Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway.

Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1ß and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

Safety and efficacy of lodoxamide in vernal keratoconjunctivitis.

OBJECTIVE: To observe the safety and efficacy of topical Lodoxamide eye drops in patients with diagnosed vernal keratoconjunctivitis (VKC). METHODS: This study was conducted at Department of Pharmacology and Therapeutics, BMSI, JPMC, Karachi in collaboration with Department of Ophthalmology, JPMC, Karachi, from April to October, 2009. A total of forty patients with diagnosed vernal keratoconjunctivitis were selected and enrolled consecutively from the out patient department (OPD) of Ophthalmology. Each patient received two drops of Lodoxamide eye drops topically in each eye four times daily. Patients were examined with a torch and slit lamp at baseline and follow-up visits. RESULTS: Out of 40 patients included, 39 completed the study and there was a significant effect of the drug on symptoms and signs of the disease. At the end of the study, 38 (97.4%) were cured, with few side effects. The cure criteria was based on patient's history of becoming symptom-free and resolution of ocular signs. CONCLUSION: Topical lodoxamide eye drops, when used for treatment of VKC, are effective with fewer adverse effects.

[Evaluation of the efficacy and safety of lodoxamide in patients with allergic eye diseases]. / Procjena ucinkovitosti i sigurnosti lodoksamida u bolesnika s alergijskim bolestima ociju.

PURPOSE: To evaluate the effectiveness of lodoxamide in the therapy and prophylaxis of the ocular allergies. PATIENTS AND METHODS: This prospective study included 64 patients divided in 2 groups. In the first group there were 47 symptomatic patients suffering from seasonal allergic conjunctivitis (n = 27), perennial allergic conjunctivitis (n = 16) and giant papillary conjunctivitis (n = 4). The symptomatic patients were examined upon arrival and every 2 weeks until the symptoms were reduced. During the period, lodoxamide drops were administered 4 times a day. In the second group there were 17 patients who had a history of seasonal ocular allergies during previous years but were still not symptomatic upon arrival. In the group of 17 patients who were very likely to develop ocular allergy but up to inclusion into the study had no ocular symptoms, 12 (70%) presented with allergic rhinitis while 5 (30%) had asthma. The symptoms intensity (itching, discomfort, foreign body sensation, pain, tearing) was graded on a 0-3 scale. The clinical signs (follicles, papillae, hyperemia, conjunctival edema, Trantas dots, stromal infiltrates) were detected on a slit lamp examination and graded on a 0-3 scale. RESULTS: In the group of 47 symptomatic patients 2-4 weeks after lodoxamide administration, 70-80% of symptomatic patients examined clinically had less or no follicles, 60-70% had reduced or no edema, the secretion was stopped or greatly reduced in 50-70% of patients. All of the patients reported reduced or no itching, 60% of patients reported less discomfort, photophobia and reduced tearing. In the asymptomatic group two weeks after the initiation of the prophylaxis 88% of patients were still with no ocular signs of allergy while 12% of patients had a conjunctival hyperemia and follicles. After 4 weeks of the prophylaxis 76% of patients patients were still asympthomatic while only 4 developed a mild form of allergic conjunctivitis (conjunctival hyperemia and papillae), but less severe than during previous episodes. CONCLUSION: Lodoxamide was effective in reduction of symptoms and clinical signs of the ocular allergies. The best results were obtained if the drug was administered as a prophylaxis or very early in the course of the disease.

Comparison of lodoxamide 0.1% ophthalmic solution and levocabastine 0.05% ophthalmic suspension in vernal keratoconjunctivitis.

PURPOSE: To compare the clinical efficacy and safety of lodoxamide 0.1% ophthalmic solution with levocabastine 0.05% ophthalmic suspension, each given four times daily (QID) for three months to patients with vernal keratoconjunctivitis (VKC). METHODS: The study was conducted multinationally according to a triple-masked parallel design in 95 VKC patients, with assessments at baseline then monthly during the three months of treatment. The primary efficacy variables were a Physician's Clinical Judgement Scale and a Patient's Overall Judgement Scale of improvements from baseline. Signs and symptoms of VKC were also assessed. RESULTS: Both primary efficacy variables showed significantly greater overall improvement of VKC from baseline with lodoxamide than levocabastine. The superiority of lodoxamide was demonstrated by the Physician's Clinical Judgement Scale at months 2 and 3, with a trend, at month 1, and by the Patient's Overall Judgement Scale at months 1, 2 and 3. All signs and symptoms of VKC improved significantly from baseline at all time points, regardless of treatment (p<0.001). However, relative to levocabastine, conjunctival discharge, photophobia and lacrimation were significantly reduced by lodoxamide at months 1, 2 and 3, itching at months 2 and 3, and bulbar conjunctiva at month 3. The temporal improvement of superior tarsal papillae did not differ significantly between treatments. Both were well tolerated. CONCLUSIONS: Lodoxamide 0.1% and levocabastine 0.05% eye drops, instilled four times daily for three months, were effective, safe and well tolerated by patients with VKC, but lodoxamide was significantly superior to levocabastine.

