment in contour (cup shape), and (3) height variation contour (variation in relative nerve fibre layer height at the disc margin). Data were analysed using analysis of covariance, with age as the covariate. RESULTS: Volume above reference, third moment in contour, and mean height contour were significantly different between each of the three diagnostic groups (p < 0.001). Height variation contour showed no significant difference among the three diagnostic groups (p = 0.906). CONCLUSIONS: The HRT variables measuring rim volume, cup shape, and mean nerve fibre layer height distinguished between (1) subjects with elevated intraocular pressures and normal nerve heads, and glaucomatous optic nerve heads, and (2) glaucomatous optic nerve heads with and without repeatable visual field abnormality. This study did not directly assess the ability of the HRT to identify patients at risk of developing glaucoma. It is hypothesised that the greatest potential benefit of laser scanning tomography will be in the documentation of change within an individual over time.     

p75 neurotrophin receptor induction and macrophage infiltration in peripheral nerve during experimental diabetic neuropathy: possible relevance on regeneration

In this study we examined the expression of the neurotrophin receptor p75 (p75NTR) and the activation of macrophages in the sciatic nerve of rats at different time points after the induction of diabetes with streptozotocin (STZ). Northern blot and immunocytochemical analysis showed that p75NTR was not detectable in the sciatic nerve by Week 2 after STZ treatment. At this time, single nerve fiber immunostaining using ED1 monoclonal antibody revealed that active macrophages were infiltrating the endoneurium, which had a normal morphological aspect. By Weeks 5 and 15 p75NTR mRNA and protein were induced in the endoneurium of diabetic animals. Immunocytochemical analysis of teased single nerve fibers showed that p75NTR protein was distributed uniformly along isolated fibers with no pathological evidence of axonal degeneration or myelin disruption. At this time, cells of the phagocyte lineage had already disappeared from the nerve. These data show that during experimental diabetic neuropathy, the endoneurial induction of p75NTR is localized along isolated nerve fibers showing no morphological alterations, and in time, follows the recruitment of active macrophages in the nerve, suggesting that these cells, directly or through their products, can influence p75NTR induction. This process might play an important role in STZ diabetic neuropathy, as a response to decreased levels of neurotrophins such as NGF and promoting nerve regeneration in the early phases of the disease.     

Application of nearest-neighbor and cluster analyses in pharmaceutical lead discovery

CASE REPORT: A case history of unanticipated radiation-induced bilateral optic neuropathy, 18 months after induction chemotherapy and radiation therapy for a locally advanced nasopharyngeal carcinoma, is presented. Retrospective reanalysis of the radiation therapy technique, with emphasis on the doses received by the optic pathway structures, was performed. These re-calculations revealed unexpectedly high doses in the range 79 to 82 Gy (cumulative external and brachytherapy dose) at the level of the optic nerves, which explained the observed radiation injury. CONCLUSION: Routine implementation of computed tomography for 3D dose planning purposes is therefore advocated. Review of the current literature confirms the importance of 3D dose planning in avoiding this complication and high-lights the role of MRI in establishing the diagnosis of radiation-induced optic neuropathy.     

Transjugular intrahepatic portosystemic shunt: a medical perspective

We studied the ability of cilostazol (CL), an antithrombotic and vasodilating agent, to prevent functional, structural and biochemical abnormalities including delayed motor nerve conduction velocity (MNCV), morphological changes in myelinated fibers, and decreased Na(+)-K(+) -ATPase activity in the peripheral nerves of rats with streptozotocin (STZ)-induced diabetes. Cilostazol treatment (30 mg/kg/day p.o.) for 10 weeks significantly prevented the delay in MNCV in the tail nerve, and morphometric analysis of the sural nerves revealed that this dose of cilostazol had a significant effect on reduction of average size of myelinated fibers. In untreated diabetic rats, cyclic AMP content and Na(+)-K(+)-ATPase activity of peripheral nerve were each significantly less than in normal control rats. Cilostazol (30 mg/kg/day) prevented reduction of Na(+)-K(+)-ATPase activity. Decrease in cyclic AMP content was completely prevented with both doses of cilostazol (30 and 10 mg/kg/day). These findings suggest that cilostazol may have beneficial effects in the treatment of diabetic neuropathy, possibly via improvement of nerve Na(+)-K(+) -ATPase activity and cyclic AMP content. Cilostazol may thus be a potent drug for the clinical treatment of diabetic neuropathy.     

