Polygraphy vs. polysomnography: missing osas in symptomatic snorers--a reminder for clinicians.

PURPOSES: The purposes of this study are to investigate the usefulness of polygraphy (PG) in diagnosing obstructive sleep apnea (OSA) in sleepy/tired snorers compared to polysomnography (PSG) and, further, to search for suspected respiratory arousals in the PG. METHODS: One hundred eighty-seven adults suffering from sleepiness/tiredness and snoring had undergone ambulant PG and were considered to be normal, using American Academy of Sleep Medicine's 2007 hypopnea criteria A. After approximately 7 months, in-lab PSG was performed using hypopnea criteria B, where arousals are also recognized. Validated questionnaires (Hospital Anxiety and Depression Scale, self-rated general health) were answered. In a subgroup, the sensitivity and specificity were calculated for flow limitation index (FLI) and flattening index (FlatI) in PG compared with the respiratory distress index (RDI) in PSG. RESULTS: Despite the normal PG, at PSG, the median RDI was 11.0 (range, 0-89.1). One hundred sixty-eight out of one hundred seventy-eight (90%) were found to have at least mild OSA and 119/187 (64%) with moderate-severe OSA according to the RDI values. The sensitivity and specificity were low (<70%) for FLI and FlatI. Forty-nine percent of the patients rated anxiety at borderline or pathological levels, 35% rated corresponding depression levels, and 45% rated poor or fair general health. CONCLUSIONS: PG was insufficient to rule out OSA when the respiratory events were mainly associated with arousals. Almost half of these patients experience low general health and psychiatric problems. We recommend a full-night PSG when PG is "normal", and patients have symptoms of snoring and sleepiness/tiredness.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Increasing the enrolment of rural applicants to the faculty of medicine and addressing diversity by using a priority matrix approach to assign values to rural attributes.

In an external review of the admissions process for the Faculty of Medicine, University of Manitoba, Canada, it was suggested that admissions policies be modified to increase the enrolment of students more likely to practise in rural locations, by selecting a cohort of students with attributes reflecting potential for rural practice. A broad-based Working Group devised a framework for scoring personal attributes reflecting a potential for living and working in rural areas. This framework, based on established characteristics reported in the literature, valued applicants who had rural connections, a history of rural employment, a history of rural community service, or a combination of these attributes. Relative weights for the attributes were determined using a priority matrix approach. Historic admissions data, comprising applicants' rural origin (defined only by location of high school graduation), composite scores, and ranking, were reanalyzed to identify the magnitude of numerical constants that, when applied to composite scores, enhanced the relative ranking of eligible rural-origin applicants. This resulted in a hypothetical 29%-33% increase in the number of rural-origin students in incoming classes in those years. In the inaugural year of implementation of the policy and methodology, 60 admission offers (44.1%) were made to applicants with one or more rural attributes. Without adjustments, only 49 applicants with rural attributes (36%) would have been offered admission. This methodology resulted in a 22.4% increase in admission offers to applicants with rural attributes, and ushered in an incoming class that was more representative of the province's rural-urban demographics than in previous years. This methodology, although focused on rurality, could be equally applicable to any attribute, and to achieve greater diversity and equity among medical school applicants.

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

Aetiological treatment with itraconazole or ketoconazole in individuals with Trypanosoma cruzi/HIV co-infection.

Two Brazilian cases of Trypanosoma cruzi/HIV co-infection have recently been treated with azole derivatives. Benznidazole, the drug generally used for the treatment of Chagas disease, was initially used in one case but discontinued because of an adverse effect (retrobulbar neuritis) and replaced by itraconazole. The other case had oesophageal candidiasis, which was treated with ketoconazole, a drug that had already been shown to be effective in the treatment of Chagas disease. Since the medications were effective in reducing the T. cruzi parasitaemia in both patients, they probably helped prevent the severe morbidity sometimes associated with Chagas disease, although the HIV infections still proved fatal in both cases.

Treatment of human papillomavirus with peg-interferon alfa-2b and ribavirin.

We reported one case of human immunodeficiency virus and hepatitis C virus co-infected patient who presented a significant improvement of human papillomavirus (HPV) lesions during the treatment of chronic hepatitis using peg-interferon alfa-2b and ribavirin.