[Evaluation of efficacy and safety of sterile solution of lodoxamide in patients with ocular allergy]. / Evaluarea eficacitatii si sigurantei solutiei sterile oftalmice de lodoxamida la pacientii cu tulburari oculare alergice.

PURPOSE: Evaluating the efficiency and safety of Alomide (lodoxamide 01.%) in the treatment of allergic conjunctivitis. MATERIAL, METHOD: 12 patients have been selected during may-august 1998, in order to be treated with Alomide 4 times daily. The clinical exam of the patient included: general information, history, ocular examination. The ocular status of each patient has been evaluated with a score: the intensity of each symptom and sign has been graded between 1-3. RESULTS: In all cases, the use of Alomide induced the improvement of the typical symptoms and signs of the allergic conjunctivitis. No side effect related to the use of the drug has been noted. CONCLUSION: Due to its dual action (inhibition of both mast cells and eosinophils), Alomide covers most of the allergic response.

Treatment of common ocular allergic disorders; a comparison of lodoxamide and NAAGA.

BACKGROUND/AIMS: Lodoxamide tromethamine and N-acetyl-aspartyl glutamic acid (NAAGA) are mast cell stabilisers, both of which have been shown to be effective in the treatment of allergic conjunctivitis. The aim of this study was to compare the two compounds in patients with common ocular allergic disorders. METHODS: 73 patients participated in a double masked, randomised multicentre study. Diagnoses were chronic allergic conjunctivitis, vernal conjunctivitis, seasonal and atopic conjunctivitis. 36 patients were treated with lodoxamide 0.1% and 37 with NAAGA 4.9%, the drops being instilled four times daily for up to 56 days. RESULTS: The overall opinion of the physicians and the patients was in favour of lodoxamide at day 10 of the study. At this time, 86% of lodoxamide treated and 49% of NAAGA treated patients considered they had improved. The patients' opinion favoured lodoxamide at day 28 and both physicians' and patients' evaluations were in favour of lodoxamide at day 42. Evaluation of signs and symptoms indicated superiority of lodoxamide at days 42 and 56. Both treatments were well tolerated. CONCLUSION: While both lodoxamide and NAAGA treatments are associated with clinical improvements in patients with allergic conjunctivitis, lodoxamide may have an earlier onset of action.

Efficacy of lodoxamide 0.1% versus N-acetyl aspartyl glutamic acid 6% ophthalmic solutions in patients with vernal keratoconjunctivitis.

In a double-masked, randomized and controlled clinical trial, the effectiveness and safety of lodoxamide 0.1% eye drops were compared with N-acetyl aspartyl glutamic acid 6% (NAAGA) drops in the treatment of 120 patients with vernal keratoconjunctivitis. There were 60 patients in each of the two study groups. The drugs were instilled 4 times daily for 60 days. Follow-up examinations were made on days 7, 30 and 60. Of the 120 patients, 98 (50 in lodoxamide and 48 in NAAGA groups) were still available for follow-up on day 7, 89 (45 in lodoxamide and 44 in NAAGA groups) on day 30 and 75 (38 in lodoxamide and 37 in NAAGA groups) on day 60. Lodoxamide was clinically more effective than NAAGA. Statistically significant trends toward improvement were noted in the lodoxamide group in resolving papillae on day 30, decreasing corneal staining on days 30 and 60, relieving photophobia on day 60, tearing on days 7, 30 and 60 and itching on days 30 and 60. Lodoxamide 0.1% was more effective in lowering the mean scores for corneal staining on days 30 and 60 (p < 0.05). The composite scores for clinical signs and symptoms calculated by averaging the mean scores for signs and symptoms showed clinically significant differences in favor of the lodoxamide group. More frequent follow-up visits might have resulted in better statistical correlations. Treatment-related adverse events were reported in both groups with similar frequency but none were permanent or serious.

