Gene/Protein Disease Symptom Drug Enzyme Compound
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The authors report the case of an AIDS patient with rare neurologic manifestations: primary vasculitis of the central nervous system and VIII cranial nerve dysfunction. The authors make a review on the subject, and call special attention for the differential diagnosis. In fact, the patient, a 36 year old woman, with promiscuous life, presented with dizziness, gait ataxia, nausea, headache and hypoacusia. Seven days after the admission, she noted blurred vision in both eyes and soon she became blind. The physical examination showed bilateral optic neuritis and vestibulocochlear dysfunction, stiff neck and fever. No abnormalities were detected on CT scan. CSF showed 40 mononuclear cells/mm3, 79 mg/dl of proteins and normal glucose content. Microbiological research was negative. Serum anti-HIV test was positive. The hypothesis of primary CNS vasculitis was made, and pulse methylprednisolone therapy was introduced with good recovery of neurological syndrome except for persistent amaurosis.
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PMID:[Isolated vasculitis of the central nervous system and involvement of the 8th cranial nerve: rare manifestations of acquired immunodeficiency syndrome]. 130 67

The acquired immunodeficiency syndrome (AIDS) was first diagnosed in burundi in 1983 when a large number of patients were registered with Kaposi's sarcoma, cryptococcal meningitis, and disseminated candidiasis. In the 1st phase of the disease the vi rus is dormant. In the 2nd phase seroconversion appears; and in the 3rd phase generalized adenopathy emerges. In the 4th phase the full-blown disease appears as a result of cellular immunity deficit with emaciation, fever, sweating, chronic diarrhea, asthenia, blood parameter changes (lymphopenia, thrombocytopenia, leukopenia, anemia, and specific immune disorders). The early phases can be diagnosed by serological tests. During 1989 a group of 155 patients with 1st signs of seropositivity were studied in the central hospital of Bugumbura. The available clinical diagnostic markers were: 56 cases of herpes, 26 cases of generalized adenopathy, 25 cases of inflammatory infiltration of paraganglionic zones, 13 abscesses and phlegmons, 8 cases of chronic proctitis, 8 prurigo cases, 7 cases of chronic pneumonia and bronchitis, 4 cases of paresis of the facial nerve, 4 cases of Kaposi's sarcoma, 2 cases of fresh syphilis, 2 cases of anemia, asthenia, dizziness, and weight loss. Tomo- and zonographical X-ray study of the thorax of 80 patients aged 20-65 (51 men and 29 women) was performed. In 62 patients changes in the lungs were evident. In 2 patients tuberculosis of the lungs was diagnosed: miliary TB in a 26-year woman and disseminated TB in a 31-year man. 2 chronic and 3 bronchial, and 10 interstitial pneumonia cases were diagnosed in 15 patients with average age of 30 years. 4 patients had peribronchial and pneumonic infiltrations. In a group of 45 patients magnified picture showed no deformation in the lungs; and only 5 had respiratory organ pathology. Interstitial pneumonia was the most often diagnosed ailment by X-ray inpatients infected with HIV.
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PMID:[X-ray pulmonary manifestations in patients infected with the human immunodeficiency virus]. 196 22

The authors discuss computed tomography (CT) and magnetic resonance imaging (MRI) findings of herpes encephalitis as important adjuncts to the early diagnosis of this entity. The patient was a 42-year-old HIV-negative male who presented with a history of dizziness, headaches, and fever.
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PMID:Imaging of herpes simplex encephalitis. 841 11

4187 pregnant women with parasitemia attending 4 prenatal care clinics in rural Mangochi District, Malawi, were assigned to 1 of 4 regimens of antimalarial treatment and/or prophylaxis and followed through delivery. The aim was to examine maternal fever and to evaluate side effects and the frequency of adverse reproductive outcomes for their possible association with malaria or the antimalarial drug regimens. The regimens were 3 regimens for chloroquine (CQ), 1 of which was the current standard of care in Malawi, and a mefloquine (MQ) regimen. 25% of the pregnant women claimed to have had at least 1 febrile episode before their first prenatal care visit. Blood smear tests revealed the parasitemia prevalence rate at enrollment to be 44.4%. The sensitivity of fever to identify parasitemic pregnant women was 24%. Fever's specificity was 71%. Only high density parasitemia (10,000 parasites/sq m) was associated with fever (44.9% vs. 25.4% for no parasitemia; odds ratio [OR] = 2.54; p 0.000001). Other significant factors associated with high fever were low parity, enrollment in the rainy season, HIV seropositivity, use of antimalarial prophylaxis before enrollment, high socioeconomic status, normal maternal height and weight, and literacy. The sensitivity of first or second pregnancy to identify parasitemic women was 71%. Its specificity was 57%. About 60% of women from both CQ and MQ treatment groups had side effects after a treatment dose. About 25% had side effects after a prophylactic dose. The leading side effects were itching, dizziness, and gastrointestinal disturbances. There were few serious side effects. Among all women, the spontaneous abortion rate was 1.2% and the stillbirth rate was 3.9%. Women in the CQ and MQ treatment groups had similar abortion and stillbirth rates. Based on these findings, the researchers concluded that using fever as a means to identify parasitemic women is unreliable. They recommend antimalarial treatment and/or prophylaxis for all pregnant women, but when resources are limited it should be administered to women in their first or second pregnancy.
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PMID:Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine. 870 37

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1. Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine. Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000 mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended. Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (< 400 copies/ml) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study. Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.
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PMID:Efavirenz. 987 93

