Immunogenicity of booster vaccination with a virosomal hepatitis A vaccine after primary immunization with an aluminum-adsorbed hepatitis A vaccine

BACKGROUND: Increasing numbers of individuals are traveling to areas of high hepatitis A endemicity and require immunization against the hepatitis A virus (HAV). The option of using a virosomal, aluminum-free, HAV vaccine (Epaxal) for booster immunization following primary vaccination with an aluminum-adsorbed vaccine has been assessed. METHODS: In total, 142 healthy subjects, 79 men and 63 women, aged 12 to 72 years, were injected intramuscularly with a booster dose of Epaxal (0.5 mL containing < or =500 RIA units of HAV antigen) 6 to 24 months after primary vaccination with Havrix (0.5 or 1.0 mL containing 720 or 1440 ELISA units of HAV antigen, respectively, adsorbed onto aluminum hydroxide). Anti-HAV antibody titers were measured on days 0 and 28 by an enzyme immunoassay. Adverse events were recorded for 1 month postinjection. RESULTS: Overall, 98/118 subjects (83%) with no serologic evidence of past HAV infection were still seroprotected at enrolment (anti-HAV antibody titer < or = 20 mIU/mL). The seroprotection rate was 87% in those primed with Havrix 1440 6 to 12 months earlier (n=93) and 60% in those primed < or =12 months before enrolment (n=20, mean 16 months). The geometric mean anti-HAV antibody titer increased from 65 mIU/mL at day 0 to 1,722 mIU/mL at day 28 after a single booster dose with Epaxal in evaluable subjects who were primarily vaccinated with either a single dose of Havrix 1440 (n=111) or two separate doses of Havrix 720 (n=4). All subjects were seroprotected at day 28, and 98% showed at least a four-fold increase in anti-HAV antibody titer. Epaxal was well tolerated and no serious adverse events were reported. At day 28, the tolerability of the vaccination was judged as either "very good" or "good" by 96% of vaccinees and by all investigators. CONCLUSION: Epaxal can be successfully used to boost immunization following primary vaccination with an aluminum-adsorbed vaccine, and is well tolerated.     

Safety and Immunogenicity of a High–Potency Inactivated Hepatitis A Vaccine

Background: In recent years, several hepatitis A vaccines have been developed. We wished to evaluate the safety, reactogenicity, and immunogenicity of an inactivated hepatitis A vaccine, containing 1440 EI.U., and to monitor the kinetics of the antibodies monthly for the first year after administration of a single dose of vaccine.
Methods: We conducted an open clinical trial, started in March 1992 and completed in July 1993, at two general hospitals and one pediatric hospital in Antwerp, Belgium, with 194 healthy adult healthcare volunteers. Each volunteer received a single dose hepatitis A vaccine, given intramuscularly at month 0 and a booster at month 12. We undertook serologic follow-up of antihepatitis A virus (antiHAV) antibodies and liver enzymes at day 15 and at months 1, 6, 9, 12, and 13. For a random subgroup of participants, blood samples were taken monthly. In addition, all participants noted local and general symptoms following administration of the vaccine.
Results: This single dose vaccine was well-tolerated; 2 weeks after the vaccination, 80% of the participants had seroconverted (antiHAV antibodies ≥ 20 mlU/mL); after 1 month, seroconversion reached 99% (geometric mean titer (GMT): 383 mlU/mL). One year after the single dose of vaccine, 94% still had antiHAV antibodies above 20 mlU/mL (GMT: 176 mlU/mL). One month afterthe booster dose, seroconversion was 100%, and GMT increased from 176 mlU/mL at month 12 to 4775 mlU/mL at month 13.
Conclusions: The single dose hepatitis A vaccine is safe and highly immunogenic; it gives a rapid antibody production and a rapid increase of GMT. The persistence of protective antibodies until month 12 allows a booster at month 12. This schedule will easily fit into existing travel or occupational health vaccination schedules and will improve vaccination compliance.     

Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal) in the elderly

BACKGROUND: Protection against hepatitis A virus (HAV) in the elderly is becoming more important as more senior travelers visit areas of high HAV endemicity, and less have protective antibodies acquired after natural infection during childhood. This study assessed the immunogenicity and safety of hepatitis A vaccine in elderly compared to young adults. METHODS: In this open, uncontrolled study, subjects of 18 to 45 years or < or = 50 years of age received two doses of aluminum-free, virosomal HAV vaccine, Epaxal (Berna Biotech Ltd, formerly Swiss Serum and Vaccine Institute, Bern, Switzerland) 12 months apart. RESULTS: After both the basic and the booster doses, geometric mean titers (GMT) for anti-HAV antibodies were 1.7-fold higher in subjects younger than 45 years compared with those < or = 50 years of age. The proportional increase in GMT after the booster dose, however, was similar in younger and older subjects. Seroprotection (< or = 20 mIU/mL) rates in the younger and older subjects were 100 and 65%, respectively, after the first vaccination and 100 and 97%, respectively, after the booster dose. Systemic and local adverse events were mainly mild and short-lived. CONCLUSION: These data show that HAV virosomal vaccine (Epaxal) is well tolerated and immunogenic in elderly subjects. The clinical relevance of lower seroconversion rates after the primary dose is unknown in this population of travelers.     

Response to Hepatitis A Vaccine in Children after a Single Dose with a Booster Administration 6 Months Later

Background: Children are of an age group susceptible to infection by the hepatitis A virus (HAV). Active immunization of children against HAV became reality in 1993, when the first pediatric hepatitis A vaccine was licensed. This initial vaccine required two injections to induce a full immune response in recipients. The purpose of this study was to assess the feasibility of a single dose primary vaccine plus a booster after 6 months against hepatitis A in children.
Methods: A total of 60 healthy and seronegative children between 2 and 13 years of age were administered inactivated hepatitis A vaccine, containing 720 enzyme-linked immunosorbent assay (ELISA) units (EL.U) of hepatitis A antigen, intramuscularly in the deltoid region at months 0 and 6. Symptoms were recorded by parents or guardians on individual diary cards. Antibodies against HAV (antiHAV) were measured using an ELISA inhibition assay, and a seropositive titer was defined as being ≥20 mIU/mL.
Results: Fifteen days after the single primary dose, 96% of the vaccinees were seropositive with a geometric mean titer (GMT) of 351 mIU/mL The seropositivity rate reached 100% 1 month after the first dose, with a GMT of 305 mIU/mL Prior to the second dose at month 6, 93% remained seropositive, and the GMT was 153 mIU/mL. By month 7, 1 month after the second vaccination, the seropositivity rate recovered to 100% with a rise in GMTs to 3644 mIU/mL. Local symptoms were reported after 23.9% of doses, and general symptoms after 19.7% of doses. All symptoms were of short duration and resolved spontaneously.
Conclusions :This inactivated vaccine against hepatitis A is safe, well-tolerated, and excellently immunogenic when administered to children following a single dose plus booster course at months 0 and 6.     

Immune Response to Hepatitis A Vaccine Combined or Given Simultaneously with Typhoid Fever Vaccine

Background: Because both hepatitis A and typhoid vaccination are frequently indicated in the same traveler, a prospective, randomized controlled study was performed to evaluate the feasibility of simultaneous administration of hepatitis A and typhoid fever vaccines in adult volunteers.
Methods: Two groups of 25 subjects received either separate injections of hepatitis A (Havrix™, SmithKline Beecham Biologicals) and typhoid fever (Typhim Vi™, Pasteur-Mérieux) vaccines in opposite arms, or a syringe-mixed combination of both vaccines as a single injection. A booster dose of Havrix was given at 6 months.
Results: The immune response to hepatitis A tended to be higher in the mixed-injection group, but this difference was significant (p=.048) only following the booster dose. Adverse reactions were generally mild with no differences between the two groups.
Conclusion: A combined formulated vaccine against both typhoid fever and hepatitis A is feasible and offers more convenience without added adverse reactions to travelers who have appropriate indications for both vaccines.     

Safety and immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Chilean children

