Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalidomide, in development by Celgene, inhibits the effects of elevated TNFalpha and may consequently be of use in a range of diseases including cachexia, bacterial meningitis, rheumatoid arthritis, septic shock, AIDS, tuberculosis, multiple sclerosis, ulcerative colitis, graft-versus-host disease and systemic lupus erythematosus. In July 1998, Celgene received clearance from the US FDA to market and sell Thalomid (thalidomide) for the treatment of erythema nodosum leprosum (a severe and debilitating condition associated with leprosy) [291919], following a recommendation for approval by the FDA advisory committee in September 1997 [261846,263970]. In that same month, Celgene filed an IND for the treatment of the chronic autoimmune disorders Behcet's disease, and aphthosis [264366]. The trial will be conducted by investigators at the Mayo Clinic and Bowman Gray School of Medicine. It will be divided into two phases, the first phase lasting 4 weeks in which patients will receive 100 mg thalidomide or placebo, and a second open-label phase which will call back all patients to receive the same dose of thalidomide over a 24-week period. It will be determined whether the drug significantly reduces existing ulcerations and inhibits the formation of new lesions. Positive results of a National Institute of Allergy and Infectious Diseases trial for aphthous ulceration of the mouth in HIV-infected patients prompted Celgene to commence a pivotal trial for the same indication. A total of 84 patients will be randomized to 100 mg, 200 mg or 400 mg thalidomide/day for 4 weeks. Patients achieving a full response after 4 weeks will be re-randomized on 100 mg thalidomide or placebo for up to another year [248356]. The company has also completed the pivotal phase III trial for AIDS-related cachexia [225437]. Results from a pivotal phase II/III trial showed that the drug significantly increased body weight in AIDS patients, but also increased viral load initially. A total of 99 patients, who had lost more than 10% of their body weight due to HIV infection, received either 100 or 200 mg/day of thalidomide or placebo orally for 8 weeks. Although there was a significant increase in body weight associated with the 100 mg dose (p = 0.025), there was no difference in body weight changes between patients treated with 200 mg doses and those on placebo. There was a 55% dropout rate at the higher dose due to side-effects such as somnolence, rash, neutropenia, neuropathy and dizziness. Viral load was significantly increased after 4 weeks of treatment. However, there was no further increase in viral load at 8 weeks, and patients were not receiving triple combination antiviral therapy [243943]. In April 1996, Celgene initiated a phase II trial of thalidomide in London for the treatment of chronic intractable diarrhea in HIV positive patients. The double-blind, placebo-controlled trial will involve up to 120 patients, aged 18 to 65 inclusive, at three centers for 28 days of therapy; those on drugs will be orally dosed with 100 mg of thalidomide daily at bedtime. The primary endpoint is reduction in the occurrence of diarrhea [205006,206218]. The trial will be conducted in the US, the UK and Mexico [210069]. The company expanded its clinical trial program in June 1996, for use of thalidomide in graft versus host disease and AIDS complications, such as debilitating ulcers of the digestive system [212461]. A phase II trial for the treatment of cachexia in cancer patients was carried out at St George's Hospital, London. Ten patients received thalidomide (100 mg) orally for 8 weeks and ten received placebo. The study was structured to determine the ability of thalidomide to reduce or stabilize the symptoms of cachexia. Quality of life and levels of disease markers will also be assessed. Results showed that after a 3-week treatment period, patients who received thalidomide gained an average 4.5% in overall body weight versus 0.9% with placebo [190161]. Results from a 65 patient multicenter phase II/III trial for cachexia are still awaited [221227]. Celgene is also conducting a double-blind, placebo-controlled pivotal trial for the treatment of rheumatoid arthritis at New York University's Hospital of Joint Diseases. Levels of TNFalpha are increased in patients with rheumatoid arthritis. Indicators for the trial will be joint swelling and pain and levels of serological markers [177618]. A separate study is being conducted by the US National Institute for Allergy and Infectious Diseases, of thalidomide in combination with Chiron's IL-2 for the treatment of HIV infection [192218]. In vitro evidence suggests that thalidomide can inhibit the replication of HIV type 1 [169245]. In addition to the associated patent, WO-09214455, which discloses the use of thalidomide in TNF-related diseases, another Celgene patent, US-05463063, discloses a scaleable process to make high purity thalidomide [194937].
