Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its introduction in 1987, zidovudine monotherapy has been the treatment of choice for patients with HIV infection. Unfortunately it has been established that the beneficial effects of zidovudine are not sustained due to the development of resistant viral strains. This has led to the strategy of combination therapy, and in 1995 treatment with zidovudine plus didanosine, or zidovudine plus zalcitabine, was demonstrated to be more effective than zidovudine monotherapy in preventing disease progression and reducing mortality in patients with HIV disease. Recent work demonstrates an even greater antiviral effect from triple therapy with 2 nucleosides, zidovudine plus zalcitabine with the addition of saquinavir, a new protease inhibitor drug. The HIV protease enzyme is responsible for the post-translational processing of gag and gag-pol polyprotein precursors, and its inhibition by drugs such as saquinavir, ritonavir, indinavir and VX-478 results in the production of non-infectious virions. As resistance may also develop to the protease inhibitors they may be used in combination, and future strategies may well include quadruple therapy with 2 nucleoside analogues plus 2 protease inhibitors. Administration of protease inhibitors alone or in combination with other drugs does raise a number of important pharmacokinetic issues for patients with HIV disease. Some protease inhibitors (e.g. saquinavir) have kinetic profiles characterised by reduced absorption and a high first pass effect, resulting in poor bioavailability which may be improved by administrating with food. Physiological factors including achlorhydria, malabsorption and hepatic dysfunction may influence the bioavailability of protease inhibitors in HIV disease. Protease inhibitors are very highly bound to plasma proteins (> 98%), predominantly to alpha 1-acid glycoprotein. This may influence their antiviral activity in vitro and may also predispose to plasma protein displacement interactions. Such interactions are usually only of clinical relevance if the metabolism of the displaced drug is also inhibited. This is precisely the situation likely to pertain to the protease inhibitors, as ritonavir may displace other protease inhibitor drugs, such as saquinavir, from plasma proteins and inhibit their metabolism. Protease inhibitors are extensively metabolised by the cytochrome P450 (CYP) enzymes present in the liver and small intestine. In vitro studies suggest that the most influential CYP isoenzyme involved in the metabolism of the protease inhibitors is CYP3A, with the isoforms CYP2C9 and CYP2D6 also contributing. Ritonavir has an elimination half-life (t1/2 beta) of 3 hours, indinavir 2 hours and saquinavir between 7 and 12 hours. Renal elimination is not significant, with less than 5% of ritonavir and saquinavir excreted in the unchanged form. As patients with HIV disease are likely to be taking multiple prolonged drug regimens this may lead to drug interactions as a result of enzyme induction or inhibition. Recognised enzyme inducers of CYP3A, which are likely to be prescribed for patients with HIV disease, include rifampicin (rifampin) [treatment of pulmonary tuberculosis], rifabutin (treatment and prophylaxis of Mycobacterium avium complex), phenobarbital (phenobarbitone), phenytoin and carbamazepine (treatment of seizures secondary to cerebral toxoplasmosis or cerebral lymphoma). These drugs may reduce the plasma concentrations of the protease inhibitors and reduce their antiviral efficacy. If coadministered drugs are substrates for a common CYP enzyme, the elimination of one or both drugs may be impaired. Drugs which are metabolised by CYP3A and are likely to be used in the treatment of patients with HIV disease include the azole antifungals, macrolide antibiotics and dapsone; therefore, protease inhibitors may interact with these drugs. (ABSTRACT TRUNCATED)
 ...
PMID:Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. 908 59

This article suggests ways to manage the dose-limiting adverse reactions caused by foscarnet so that this agent may be used with confidence as first-line therapy in patients with cytomegalovirus (CMV) disease. Foscarnet (trisodium phosphonoformate) has been used for the treatment of CMV disease in patients who are infected with HIV. Some physicians who treat patients with CMV infection are reluctant to use foscarnet because of the serious adverse effects that may occur, especially during the induction period. The most frequently reported serious adverse effects are nephrotoxicity, electrolyte disturbances, nausea, penile ulcerations and seizures. The nephrotoxicity associated with foscarnet is attributable to renal tubular damage, and may be minimised by calculating and infusing the appropriate dose after hydrating the patient. Monitoring serum electrolyte levels and replacing electrolytes before symptoms occur may limit the development of dosage-limiting toxicities. Nausea occurring during foscarnet infusions may be ameliorated by using antiemetics and slowing the infusion rate. Seizures associated with the use of this agent are mostly a result of the simultaneous presence of other CNS pathologies. Penile ulcers are best managed by stopping the infusion until the ulcers heal; they may be prevented by paying careful attention to personal hygiene.
 ...
PMID:Minimising the dosage-limiting toxicities of foscarnet induction therapy. 911 93