The safety and immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix?) were assessed in 240 healthy Chilean children randomized to receive 3 doses of PHiD-CV (PHiD-CV group) or hepatitis A vaccine (HAV control group) at 2-4-6 months of age. All were offered 1 HAV dose at 12 months (outside study). The PHiD-CV group received a second HAV dose at 18-21 months and PHiD-CV booster at 20-23 months. The HAV control group received 2 PHiD-CV catch-up doses at 18-21 and 20-23 months. Adverse events were recorded and pneumococcal antibody responses and opsonophagocytic activity (OPA) were measured. Both PHiD-CV vaccination schedules were well tolerated and immunogenic against the pneumococcal vaccine serotypes and protein D. The reactogenicity of PHiD-CV primary, booster and catch-up doses was in line with previous PHiD-CV studies, although generally higher than with HAV. For each vaccine serotype, the percentage of subjects with antibody concentrations ≥0.2 μg/ml (GSK's 22F-inhibition ELISA) was at least 93.2% following 3 PHiD-CV primary doses and at least 97.4% post-booster; percentages with OPA titers ≥8 were at least 91.7% post-booster. After 2-dose catch-up, at least 94.3% of children had antibody concentrations ≥0.2 μg/ml against each serotype except 6B (84.3%); at least 95.2% had OPA titers ≥8 except against serotypes 1, 5 and 6B. In conclusion, the safety profiles of 2 PHiD-CV vaccination schedules (3-dose primary plus booster and 2-dose catch-up) were in line with previous studies and PHiD-CV was immunogenic for all 10 vaccine serotypes and protein D.     

Tolerance and immunogenicity of the simultaneous administration of virosome hepatitis A and yellow fever vaccines

BACKGROUND: The purpose of this study was to evaluate the tolerance and immunogenicity of a hepatitis A vaccine using immunopotentiating reconstituted influenza virosomes (IRIV) as adjuvant when administered simultaneously with a yellow fever vaccine (YFV). METHOD: An open prospective trial with two parallel groups was conducted with 105 volunteers to study the effect of these vaccinations on the anti-hepatitis A virus (HAV) antibody response. Half of the volunteers (53) received one dose of IRIV-HAV vaccine (Epaxal) and one dose of live attenuated YFV (Stamaril) on the same day at two different sites. Fifty-six volunteers were given a single injection of IRIV-HAV as a control group. Anti-HAV titers were measured at days 14, 28, months 3, 12, 13, and 24 using a standardized test (Enzymun test Anti-HAV). Neutralizing yellow fever antibodies were measured at days 14 and 28 for the YFV recipients. Regarding vaccine tolerance, the volunteers were asked to record all their adverse reactions on a standard report sheet for the 6 days following the immunization. RESULTS: Seroconversion rates for HAV were 88% after 14 days and 100% after 4 weeks. There was no statistically significant difference between the two groups every time the titers were checked (IRIV-HAV vs HAV only: D14: 81 vs 101; D28: 275 vs 368; M3: 153 vs 169; M12: 117 vs 226; geometrical mean titers (GMT) in mIU/mL). However, lower titers were found among male volunteers, and were not attributable to YFV administration. The seroconversion rates for YFV were 90% after 14 days and 96% after 4 weeks. No serious general side-effects and only mild local reactions were reported. The administration of a booster of IRIV-HAV at 12 months resulted in a 24-fold increase in GMT. CONCLUSION: When needed, the simultaneous administration of the IRIV-HAV and YFV is immunogenic, safe and well-tolerated, as volunteers seroconverted to both antigens, with no cross-interference.     

Clinical Trial: High-dose furosemide plus small-volume hypertonic saline solutions vs. repeated paracentesis as treatment of refractory ascites

Background  In patients with cirrhosis, ascites is defined as refractory when it cannot be mobilized or recurs early in standard diuretic therapy.
Aim  To compare the safety and efficacy of intravenous high-dose furosemide + hypertonic saline solutions (HSS) with repeated paracentesis in patients with cirrhosis and refractory ascites.
Patients and methods  Eighty-four subjects (59/25 M/F) with cirrhosis, mostly of viral aetiology, admitted for refractory ascites, were randomly assigned to receive furosemide (250–1000 mg/bid i.v.) plus HSS (150 mL H₂O with NaCl 1.4–4.6% or 239–187 mEq/L) (60 patients, Group A) or to repeated paracentesis and a standard diuretic schedule (24 patients, Group B).
Results  During hospitalization, Group A patients had more diuresis (1605 ± 131 mL vs. 532 ± 124 mL than Group B patients; P  < 0.001) and a greater loss of weight at discharge (−8.8 ± 4.8 kg vs. −4.5 ± 3.8 kg, P  < 0.00). Control of ascites, pleural effusions and/or leg oedema was deemed significantly better in Group A.
Conclusions  This randomized pilot study suggests that HHS plus high-dose furosemide is a safe and effective alternative to repeated paracentesis when treating hospitalized patients with cirrhosis and refractory ascites. Larger studies will be needed to evaluate long-term outcomes such as readmission and mortality.     