Haptoglobin polymorphism in a HIV-1 seropositive Brazilian population.

BACKGROUND: Haptoglobin (Hp) is a plasma protein with antioxidant and immunomodulatory properties. Three main genotypes/phenotypes (Hp1-1, Hp2-1, Hp2-2) show distinctive efficiencies in their activities and have been related to susceptibility and outcome in different diseases, including HIV infection. OBJECTIVE: To compare Hp genotype distribution between HIV-1 seropositive patients and healthy controls. METHODS: 387 Brazilian HIV-1 seropositive patients, subclassified as A, B, and C according to the Centers for Disease Control, were compared with 142 healthy controls. The influence of the polymorphism on iron status (serum iron, ferritin, transferrin, transferrin saturation), acute phase proteins (Hp, C reactive protein, fibrinogen, albumin), the HIV-1 viral load, and CD4+ T lymphocyte counts was examined. RESULTS: Apart from finding lower Hp concentrations among individuals with genotype Hp2-2, no other significant difference was observed. CONCLUSIONS: No association was found between Hp genotype and either HIV status or indices of HIV progression.

Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. Collaborative Famciclovir HIV Study Group.

OBJECTIVE: To compare the efficacy and safety of 7 days' treatment with famciclovir 500 mg twice a day versus acyclovir 400 mg five times a day, for mucocutaneous herpes simplex virus (HSV) infection in HIV-infected individuals. DESIGN: Randomized, double-blind, parallel-group study to demonstrate equivalence for the primary efficacy parameter. SETTING: Forty-eight hospital-based or specialist public-health clinics in 12 countries. PATIENTS: Two-hundred and ninety-three HIV-positive patients with recurrent HSV infection (orolabial or genital) starting treatment within 48 h of first appearance of herpetic lesions. MAIN OUTCOME MEASURES: Proportion of patients developing new lesions during treatment (primary outcome measures); Time to complete healing of lesions, time to cessation of viral shedding, time to loss of lesion-associated symptoms, number of withdrawals due to treatment failure (secondary outcome measures). RESULTS: Equivalence was defined prospectively and famciclovir was equivalent to acyclovir in preventing new lesion formation: new lesions occurred in 16.7% and 13.3% of patients, respectively [difference, 3.4%; 95% confidence interval (CI), -4.8-11.5]. The groups were comparable in time to complete healing (median 7 days for both groups; hazard ratio, 1.01; 95% CI, 0.79-1.29; P = 0.95), cessation of viral shedding (median of 2 days [hazard ratio = 0.93; 95% C.I. 0.68, 1.27; p = 0.64]), and loss of lesion-associated symptoms (median 4 days; hazard ratio, 0.99; 95% CI, 0.75-1.30; P = 0.93). Similar numbers in each group withdrew because of treatment failure. There were no differences between groups in the incidence of adverse events. CONCLUSIONS: Famciclovir given twice a day is as effective and well tolerated as high-dose acyclovir for mucocutaneous HSV infections in HIV-infected individuals, and has the convenience of less frequent dosing.

Vitamin A and risk of HIV-1 seroconversion among Kenyan men with genital ulcers.

BACKGROUND: Vitamin A is involved in normal immune function and the maintenance of mucosal integrity through complex effects on cellular differentiation. OBJECTIVE: We sought to determine whether serum vitamin A levels were associated with altered susceptibility to primary infection with HIV-1 in men with high-risk sexual behaviour and genital ulcers who presented for treatment at an STD clinic in Nairobi, Kenya. METHODS: HIV-1 seronegative men were prospectively followed. Vitamin A levels at study entry were compared among 38 men who HIV-1 seroconverted versus 94 controls who remained HIV seronegative. RESULTS: Vitamin A deficiency (retinol less than 20 microg/dl) was very common and was present in 50% of HIV-1 seroconverters versus 76% of persistent seronegatives. Seroconversion was independently associated with a retinol level greater than 20 microg/dl (HR 2.43, 95% CI 1.25-4.70, P = 0.009), and a genital ulcer aetiology caused by Haemophilus ducreyi (HR 3.49, 95% CI 1.03-11.67, P = 0.04). Circumcision was independently associated with protection (HR 0.46, 95% CI 0.23-0.93, P = 0.03). CONCLUSION: Vitamin A deficiency was not associated with an increased risk of HIV-1 infection among men with concurrent STD. A decreased risk of HIV-1 seroconversion was independently associated with lower retinol levels. The effects of vitamin A on macrophage and lymphoid cell differentiation may paradoxically increase mucosal susceptibility to HIV-1 in some vulnerable individuals, such as men with genital ulcers. Lack of circumcision and chancroid are confirmed as important co-factors for heterosexual HIV-1 transmission. The role of vitamin A in heterosexual HIV-1 transmission requires further study.