The present study evaluated smooth pursuit eye movement (SPEM) function in 36 cocaine-dependent patients, with or without a paternal history of alcoholism, and 12 nondrug-dependent normal volunteers. None of the subjects in either group met DSM-III-R diagnostic criteria for schizophrenia, or delusional, major affective, or schizotypal personality disorders. None possessed a history of seizures, significant head injury, HIV-1 infection, or regular medication use. SPEMs were elicited by a pendulum, oscillated at 0.5 Hz, and recorded using electro-oculographic techniques. Tracking accuracy was estimated by the power of the horizontal electro-oculograph at the stimulus oscillation frequency. Analyses revealed that the SPEM tracking accuracy of cocaine-dependent patients without a paternal history of alcoholism was superior to that of the normal control group. SPEM tracking in these patients correlated positively with years of cocaine and polysubstance abuse. In contrast, patients with a paternal history of alcoholism exhibited subnormal SPEM tracking performance. These differences could not be explained by other family history, demographic, or drug use variables.
 ...
PMID:Smooth pursuit eye movement dysfunction in abstinent cocaine abusers: effects of a paternal history of alcoholism. 926 43

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.
 ...
PMID:Zinc metabolism in the brain: relevance to human neurodegenerative disorders. 936 Dec 93

Cerebral tuberculosis (TB) was diagnosed in 6 (4%) of 156 HIV-infected patients with TB seen at our institution over 6 years. We describe here the clinical and radiologic features of these cases and of 15 others reported in the literature. Of the 21 patients, 59% were intravenous drug users. Presenting symptoms were fever (76%), confusion (52%), seizures (38%), and headache (38%). Fourteen patients (66%) had previous or active extracerebral TB at presentation. Cranial CT scan showed ring-(62%) or nodular-(24%) enhancing lesions or mixed forms (14%). Among the 12 patients who underwent a brain biopsy, bacteriologic evidence of TB was found in 9. Four patients (19%) died during hospitalization. Among the 17 others who received antituberculous therapy, only 1 developed neurologic sequelae. Five patients also received steroid therapy to control cerebral edema or paradoxical growth of the cerebral mass lesions. TB should be considered as a cause of cerebral mass lesions in HIV-infected patients, especially if tuberculous infection is suspected at other sites.
 ...
PMID:Cerebral tuberculosis in patients with the acquired immunodeficiency syndrome (AIDS). Report of 6 cases and review. 941 28

Toxoplasmosis of the central nervous system (CNS) is the most common cause of intracerebral lesions in patients with AIDS. It is now standard clinical practice to treat empirically, based on clinical and radiographic findings, and to perform a biopsy of the lesion only in those patients who fail to have a clinical and radiographic response after two weeks of therapy. This study describes the presentation and response to therapy of central nervous system toxoplasmosis in patients with AIDS at a private practice in Mexico City. A retrospective chart and radiology review of all patients with AIDS treated empirically for toxoplasmosis between 1988 and 1993 was performed. A total of 177 patients with AIDS were seen, nine (5.1%) had toxoplasmosis. Patients with toxoplasmosis were males with a median age of 39 years (range 26 - 65). In two patients, toxoplamosis of the CNS was the initial manifestation of HIV infection, all others had a prior diagnosis of AIDS with a mean of 10 months between their first AIDS defining event and the diagnosis of toxoplasmosis. The median CD4+ T-cell count at the time of the diagnosis of toxoplamsosis was 78 cells/microL. Most patients had headache associated with other focal neurological symptoms such as hemiplegia (2), hemiparesis (2) or seizures (4). Only 4 out of 9 patients had fever as part of their initial clinical presentation. Serum IgG antibodies against Toxoplasma gondii were positive in 6 out of 7 patients tested, while IgM antibodies were negative in all patients. On imaging studies (Computerized Tomography or Magnetic Resonance Imaging), 4 patients had a single lesion while the rest had two or more lesions. Two patients were initially treated with pyrimethamine/sulfadiazine and were later changed to pyrimethamine/clindamycin, which was the treatment given from the beginning to all other patients. One patient died of an intralesional hemorrhage two weeks after the diagnosis despite adequate therapy. The probability of surviving 6 months after the diagnosis of toxoplasmosis was 60%. The findings of these authors are similar to those reported in other series where toxoplasmosis of the CNS is a late complication of HIV infection associated with a CD4+ cell count of < 100 cells/microL. However, survival was short in spite of a good response to therapy.
 ...
PMID:Toxoplasmosis of the central nervous system in patients with AIDS in Mexico. 942 78