Hepatitis A and B Infections Among Expatriates in Papua New Guinea: A Missed Opportunity for Immunization

Background: Hepatitis A (HAV) and hepatitis B (HBV) are hyperendemic among the indigenous population of Papua New Guinea (PNG), but little is known of the recent epidemiology of these diseases among the large number of expatriates living in PNG.
Methods: The authors sought to determine the prevalence and rate of acquiring HAV and HBV antibody markers in expatriate missionaries, using a cross-sectional serosurvey method.
Results: The authors entered 501 subjects into the study; the subjects had a mean time in-country of 100 months. Evidence for past infection with HAV was found in 47% of subjects (n=179) who had not received gamma globulin. Being a health care worker did not increase the probability of being HAV positive, but being a houseparent who cared for missionary children did (p=.06). Fifty percent of children <21 years old had positive HAV markers. Having a family member with a history of supposed "hepatitis" significantly increased the probability of being HAV positive (p=.0001). Evidence for past infection with HBV was found in 9.5% of subjects (n=46). Among those with evidence of past infection, 31% were <16 years old. Both infections are acquired more rapidly in children than in adults, and HAV is acquired more rapidly than HBV.
Conclusions: Expatriates living in the hyperendemic setting of PNG have high seroprevalence rates for evidence of infection with HAV (47%) and HBV (9.5%). Children have rates of infection equal to, or greater than, adults in this setting. Expatriates living in countries with high endemic rates of HAV and HBV infection are at high risk of acquiring these infections and should be targeted to receive information about the risks of disease and the benefits of immunization.     

Initial human experience with MK-462 (rizatriptan): a novel 5=HTID agonist

Aim We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers.
Methods Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion.
Results MK-462 was rapidly absorbed with a median t _max of 1.3 h (range 1–3 h) vs a t _max for sumatriptan of 2.5 h (range 1–4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5–10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness.
Conclusions These results indicate that the novel 5-HT_1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.     

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1  mg ( n =18 young; n =11 elderly) or 2  mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1  l  kg⁻¹ for 1  mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8  h for 1  mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.     

Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen

Aims The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13  M, 12  F) suffering from recurrent high-grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120  mg/m² twice daily).
Methods Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7  h post dose. Tamoxifen and metabolites were analysed by h.p.l.c.
Results Steady-state plasma concentrations (mean  μm±s.d.) were determined for tamoxifen (2.94±3.44), N -desmethyltamoxifen (4.37±2.13), N -desdimethyltamoxifen (1.49±0.54), 4-hydroxytamoxifen (0.13±0.05) and tamoxifen primary alcohol (1.07±0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone-treated patients than untreated patients: 3.94±4.35  μm (95% C.I.: 1.43–6.46) vs 1.67±0.84  μm (95% C.I.: 1.11–2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85±0.87  μm (95% C.I.: 1.37–2.34) vs 4.58±5.05  μm (95% C.I.: 0.97–8.19), with vs without. The differences approached but did not reach statistical significance ( P =0.065 and 0.078 respectively).
Conclusions There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.     

Bradykinin-induced venodilation is not different in blacks

Aims The aim of this study was to determine whether young, normotensive blacks who have been recently demonstrated to have a venodilator response to isoprenaline decreased compared with whites, also have an decreased vasodilatory response to bradykinin.
Methods Eleven black and 11 white subjects were studied. Full dose-response curves to bradykinin (dosing range 0.5–500  ng min⁻¹ ) were generated in hand veins preconstricted with phenylephrine (dosing range 20–6800  ng min⁻¹ ).
Results The groups had a similar maximal response to bradykinin (57.6±32.2% vs 67.8±49.3%, P =NS 95% confidence interval for the difference (CI): −47.3, 26.8). Also, the log of the dose that produced half maximal response to bradykinin was similar for the two groups (0.89±0.58 vs 0.78±0.61  ng min⁻¹, P =NS, 95% CI: −0.42, 0.64). There was no difference between the two groups in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein.
Conclusion Diminished vasodilatory response to endothelium-derived relaxing factor (EDRF) does not seem to be associated with the increased prevalence of hypertension in blacks.     