Amantadine kinetics in healthy elderly men: implications for influenza prevention.

Amantadine kinetics were investigated in 10 healthy elderly men 60 to 76 yr old. We calculated a dose that would yield the same trough steady-state plasma amantadine concentration (Cpss; 300 ng/ml) as a 200 mg/day dose taken by young healthy adults; this dose prevents influenza A virus infection and is well tolerated by this population. With a one-compartment open model, kinetic parameters were calculated after a single dose of 25, 50, or 75 mg or the same dose twice a day for 10.5 days. Peak concentration occurred 4.0 to 8.0 hr after dosing, but the calculated AUC was proportional to dose, indicating that relative bioavailability was independent of dose. This was supported by recovery of 88% of the single doses in urine. No change in apparent volume of distribution was found. Log trough Cpss increased with dose. Trough Cpss varied less than 300% for equivalent doses. There was first-order elimination of drug from plasma, with a median t1/2 of 28.9 hr (range 18.5 to 45.0 hr), and elimination was independent of dose and creatinine clearance. The median ratio of renal amantadine clearance to creatinine clearance was 2.07 (range 0.64 to 4.20), suggesting renal tubular secretion. Compared to data from healthy young adults, the t1/2 was doubled and renal drug clearance was diminished in elderly men. To achieve the target trough Cpss of 300 ng/ml, healthy older men must take amantadine at a dose of 1.4 mg/kg/day, and we suggest that this is a rational dose for evaluation of efficacy and safety for influenza A prophylaxis in this population.

Amantadine kinetics in healthy young subjects after long-term dosing.

We investigated the disposition of amantadine in 13 healthy, young adults after long-term dosage. Doses of 25, 100, or 150 mg, randomly allocated, were taken at 12-hr intervals in syrup for 31 doses. A 1-compartment open model and complete bioavailability were assumed. Absorption rate was variable with peak concentrations in plasma occurring at 1 to 12 hr. Since the calculated area under the plasma concentration against time curve was proprotional to it, relative bioavailability was independent of dose at steady state. As the dose increased, the apparent volume of distribution decreased. Intra- and intersubject variations in trough plasma drug concentrations at steady state were less than triple for equivalent doses. Elimination of drug from plasma was consistent with a first-order process. Plasma half-lifes (t1/2s) ranged from 10.2 to 31.4 hr and were independent of dose or creatinine clearance. The ratio of renal drug clearance to creatinine clearance ranged from 1.26 to 14.97, suggesting substantial renal tubular secretion. The median ratio of plasma drug clearance to renal drug clearance approached unity.

Pharmacokinetics and pharmacodynamics of bambuterol, a long-acting bronchodilator pro-drug of terbutaline, in young and elderly patients with asthma.

Disposition and efficacy of bambuterol were studied in 10 younger (20 to 37 years) and 10 older (69 to 76 years) patients with asthma (nine men and 11 women) at steady state, after single daily doses of 20 mg (50 mumol) for 1 week. There was a greater area under the concentration versus time curve for terbutaline during a dose interval in older patients compared with younger patients (558 +/- 171 and 376 +/- 149 nmol.hr/L, respectively [mean +/- SD], p less than 0.021). This was reflected in a lower apparent plasma terbutaline clearance in older patients compared with younger patients (1.22 +/- 0.33 and 2.32 +/- 1.26 L/hr/kg, respectively, p less than 0.023). Peak drug concentration was not different by age. Plasma cholinesterase levels were depressed by about 70% in both groups compared with pretreatment activity. Peak expiratory flow rate increased in both groups. Improvement in forced expiratory volume in 1 second and forced vital capacity was detected only in the younger patients. A small decrease in heart rate and diastolic blood pressure occurred in both patient groups. Bambuterol appears to offer the possibility of once-daily therapy in both younger and older patients with asthma.

Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults.

Amantadine dose, plasma concentration, prophylactic and adverse effect relationships for prevention of influenza A virus infection in healthy young adult subjects were investigated in a double-blind, placebo-controlled study. Seventy-four subjects with hemagglutination inhibition antibody titers less than or equal to 16 against an attenuated influenza A virus AF9/Montreal/3/72 (H3N2) were randomly allocated to groups taking 0 (placebo), 25, 100, or 150 mg amantadine syrup prophylactically twice a day for 31 doses. Eighteen other subjects were randomly allocated to control groups for investigation of drug toxicity (150 mg) or concurrent other virus infection (placebo). Steady-state trough plasma concentrations were 110 +/- 39, 302 +/- 80, and 572 +/- 207 ng/ml (X +/- SD) for the three amantadine doses and increased out of proportion to dose. Prophylaxis groups were challenged intranasally with virus after the fifth dose at steady state; control subjects received saline solution. No subject became ill. Input virus was recovered 48 or 72 hr after challenge from nose or throat swabs of nine of 21 subjects taking placebo, one of 18 subjects taking 100 mg amantadine, three of 18 subjects taking 25 mg amantadine, and six of 17 subjects taking 150 mg amantadine. There were no differences in seroconversion rates or adverse symptoms. Our data do not support a change in the recommended amantadine prophylactic dose for influenza A virus infection in healthy young adults. We defined trough steady-state plasma concentrations associated with the recommended amantadine dose of 100 mg twice a day that should be mimicked in devising dose schedules for populations with differing amantadine kinetics.

Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine.

We studied the short-term effect of oral doses of quinine and quinidine on the renal clearance of amantadine in healthy young (age range, 27 to 39 years) and older (age range, 60 to 72 years) adults of both genders in a three-limbed randomized crossover study. Renal clearance of amantadine (13.2 +/- 5.8 L/hr) was significantly inhibited by quinine (9.7 +/- 4.8 L/hr) and quinidine (8.9 +/- 4.0 L/hr) only in male subjects and was not associated with age. The chiral selectivity for the renal clearance of quinidine over quinine was confirmed and extended with the suggestion of both age- and gender-associated changes on the renal clearance ratio for these two diastereomeric drugs. These data support the continued use of amantadine for studies on the renal elimination of organic cationic drugs.

Nadolol antihypertensive effect and disposition in young and elderly adults with mild to moderate essential hypertension.

Nadolol was effective and well tolerated as once-daily monotherapy for mild to moderate essential supine diastolic hypertension (SDBP) in 10 young (mean age, 39 years) and 12 elderly (mean age, 68 years) patients in a single-blind, placebo-baseline, escalating-dose study. Doses required to reduce SDBP to 90 mm Hg were not different in young (1.08 +/- 0.21 mg/kg/day) and elderly (0.82 +/- 0.14 mg/kg/day) patients (mean +/- SE). Trough plasma nadolol concentrations at steady state were similar and were linearly related to dose in both groups. More unchanged nadolol was recovered in 24-hour urine samples from young subjects (15.6% +/- 1.9%) than from elderly ones (10.7% +/- 1.1%) (p = 0.028). With increasing nadolol doses, plasma norepinephrine concentration increased and isoproterenol sensitivity decreased in both young and elderly subjects, and creatinine clearance and plasma active renin levels were unchanged; plasma inactive renin levels increased in the young, and aldosterone concentration declined in the elderly with the lowest nadolol dose.

The role of alpha 1-adrenoceptor-mediated collateral excitation in the regulation of the electrical activity of locus coeruleus neurons.