Neurologic dysfunction and neuropathology are common findings in patients infected with HIV and in cats infected with feline immunodeficiency virus (FIV). The pathogenesis of lentivirus-associated alterations in the central nervous system (CNS) is multifactorial. Because seizures, alterations in memory, and behavioral changes are clinical manifestations in adults and children infected with HIV, we explored the possibility that changes in neuronal structure may occur in the hippocampus. To do this, we examined the dentate gyrus of FIV-infected cats, an animal model of HIV infection. Neuropathologic findings included gliosis within the hilus of the dentate gyrus and granule cell axonal sprouting. Using the Timm's method, which labels axons of dentate gyrus granule cells, abnormally high amounts of staining were observed in the inner one third of the molecular layer in 45% of FIV-infected cats (n = 11) and in none of the controls (n = 19). Prominent axonal sprouting was seen in three FIV-infected cats that were infected as kittens, suggesting that younger cats may be more susceptible. Axon reorganization of the dentate granule cells has been hypothesized to underlie complex partial seizure activity in human temporal lobe epilepsy. These results suggest that FIV infection causes granule cell axon reorganization in the hippocampus of cats. A similar neuropathogenetic mechanism may contribute to neurologic dysfunction in HIV-infected patients.
 ...
PMID:Axonal sprouting in hippocampus of cats infected with feline immunodeficiency virus (FIV). 943 52

A twenty-six year old, previously healthy nurse presented with new onset of seizures and was given a clinical diagnosis of herpes simplex encephalitis. After treatment with acyclovir there was incomplete resolution of the lesions by MRI scans and within a few months the patient's neurologic symptoms worsened, prompting a stereotactic biopsy. A diagnosis of progressive multifocal leukoencephalopathy (PML) was made using electron microscopy, and in situ hybridization studies. Subsequent to this biopsy, she was shown to be infected with human immunodeficiency virus (HIV) and had a CD4 T-cell count of 63. She had no known risk factors for HIV infections and had been tested as recently as eighteen months previously during her pregnancy. Neither the husband nor the child were positive for HIV. PML as a presenting sign of HIV infection is rare.
 ...
PMID:Case of the month: September 1997--a 26 year old woman with new onset seizures. 945 83

We report on a 32-year old HIV-infected male patient who was admitted to the hospital in a comatose state. A cryptococcus neoformans septicemia with meningoencephalitis was diagnosed. Intravenous treatment with amphotericin B was initiated and replaced three weeks later by fluconazole per os. With this therapy the patient recovered quite well. However, following two grand mal epileptic seizures he suddenly fell into a deep coma 22 days after admission to the hospital. The cause of the encephalopathy remained unclear, and the patient died 2 days later. Autopsy revealed a severe meningoencephalitis and a pneumonia due to cryptococcus neoformans. Departing from this case we discuss diagnosis, clinical presentation and treatment of cryptococcus meningoencephalitis.
 ...
PMID:Cryptococcosis, epileptic seizures and encephalopathy in a HIV-infected patient. 948 May 18

In herpes simplex encephalitis (HSE), simultaneous electro-encephalogram (EEG) and evoked potential studies have not been reported, although EEG changes have been described. In this communication, EEG, somatosensory and motor evoked potentials have been reported in 9 patients with HSE. The patients' age ranged between 2 and 70 years and 3 were females. Seven patients had seizures, CT scan was abnormal in 6 and MRI in remaining 3 patients. Seven patients received acyclovir therapy; one patient died and 6 had poor outcome. The initial EEG was carried out within 5 days of ictus and was abnormal in all the patients. The EEG abnormalities included frontotemporal delta slowing in 5, periodic lateralised epileptiform discharge in 3, runs of spike and periodic activity in one patient each. At 3 months, EEG was normal in 6 patients but it did not correlate with clinical recovery. Central motor conduction time (CMCT) to upper limb and median somatosensory evoked potential (SEP) were normal in all. CMCT to lower limbs and tibial SEPs were unrecordable in one patient who had wide spread herpes simplex virus (HSV-1) infection associated with AIDS, and died on 18th day of illness. From this study, we conclude that EEG although is frequently abnormal and may provide useful diagnostic information in a setting of encephalitis but evoked potential changes are infrequent; and if present an association of HIV infection should be considered.
 ...
PMID:Neurophysiological studies in herpes simplex encephalitis. 963 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>