We present SPET brain perfusion findings in 32 patients who suffered mild traumatic brain injury without loss of consciousness and normal computed tomography. None of the patients had previous traumatic brain injury, CVA, HIV, psychiatric disorders or a history of alcohol or drug abuse. Their ages ranged from 11 to 61 years (mean = 42). The study was performed in 20 patients (62%) within 3 months of the date of injury and in 12 (38%) patients more than 3 months post-injury. Nineteen patients (60%) were involved in a motor vehicle accident, 10 patients (31%) sustained a fall and three patients (9%) received a blow to the head. The most common complaints were headaches in 26 patients (81%), memory deficits in 15 (47%), dizziness in 13 (41%) and sleep disorders in eight (25%). The studies were acquired approximately 2 h after an intravenous injection of 740 MBq (20.0 mCi) of 99Tcm-HMPAO. All images were acquired on a triple-headed gamma camera. The data were displayed on a 10-grade colour scale, with 2-pixel thickness (7.4 mm), and were reviewed blind to the patient's history of symptoms. The cerebellum was used as the reference site (100% maximum value). Any decrease in cerebral perfusion in the cortex or basal ganglia less than 70%, or less than 50% in the medial temporal lobe, compared to the cerebellar reference was considered abnormal. The results show that 13 (41%) had normal studies and 19 (59%) were abnormal (13 studies performed within 3 months of the date of injury and six studies performed more than 3 months post-injury). Analysis of the abnormal studies revealed that 17 showed 48 focal lesions and two showed diffuse supratentorial hypoperfusion (one from each of the early and delayed imaging groups). The 12 abnormal studies performed early had 37 focal lesions and averaged 3.1 lesions per patient, whereas there was a reduction to--an average of 2.2 lesions per patient in the five studies (total 11 lesions) performed more than 3 months post-injury. In the 17 abnormal studies with focal lesions, the following regions were involved in descending frequency: frontal lobes 58%, basal ganglia and thalami 47%, temporal lobes 26% and parietal lobes 16%. We conclude that: (1) SPET brain perfusion imaging is valuable and sensitive for the evaluation of cerebral perfusion changes following mild traumatic brain injury; (2) these changes can occur without loss of consciousness; (3) SPET brain perfusion imaging is more sensitive than computed tomography in detecting brain lesions; and (4) the changes may explain a neurological component of the patient's symptoms in the absence of morphological abnormalities using other imaging modalities.
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PMID:SPET brain perfusion imaging in mild traumatic brain injury without loss of consciousness and normal computed tomography. 1045 61

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.
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PMID:Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects. 1046 24

About one third of patients with HIV infection show neurological complications with considerable morbidity and high mortality. This is an actualized review of the most important neurological manifestations resulting from primary HIV infection, from secondary opportunistic infections, or as complications of antiretroviral therapy. The primary neurological manifestations, including HIV-associated dementia complex, myelopathies, peripheral neuropathies and myopathies, the more common opportunistic infections, primary central nervous system lymphoma and cerebrovascular diseases, are discussed in the light of new evidence in diagnosis, therapy and prognosis. Cognitive and psychiatric symptoms, visual changes, headache, seizures, dizziness, involuntary movements, gait disturbances, cranial neuropathies and focal deficits are the common neurological symptoms in HIV infection which are described under the aspect of differential diagnosis. It is important to bear in mind that nearly all information available to date on this subject concerns HIV patients in the period before combination therapies (including protease inhibitors). The introduction of highly active antiretroviral therapy (HAART) with protease inhibitors in 1995, and non-nucleoside reverse transcriptase inhibitors, have opened up new therapeutic modalities with a new emphasis on earlier detection and treatment of neurological complications. The prognosis of different HIV-associated neurological diseases has considerably improved, as recently shown in the case, for example, of progressive multifocal leucoencephalopathy.
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PMID:[Neurological complications of HIV infection. Review: new diagnostic, therapeutic and prognostic aspects]. 1081 41

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz; other compounds are under evaluation. NNRTIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions with compounds utilizing the same metabolic pathway, particularly PIs, whose plasma levels are altered in the presence of NNRTIs. NNRTIs are drugs with a low genetic barrier, i.e. a single mutation in RT genoma induces a high-level of phenotypic resistance, preventing the use of NNRTIs as monotherapy. In naive patients, several trials have shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as second-line therapy. However, due to the rapid emergence of resistant virus to these compounds in case of incomplete viral suppression, NNRTIs should not be added to current failing antiretroviral regimen. The most common side-effect reported with nevirapine and delavirdine is rash. The incidence of rash is rather similar under these two compounds, but severe rash is less frequent with delavirdine. The most common adverse reactions reported with efavirenz are central nervous system complaints such as dizziness. Rash is reported less frequently than with nevirapine or delavirdine, and is usually mild. NNRTIs resistance mutations are located in the amino acid residues aligning the NNRTI-binding "pocket" site. High-level resistance is often associated with a single point mutation which develops within this site (especially codon groups 100 - 108 and 181 - 190). Patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations. NNRTIs should always be used as part of a potent antiretroviral therapy to insure suppression of viral replication, thus circumventing the rapid selection of cross-resistant variants.
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PMID:[Non-nucleoside reverse transcriptase inhibitors]. 1092 53

(+)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (+)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals. In addition, (+)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (+)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (+)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t(1/2)) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (+)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (T(max)) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (+)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (C(max)), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (+)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (+)-calanolide A in healthy, HIV-negative individuals.
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PMID:Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. 1130 99


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