The physiological role of two types of autoreceptors, alpha 1- and alpha 2-adrenoceptors, located on the somadendritic membranes of locus coeruleus neurons, was studied in the developing and adult rat brain. Animals from birth to adulthood were anesthetized with urethan, and single-unit activity was recorded extracellularly in the locus coeruleus. The spontaneous firing of most locus coeruleus neurons was inhibited by iontophoretic application of noradrenaline at a high concentration, while noradrenaline at a low concentration frequently caused excitation of the neurons, predominantly in the developing brain. A similar excitation was also produced by iontophoretic application of the alpha 1-agonist phenylephrine. These excitations were antagonized by the alpha 1-antagonist, 2-beta [4-hydroxyphenylethylaminomethyl]-tetralone, while this antagonist had little effect on glutamate-induced excitation. The noradrenaline- and phenylephrine-induced excitation occurred more frequently in the neurons having little or no spontaneous activity. Electrical stimulation of the dorsal noradrenergic bundle arising in the locus coeruleus produced both inhibition and excitation. The excitatory responses were manifest primarily in early developmental stages, and occurred predominantly when the neurons had little or no spontaneous activity. When the neurons began firing at relatively high rates, the effects of dorsal noradrenergic bundle stimulation became principally inhibitory. Since the excitation evoked by dorsal noradrenergic bundle of stimulation was blocked by the alpha 1-antagonist, the excitation was thought to result from activation of alpha 1-adrenoceptors by noradrenaline released from the terminals of recurrent axon collaterals of locus coeruleus neurons themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacokinetics of amantadine hydrochloride.

Amantadine is a drug with diverse uses ranging from prevention of influenza A illness to the treatment of patients with Parkinson's disease. It is available only in oral formulations from which it is well absorbed and widely distributed, little drug being present in the circulation. Apparent volume of distribution is inversely related to dose over the therapeutic range and accounts in part for a noteworthy logarithmic increase in plasma concentration as a function of dose. Elimination is primarily by renal clearance by both glomerular filtration and tubular secretion. Amantadine accumulates in patients with renal dysfunction. Hence, doses must be reduced in such patients to avoid toxicity. Interactions with other drugs appear uncommon. Relationships have been demonstrated between amantadine therapeutic effects and plasma concentrations in different study cohorts, but not in individual patients. Dose schedules have been suggested for individuals in whom amantadine kinetics are different from healthy subjects. However, these schedules are controversial in their choice of target concentrations and in being untested as to predictive value.

Helicobacter pylori promotes development of pepsinogen-altered pyloric glands, a preneoplastic lesion of glandular stomach of BALB/c mice pretreated with N-methyl-N-nitrosourea.

H. pylori is thought to be a stomach carcinogen. Since no experimental model has hitherto been established to clarify the relationship between H. pylori and stomach carcinogenesis, the effects of infection with the bacteria on experimental carcinogenesis in the glandular stomach of mice were investigated. BALB/c mice were given salty diet or N-methyl-N-nitrosourea (MNU) and administered broth culture of H. pylori. The incidence of pepsinogen-altered pyloric glands, considered as precancerous lesions, was increased in the H. pylori inoculated group pre-treated with MNU. The findings provide the new experimental model demonstrating the relationship between stomach cancer and H. pylori.

Hormonal regulation of mitochondrial Tim23 gene expression in the mouse mammary gland.

Tim23, a mitochondrial inner membrane protein, is essential for cell viability. Mouse Tim23 cDNA consisted of 1142 nucleotides plus poly(A) at the 3' end. In situ hybridization showed that mammary epithelial cells expressed Tim23 mRNA during pregnancy. In order to examine the hormonal regulation of the Tim23 gene expression at lactogenesis, the quantity of Tim23 mRNA in the mammary gland was determined by the competitive RT-PCR. The level of Tim23 mRNA was low until mid-pregnancy, increased toward the end of pregnancy and was the highest on day 18 of pregnancy. On day 13 of pregnancy, Tim23 mRNA increased 2.7-fold between 8 and 16 h after ovariectomy but this increase was cancelled out by the simultaneous operation of adrenalectomy. In adreno-ovariectomized mice, the administration of cortisol increased Tim23 mRNA 2-fold but with progesterone, the stimulatory action of cortisol was no longer observed. The results indicated that the expression of the Tim23 gene became active in response to glucocorticoid.