Electrophysiologic findings in multifocal motor neuropathy

We performed detailed electrophysiologic studies on 16 patients with clinically defined multifocal motor neuropathy and found a wide spectrum of demyelinating features. Only five patients (31%) had conduction block in one or more nerves. However, in 15 patients (94%) at least one nerve showed other features of demyelination. We also noted a significant degree of superimposed axonal degeneration in 15 patients. Eight patients (50%) had individual nerves with pure axonal injury, despite the presence of demyelinating features in other nerves. Antiganglioside antibodies were elevated in four of five patients with conduction block and five of 11 patients without conduction block. We conclude that multifocal motor neuropathy is characterized electrophysiologically by a wide spectrum of axonal and demyelinating features. Diagnostic criteria requiring conduction block may lead to underdiagnosis of this potentially treatable neuropathy.     

The role of axonal ion conductances in diabetic neuropathy: a review

Diabetic neuropathy is a common complication in diabetes mellitus. Diabetic neuropathy is accompanied by alterations in axonal excitability, which can lead to either "positive" (paresthesia, dysesthesia, pain) and/or "negative" (hypesthesia, anesthesia) symptoms. The mechanisms underlying these alterations in axonal excitability are not well understood. Clinical tests reveal reduced nerve conduction velocity and axonal loss, but fail to explain nerve excitability. Many different factors have been suggested in relation to the pathophysiology of diabetic neuropathy. There are probably as many factors as there are different clinical pictures in diabetic neuropathy. Nevertheless, it seems that hyperglycemic hypoxia is mainly responsible for the electrophysiological changes seen in damaged diabetic nerves. This article summarizes experimental data indicating that a dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and/or conduction of action potentials in diabetic neuropathy.     

Imaging of external instabilities of the patella. State of the art

Recent articles in the scientific literature have described major advances in our understanding of the anatomy and vascular relationships of the optic nerve (cranial nerve II) and of the diagnosis and treatment of a variety of disorders affecting this nerve, including congenital anomalies of the optic disc, dominant hereditary optic neuropathy, anterior and retrobulbar arteritic and nonarteritic ischemic optic neuropathy, optic neuritis, Cuban epidemic optic neuropathy, toxic and nutritional optic neuropathies, radiation-induced optic neuropathy, AIDS-related optic neuropathy, optic neuropathies caused by tumors, and papilledema.     

The PML/RARalpha fusion protein inhibits tumor necrosis factor-alpha-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts

We investigated the effect of the acute promyelocytic leukemia (APL) specific PML/RARalpha fusion protein on the sensitivity to TNF-alpha-mediated apoptosis. The U937 leukemia cell line was transduced with PML/RARalpha cDNA. PML/RARalpha expression caused a markedly reduced sensitivity to TNF-alpha, even if apoptosis was triggered by agonistic antibodies to TNF-alpha receptors I and II (TNF-alphaRI, II). PML/RARalpha induced a 10-20-fold decrease of the TNF-alpha-binding capacity via downmodulation of both TNF-alphaRI and TNF-alphaRII: this may mediate at least in part the reduced sensitivity to TNF-alpha. Furthermore, the fusion protein did not modify Fas expression (CD95) or sensitivity to Fas-mediated apoptosis. The pathophysiological significance of these findings is supported by two series of observations. (a) Fresh APL blasts exhibit no TNF-alpha binding and are resistant to TNF-alpha-mediated apoptosis. Conversely, normal myeloblasts-promyelocytes show marked TNF-alphaR expression and are moderately sensitive to TNF-alpha-mediated cytotoxicity. Similarly, blasts from other types of acute myeloid leukemia (AML M1, M2, and M4 FAB types) show an elevated TNF-alpha binding. (b) The NB4 APL cell line, which is PML/RARalpha+, shows low TNF-alphaR expression capacity and is resistant to TNF-alpha-triggered apoptosis; conversely a PML/RARalpha- NB4 subclone (NB4.306) exhibits detectable TNF-alpha-binding capacity and is sensitive to TNF-alpha-mediated cytotoxicity. These studies indicate that the PML/RARalpha fusion protein protects against TNF-alpha-induced apoptosis, at least in part via downmodulation of TNF-alphaRI/II: this phenomenon may play a significant role in APL, which is characterized by prolonged survival of leukemic blasts.     