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PMID:Thalidomide Celgene Corp. 1846 84

A 41-year-old human immunodeficiency virus (HIV)-positive man was hospitalized with complaints of a 4-week history of nausea and vomiting, associated with decreased oral intake, and a 4-day history of frontal headache and fever. His medical history was significant for a gunshot wound to the head 3 years prior, with a residual seizure disorder. He also had two previous hospitalizations, both for culture-negative bacterial meningitis; the first episode occurred 12 months before admission and the second episode occurred 5 months later. At that time, he was found to be positive for serum antibodies against HIV and a CD4+ T-lymphocyte count of 126/mm3. He had no known drug allergies and was not receiving any medication. On admission, the patient was febrile (104.0 degrees F) and hypotensive (blood pressure, 92/40 mm Hg). Pertinent physical examination findings included cachexia with bitemporal wasting, dry mucus membranes, adherent white patches on the oral mucosa, and negative Kernig's and Brudzinski's signs. His laboratory results revealed macrocytic anemia, a decreased serum sodium of 125 mEq/L, and a normal total leukocyte count with a CD4+ T-lymphocyte count < 50/mm3. Lumbar puncture opening pressure was elevated at 160 mm Hg, and cerebrospinal fluid analysis showed an increased white cell count of 97/microL (84% lymphocytes), a decreased glucose level of 26 mg/dL, and a decreased protein level of 42 mg/dL. The patient was started on empiric therapy that included intravenous ampicillin and cefotaxime, oral Bactrim, and clotrimazole lozenges for thrush. Cerebrospinal fluid culture was positive for Escherichia coli, sensitive to cefotaxime. Two days later, the patient developed fine, erythematous, nonblanchable macules primarily on his abdomen, with minimal involvement of his thorax and back. His skin lesions remained unchanged for the next 2 weeks. Repeat lumbar puncture was performed after 14 days of cefotaxime. The cerebrospinal fluid analysis showed an elevated white cell count of 7/microL (100% lymphocytes), a decreased glucose level of 53 mg/dL, and a decreased protein level of 33 mg/dL. The cerebrospinal fluid culture was now positive for Pseudomonas aeruginosa resistant to cefotaxime. The patient was started on imipenem. On day 34 of his admission, the patient became tachypneic with complaints of dyspnea. A chest roentgenogram revealed bilateral patchy infiltrates. He was transferred to the intensive care unit and intubated for hypoxemic respiratory failure (arterial blood gas values on 6 L of oxygen: pH, 7.46; bicarbonate, 23; and oxygen saturation, 37). That evening, the patient was also noted to have diffuse petechiae and purpura in a reticulated pattern over his abdomen (Figure 1A and 1B), most heavily concentrated in the periumbilical region, extending to the axillae and upper thighs. A 3x3-mm punch biopsy from abdominal skin demonstrated Strongyloides stercoralis larvae in the dermis (Figure 2A and 2B). His sputum specimen was teeming with adult S stercoralis worms (Figure 3) and, subsequently, numerous S stercoralis larvae were observed not only from the bronchoalveolar lavage but also from the nasogastric fluid specimen. These findings confirmed the diagnosis of disseminated strongyloidiasis. On hospital day 35, the patient was doing poorly and was started on thiabendazole (1250 mg twice daily for 28 days). Nine days later, ivermectin (4.5 mg once daily for 3 days for 2 courses) was also added. He continued to clinically deteriorate. The patient died 31 days after systemic antihelminthic treatment was initiated.
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PMID:Cutaneous manifestations of Strongyloides stercoralis hyperinfection in an HIV-seropositive patient. 2167 5