New therapeutic agents marketed in 1993.

In 1993, the Food and Drug Administration (FDA) approved 25 new molecular entities (NMEs), 23 of which are for therapeutic use and two are diagnostic agents. Eleven of the NMEs for therapeutic use, as well a new biological agent intended for therapeutic use, were both approved and marketed in the United States in 1993. In addition, 11 other NMEs that the FDA approved before 1993 (most in late 1992) were marketed during the year. Thus, a total of 23 therapeutic agents reached the U.S. market for the first time in 1993, a considerably lower number than the 30 new therapeutic agents marketed in 1992 and the record number 31 new agents marketed in 1991. Many of the 13 therapeutic agents approved in 1993 but not marketed before the end of the year have become available in early 1994. Of the 23 new therapeutic agents first marketed in 1993, 22 are considered in this series. The one agent not reviewed is flosequinan, which was withdrawn from the market after being available only several months because of a concern about toxicity. This review considers the new agents' most important properties and, when possible, compares them with other available agents with similar properties. When additional information is needed, more comprehensive references and the product literature should be consulted.

Efficacy of lodoxamide 0.1% ophthalmic solution in resolving corneal epitheliopathy associated with vernal keratoconjunctivitis.

A multicenter, randomized, double-masked, parallel-group study compared the long-term efficacy and safety of lodoxamide 0.1% ophthalmic solution and placebo in 118 patients with vernal keratoconjunctivitis. The test drugs were instilled four times daily for 90 days. Lodoxamide 0.1% ophthalmic solution was significantly (P < .05) more effective than placebo in lowering severity scores for epithelial disease and corneal staining, evidence of the superior efficacy of lodoxamide 0.1% ophthalmic solution in reversing the corneal complications commonly associated with moderate to severe vernal keratoconjunctivitis. Additionally, lodoxamide 0.1% ophthalmic solution ameliorated the other key signs of vernal keratoconjunctivitis, including upper tarsal papillae, limbal signs (papillae, hyperemia, and Trantas' dots), and conjunctival discharge. The between-group differences in the relief of symptoms (itching, tearing, and photophobia) were clinically significant but not always statistically significant. Treatment-related adverse events were reported with similar frequency in both treatment groups, and none were serious.

Efficacy and safety of lodoxamide 0.1% vs cromolyn sodium 4% in patients with vernal keratoconjunctivitis.

A multicenter, double-masked, parallel-group clinical study compared the efficacy and safety of lodoxamide 0.1% ophthalmic solution and cromolyn sodium 4% ophthalmic solution in 120 patients with vernal keratoconjunctivitis. On various follow-up visits, the clinical efficacy of lodoxamide 0.1% was statistically superior to cromolyn sodium 4% in alleviating four of the primary symptoms (itching, tearing, foreign-body sensation, and discomfort) and five of the primary signs (Trantas' dots, palpebral conjunctival changes, bulbar conjunctival hyperemia, erythema/swelling of the eyelids and periorbital tissues, and epithelial disease). At no time during the study was cromolyn sodium 4% statistically superior to lodoxamide 0.1% in demonstrating improvements in clinical signs and symptoms of vernal keratoconjunctivitis. The physician's clinical judgment of patients' response to treatment showed lodoxamide 0.1% effected a greater and earlier improvement than cromolyn sodium 4%. Both drugs were safe for topical ophthalmic use when used four times daily for up to 28 days.

The effect of lodoxamide tromethamine on the immediate asthmatic response to allergen provocation.

The inhibition of immediate allergen-induced airflow obstruction by lodoxamide tromethamine (LT), a new drug with properties considered to be similar to those of sodium cromoglycate, was studied in twelve young asthmatic volunteers. Single aerosolized doses of 0 X 01 mg LT, 0 X 1 mg LT or placebo were administered by inhalation 15 min prior to allergen provocation at weekly intervals, in a double-blind random order study. Following inhalation of both doses of LT a significantly greater amount of allergen had to be administered to cause a 20% fall in the forced expiratory volume in one second (FEV1) from control levels than was the case following placebo pre-treatment (P less than 0 X 001). After single-dose inhalation of LT only minor unwanted effects were recorded; in particular a transient feeling of heat in the upper respiratory tract after inhalation of the higher dose of drug.