The role of focal nerve ischemia and Wallerian degeneration in peripheral nerve injury producing hyperesthesia

BACKGROUND: A new model of pain associated with an experimental peripheral mononeuropathy has stimulated interest in mechanisms of pain and their structural correlates in peripheral nerve, the site of the experimental lesion. METHODS: The pathology of the neuropathy was studied and the results correlated with alterations in nerve blood flow and with the behavioral response to heat applied to the foot. The focal neuropathy was created by loosely tying several ligatures around rat sciatic nerve, which produces hyperesthesia in the ligated limb in 3-5 days. The neuropathology was striking with epineurial and endoneurial vascular stasis, edema, and extensive nerve fiber injury in the ligated segment noted at 1 week after ligation. RESULTS: Nerve blood flow was reduced significantly in the ligated segment during the development of the hyperesthesia response, suggesting that changes in nerve blood flow caused by the ligature compression of the epineurial vessels contributes to the nerve fiber injury and pathophysiology of the model. To further test this hypothesis, the epineurial vasculature was removed from 1-cm lengths of rat sciatic nerve, which reduces nerve blood flow by 58%, and by ligation of the ipsilateral femoral artery, which focally reduces nerve blood flow by 70%, and the behavioral response to heating of the paw was evaluated at 1 week. Crush injury was used as a positive control creating Wallerian degeneration without a substantial reduction in nerve blood flow. CONCLUSIONS: The results suggest that ischemia is an important initial pathogenic mechanism in the hyperesthesia associated with the loose ligature pain model, in so far as it produces Wallerian degeneration and axonal injury. Modest degrees of ischemia producing only demyelination did not produce significant hyperesthesia.     

Nerve growth factor effects on the song control system of zebra finches

PURPOSE: The authors present the "pattern" visual evoked potentials (VEP) analysis with use of the artificial neural networks (ANN). MATERIALS AND METHODS: The study involved 11 patients with compressive chiasmal optic neuropathy, 20 patients with optic neuritis, 12 patients with anterior ischaemic optic neuropathy, 20 patients with optic nerve atrophy from neuritis, 8 patients with demyelinative neuropathy, 5 patients with oedema optic nerve, 20 healthy persons. The tests of visual evoked potentials were performed with the use of computer system UTAS-E1000. Classification of potentials was made by correlation of outputs of ANN with results of confirmed neuro-ophthalmology conditions. RESULTS: ANN of different architecture were classified correctly in 80-100% of VEP record samples. CONCLUSIONS: The obtained correctness of classification confirms usefulness of VEP analysis as the objective diagnostic method in some neuro-ophthalmological diseases and indicates application of ANN in multifactor analysis.     

Concentration-dependent effects of pentoxifylline on migration and myelin phagocytosis by macrophages

The effects of pentoxifylline (POX) on macrophage migration and myelin uptake were studied in an in vitro model of myelin phagocytosis. The POX is a phosphodiesterase inhibitor which inhibits TNF-alpha (tumor necrosis factor alpha) production and reduces ICAM-1 (intercellular adhesion molecule-1) expression by macrophages. Both of these molecules have earlier been shown to be involved in the process of myelin recognition and degradation. In the present series of experiments, cocultured peripheral nerves and macrophages were treated with different concentrations of POX. Untreated controls were massively invaded by macrophages which ingested the degenerating myelin sheaths. High concentrations of POX (100 microg ml(-1)) inhibited macrophage invasion of the nerves. Lower POX concentrations (50 microg ml(-1)), in contrast, lead to an increased myelin uptake by phagocytic cells without affecting macrophage migration. These data indicate that POX may regulate different effector functions of macrophages such as migration and myelin phagocytosis during Wallerian degeneration. This is important for inflammatory demyelinating conditions in the central or peripheral nervous system (PNS) in which macrophages are also important effector cells. Since POX is used as an immunomodulatory drug in demyelinating diseases, its effects on the described macrophage functions may be of high relevance. An increased myelin uptake during Wallerian degeneration may also support a more efficient axonal regeneration by removing axonal outgrowth inhibitors.     

Elevation of intraocular glutamate levels in rats with partial lesion of the optic nerve

BACKGROUND: Acute partial lesion of the rat optic nerve, although not a model for glaucoma, mimics some of the features of the disease. OBJECTIVE: To learn whether degeneration of rat optic nerve fibers and death of their retinal ganglion cells induced by an acute partial lesion are associated with elevated levels of glutamate, known to occur in the eyes of humans and monkeys with glaucoma. MATERIALS AND METHODS: Rat optic nerve was subjected to a partial crush injury. Aqueous humor samples were aspirated from the anterior and posterior aqueous chambers at specified times and their amino acid contents were determined by means of high-performance liquid chromatography. RESULTS: Three and 7 days after injury, intraocular glutamate and aspartate levels were found to be significantly higher than in normal or sham-operated-on eyes, and returned to normal by day 14. CONCLUSIONS: Degeneration of the optic nerve, induced by a mechanical injury of the axons, leads to intraocular elevation of glutamate and aspartate levels. These results illustrate that the model of the partial optic nerve lesion exhibits another feature typical of a long-term optic neuropathy, such as glaucoma.     

The volitional unit: a functional concept in cortico-motoneuronal connections in humans

AIM: The effect of breathing 100% oxygen on retinal and optic nerve head capillary blood flow in smokers and non-smokers was investigated using scanning laser Doppler flowmetry (SLDF) as a new non-invasive method to visualise and quantify ocular blood flow. METHOD: 10 eyes of 10 young healthy non-smoking volunteers (mean age 26 (SD 3) years) and nine eyes of nine young healthy smoking volunteers (mean age 26 (4) years) were investigated. All participants were asked not to smoke or consume caffeine containing drinks for at least 4 hours before the measurements. Blood flow measurements were performed before and after 100% oxygen was applied to the subjects through a mask over a period of 5 minutes (6 litres per minute). Juxtapapillary retinal and optic nerve head blood flow were determined in arbitrary units using SLDF representing a combination of laser Doppler flowmetry and a scanning laser system allowing visualisation and quantification of the retinal and optic nerve head blood flow. Blood flow was determined in an area of 100 microns x 100 microns. The level of carboxyhaemoglobin was determined in all subjects. A Wilcoxon matched pairs signed ranks test (non-parametric) was used for statistical evaluation. RESULTS: In the non-smoking group, retinal 'flow' was reduced by 33% (p = 0.005), optic nerve head 'flow' by 37% (p = 0.005). In the smoking group retinal flow was reduced by 10% (p = 0.01), optic nerve head flow by 13% (p < 0.008). The difference in reactivity to oxygen breathing between smokers and non-smokers was highly significant (p < 0.00001). Increased carboxyhaemoglobin levels were not found in either of the groups. A significant reduction of the mean arterial blood pressure of 6% (5%) (p < 0.02) was observed in the non-smoking group after administration of oxygen. CONCLUSION: These results indicate that hyperoxia leads to a decrease in capillary blood flow of the retina and optic nerve head secondary to vasoconstriction, and that smokers do not respond to oxygen breathing as non-smokers do. The findings might be based on factors such as long term effects of nicotine on the sympathetic and parasympathetic nervous system.     