Effect of inhaled iodoxamide tromethamine in prevention of antigen-induced bronchospasm.

Lodoxamide tromethamine, a new cromolyn-like drug, was studied to determine its effectiveness and duration of action in preventing antigen-induced bronchospasm in 15 subjects with clinically stable extrinsic asthma. All subjects underwent antigen inhalation challenge 15 min after inhalation of an aerosolized solution of 0.1 mg of lodoxamide in saline or of saline solution alone (placebo) administered on separate days according to a double-blind, random-allocation protocol. Those subjects demonstrating a protective effect of lodoxamide subsequently underwent antigen inhalation challenges at various time intervals (2 to 8 hr) after lodoxamide treatment. Thirteen of 15 subjects (87%) showed a protective effect of lodoxamide administered 15 min prior to antigen challenge. Six of the 13 subjects who were protected initially remained protected 4 hr after lodoxamide treatment and one of these six subjects was also protected at 6 to 8 hr. One additional subject not protected at 4 hr was protected at 3 hr. Lodoxamide exhibited no bronchodilator activity and was not associated with any significant side effects. Further studies are warranted to compare the effectiveness of lodoxamide with that of cromolyn sodium in protection against antigen-induced bronchospasm and to evaluate the relative efficacy and safety of lodoxamide in long-term clinical trials.

Protective effect opf lodoxamide tromethamine on allergen inhalation challenge.

Lodoxamide tromethamine (U-42,585E) is a new drug intended for prophylaxis of mast cell-mediated allergic disease. It is a water-soluble, cromolyn-like agent with demonstrated activity in rat peritoneal mast cell assay, rat percutaneous anaphylaxis (rat PCA) and sensitized rhesus monkey airway system. Ten allergen-sensitive asthmatics were pretreated with lodoxamide (0.01, 0.1, or 1.0 mg) or placebo, then challenged with serial dilutions of allergen extract. Analysis of allergen dose-response curve parameters shows that pretreatment with lodoxamide offers significant protection against experimental allergen-induced bronchoconstriction. At 0.01 mg, lodoxamide was effective in over half the subjects tested. Administration of lodoxamide by inhalation at doses of 0.1 and 1.0 mg uniformly allowed subjects to tolerate significantly larger doses of inhaled allergen. Side effects observed at these doses were minimal.

Prevention of antigen-induced bronchoconstriction by lodoxamide ethyl, a new orally active antiallergic drug.

Lodoxamide ethyl, an orally active drug with pharmacologic activity similar to that of cromolyn sodium, blocks passive cutaneous anaphylaxis (PCA) in rats and antigen-induced bronchoconstriction in guinea pigs and monkeys. Its effectiveness in preventing antigen-induced airway obstruction was studied in 12 asymptomatic asthmatic adults with immediate skin test sensitivity to ragweed, Alternaria, or animal dander. The dose required to reduce the forced expiratory volume in 1 sec (FEV1) by 20% (PD20) was determined by dosimeter bronchoprovocation challenge with the appropriate antigen. At 1-wk intervals each subject received either placebo of 1, 3, or 10 mg drug in a randomized, double-blind fashion 30 min prior to starting bronchoprovocation challenge. On average, 1 mg increased the PD20 fivefold, 3 mg about sixfold, and 10 mg about 27-fold. Dose-related side effects began 10 min after drug and lasted up to 40 min. Thus the oral administration of lodoxamide ethyl was effective in preventing antigen-induced bronchoconstriction, and both the beneficial effects and side effects are dose related.

Effect of iodoxamide ethyl on allergy skin tests.

Lodoxamide ethyl is a new cromolyn-like drug which prevents antigen-induced mediator release from mast cells and antigen-induced bronchoconstriction in sensitive animals and man. The purpose of this study was to determine the effect of a single administration of lodoxamide ethyl on allergy skin tests. The effect of this drug on allergy skin testing was studied in a double-blind design on ten adult subjects allergic to ragweed. Serial end-point titrations with short ragweed extract and with histamine were performed after a placebo and 1- and 3-mg capsules of lodoxamide ethyl. The immediate wheal-and-flare responses as well as the late allergic reaction were recorded. No statistically significant difference was found between lodoxamide ethyl and placebo in the suppression of the allergen-induced immediate wheal-and-flare response or the late allergic reaction. Furthermore, 1 and 3 mg of oral lodoxamide ethyl did not inhibit the histamine-induced cutaneous reactions.