Histomorphometry of the optic nerves of normal dogs and dogs with hereditary glaucoma

The beagle dog with hereditary primary open-angle glaucoma, unlike other animal models of human glaucoma, possesses a slowly progressive, sustained elevation of intraocular pressure. The effects of this insidious elevation in intraocular pressure on the axons of the optic nerves of three beagles at early stages of glaucoma and two beagles with advanced signs of glaucoma were compared to the optic nerves of four age-matched normal dogs. Plastic embedded optic nerve cross-sections (1 micron) 1 mm posterior to the lamina cribrosa were osmicated and stained with Toluidine Blue. Axons from 0.2 to > 2.0 microns in diameter were counted and measured in 16 cross-sectional regions of equal size within the whole optic nerve using a computerized image analysis system. The mean optic nerve axon diameters in the normal, early glaucomatous, and advanced glaucomatous dogs were 1.53, 1.25 and 1.13 microns respectively. The average total optic nerve axon count in the normal dogs was 148,303. Approximately 16% of the total axonal fibers were counted in each nerve. The counts of optic nerve axons 2.0 microns or greater in diameter were reduced by up to 60% in the central regions of the optic nerves of affected beagles. The large diameter axons of the peripheral optic nerve of the beagle dogs with glaucoma were more resistant to the elevated intraocular pressure. The counts of axons > 0.6 to 0.8 micron in diameter were significantly increased in glaucomatous beagles.     

Subclinical thyroid disease in the elderly

The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections. After 2 months, sciatic and saphenous sensory nerve conduction velocity (SNCV) and sciatic motor nerve conduction velocity (MNCV) were measured and the sciatic, sural, peroneal and saphenous nerves and dorsal and ventral roots processed for light microscopy. Treatment of control animals with NT-3 had no effect on any functional or structural parameter. Compared to control values, galactose feeding induced a sensory and motor nerve conduction deficit and a reduction in axonal caliber. Treatment with 5 and 20 mg/kg NT-3 ameliorated deficits in sciatic and saphenous SNCV in galactose-fed rats but had no effect on the MNCV deficit. NT-3 treatment also attenuated the decrease in mean axonal caliber in the dorsal root and sural nerve but not in the saphenous nerve, ventral root and peroneal nerve. These observations show that NT-3 can selectively attenuate the sensory conduction deficit of galactose neuropathy in a dose-dependent manner that depends only in part on restoration of axonal caliber of large-fiber sensory neurons.     

Pentoxifylline therapy in human immunodeficiency virus-seropositive persons with tuberculosis: a randomized, controlled trial

Macrophage activation and tumor necrosis factor-alpha (TNF-alpha) production are critical in tuberculosis immunity but may result in increased human immunodeficiency virus (HIV) expression and accelerated HIV disease progression in HIV-infected persons. Pentoxifylline inhibits expression of TNF-alpha and HIV. A double-blind, placebo-controlled study of adjunctive therapy with pentoxifylline (1800 mg/day) as a timed-release formulation was done in Ugandan HIV-infected patients with pulmonary tuberculosis. Subjects had early HIV disease (mean CD4 cell count, 380/microL) and did not receive other antiretroviral drugs. Pentoxifylline resulted in decreased plasma HIV RNA and serum beta 2-microglobulin and, in a subset of moderately anemic patients, improved blood hemoglobin levels. Trends were noted toward reduced TNF-alpha production in vitro and improved performance scores, but these did not reach statistical significance. No effect was noted on body mass, CD4 cell count, or survival. Additional studies of more potent TNF-alpha inhibitors in HIV-positive subjects with tuberculosis are warranted.