Trying to improve compliance with prophylactic penicillin therapy in children with sickle cell disease

Aims To evaluate compliance with prophylactic penicillin therapy in sickle cell disease (SCD) in children.
Methods Forty-five children aged 37±19 (9–84) months [mean±s.d; range] with homozygous SCD were recruited. After a baseline period of 2 months the patients were randomized to either the intervention or non-intervention group. The intervention consisted of a slide show explaining the pathogenesis of sickle cell disease and its complications; weekly phone calls by the clinic social worker; and a calendar. Compliance was again evaluated after the 2 month intervention period and after a further 2 month monitoring period without intervention. Compliance was monitored using the Medication Event Monitoring System. At the end of the 6 months, parents in both groups completed a questionnaire the aims of which were to determine knowledge and understanding of sickle cell disease and previous experience with infection. Patient admissions to the hospital during the study were recorded.
Results Compliance during the 2 month baseline assessment was 66.0±32.5 (1.3–98.2)% and 69.3±25.4 (19.8–96.5)% in the intervention ( n =13) and non-intervention ( n =10) groups respectively ( P =0.79). During the next 2 months, compliance in the intervention group ( n =11) was 79.0±31.4 (11.0–100.0)% and in the non-intervention group ( n =9) was 66.0±20.2 (42.2–96.8)% ( P =0.297). In the final 2 month monitoring period compliance was 82.0±34.7 (3.8–100.0)% and 65.8±25.3 (25.0–98.2)% in the intervention ( n =7) and the non-intervention ( n =6) groups respectively ( P =0.366). No statistically significant differences were found when comparing compliance between the groups.
Conclusions Compliance with prophylactic antibiotic therapy in children with sickle cell disease is highly variable and its evaluation is problematic.     

Clinical trial: protective effect of a commercial fish protein hydrolysate against indomethacin (NSAID)-induced small intestinal injury

Background  A partially hydrolysed and dried product of pacific whiting fish is marketed as a health food supplement supporting 'intestinal health'.
Aim  To examine whether the partially hydrolysed and dried product of pacific whiting fish influenced the small intestinal damaging side effects of the nonsteroidal anti-inflammatory drug, indomethacin.
Methods  Eight human volunteers completed a double-blind, placebo-controlled, crossover protocol of clinically relevant dose of indomethacin (50 mg t.d.s. p.o. for 5 days) with 7 days of fish hydrolysate or placebo starting 2 days prior to indomethacin. Changes in gut permeability were assessed using 5 h urinary lactulose:rhamnose (L/R) ratios.
Results  Fish hydrolysate given alone did not affect permeability. In the main study ( n  = 8), baseline values were similar for both arms (0.28 ± 0.05 and 0.35 ± 0.07). Administration of indomethacin (+placebo) caused a fivefold rise in L/R ratios (increasing to 1.54 ± 0.35), whereas L/R ratios in the same subjects ingesting indomethacin + fish hydrolysate was only 0.59 ± 0.14 ( P  < 0.01 vs. indomethacin alone). Dyspeptic symptoms occurred in four of eight subjects taking indomethacin alone, but zero of eight when hydrolysate was co-administered.
Conclusion  Natural bioactive products (nutriceuticals), such as fish hydrolysates, may provide a novel approach to the prevention and treatment of NSAID-induced and other gastrointestinal injurious conditions.     

Racecadotril demonstrates intestinal antisecretory activity in vivo

Background Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study.
Methods A 1 m, jejunal, Thiry–Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with ¹⁴C-polyethylene glycol. Fluxes were determined both in the basal state and 5–6 h after commencement of a 2-h infusion of cholera toxin (0.4 μg/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg).
Results Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased ( P  = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 ± 0.15 to 0.37 ± 0.13 mL/min; from 125.0 ± 16.1 to 14.7 ± 9.5 μMol/min; and from 3.41 ± 0.66 to 1.66 ± 0.61 μMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine.
Conclusions This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins.     

Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin

Aims : To evaluate absorption of protein-bound and unbound cyanocobalamin before and during treatment with omeprazole, and cobalamin levels in patients on long-term treatment with omeprazole.
Methods : In eight former duodenal ulcer patients absorption of unbound and protein-bound cobalamin was determined by measuring 24-h urinary excretion of unbound ⁵⁸Co-cyanocobalamin or protein-bound ⁵⁷Co-cyanocobalamin during a modified Schilling test. Tests were performed before and during treatment with 20 mg and 40 mg omeprazole daily for 9 days.
Serum cobalamin levels were assessed in 25 patients with gastro-oesophageal reflux disease (GERD) before and during long-term maintenance therapy with omeprazole. Mean treatment duration was 56 months (range 36–81 months).
Results : Urinary excretion of unbound cobalamin was unchanged with both dosages of omeprazole. Excretion of ⁵⁷Co-cyanocobalamin, however, decreased significantly during treatment with both 20 mg omeprazole (mean ±S.E.M.: 1.31±0.20 vs. 0.54±0.17%; P <0.02) and 40 mg omeprazole (1.25±0.26 vs. 0.29±0.06%; P <0.02).
Mean serum cobalamin levels (±S.E.M.) before and during therapy with omeprazole in GERD patients were 298±27 and 261±16 pg/mL (normal range 180–900 pg/mL), respectively ( P =N.S.).
Conclusions : Absorption of protein-bound, but not unbound, cyanocobalamin is decreased when measured by a modified Schilling test during treatment with omeprazole. However, no change in serum cobalamin levels was observed in patients with GERD after treatment with omeprazole for up to 7 years.     

Inactivated hepatitis A vaccine in Chinese patients with chronic hepatitis B infection

BACKGROUND: Hepatitis B (HBV)-infected patients have a higher morbidity and mortality when super-infected by hepatitis A (HAV). AIM: To evaluate the immunogenicity and safety of a commercial inactivated HAV vaccine in Chinese patients with chronic HBV infection. METHODS: Sixty-five HBV-infected patients (30 carriers, 22 chronic hepatitis, 13 cirrhosis), who were seronegative for HAV, received a dose of 1440 ELISA units of HAV vaccine at weeks 0 and 24. Twenty-eight healthy individuals aged 18-57 years, who were seronegative for both HBV and HAV infection, also received the same vaccination regimen. Seroconversion was defined as an anti-HAV titre >/= 33 mIU/mL. RESULTS: The seroconversion rates for the HBV-infected patients at weeks 2, 4 and 24 were 72, 91 and 80%, respectively. The corresponding geometric mean titres (GMTs) were 103, 311 and 123 mIU/mL. In the healthy control group the seroconversion rates were 86, 93 and 89% at weeks 2, 4 and 24. The corresponding GMTs were 112, 158 and 250 mIU/mL. There was no difference in the seroconversion rates between the two groups, but healthy controls had a significantly higher GMT at week 24 (P=0.04). Side-effects were more common in HBV patients. CONCLUSION: The HAV vaccine is equally efficacious in patients with chronic HBV infection.     

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250  mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
Results A two-compartment model adequately described the disposition of (+)RS-MQ. CL/ F was 6.5±1.8 l  h⁻¹, V _ss/ F 815±165  l, and k 0.0081± 0.0023  h⁻¹. The kinetics of (−)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h⁻¹, 95% CI for the difference 0.86–1.60 l h⁻¹ ) and a longer half-life (345 vs 185  h, 95% CI for the difference 47–291  h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (−)SR-MQ was significantly correlated within subjects ( r =0.69, P <0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (−)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.     

The effect of intravenous erythromycin on solid meal gastric emptying in patients with chronic symptomatic post-vagotomy–antrectomy gastroparesis

Background : Chronic symptomatic gastroparesis occurs in 3–5% of patients following vagotomy and antrectomy. Erythromycin, a macrolide antibiotic, improves gastric emptying in patients with idiopathic and diabetic gastroparesis. Erythromycin's effect on gastric emptying in patients with post-vagotomy– antrectomy gastroparesis is unknown. The aim of this study was to determine if a single dose of intravenous erythromycin (1 mg/kg or 6 mg/kg) accelerates solid meal gastric emptying in patients with chronic symptomatic post-vagotomy–antrectomy gastroparesis.
Methods : Six patients were entered into the study, three males and three females, with a mean age of 50 years. Four patients were randomized to receive erythromycin 6 mg/kg and two patients 1 mg/kg. The mean time since initial surgery was 9.2 years (range 1–16 years) with five patients having undergone a Roux-en-Y revision.
Results : Intravenous erythromycin significantly lowered percentage gastric retention at 120 min, from a baseline of 90.5±6% (S.E.M.) to 40.1±4.8% after erythromycin ( P =0.0002). Erythromycin improved gastric emptying in each patient by at least 40%. Intravenous erythromycin significantly accelerated the rate of gastric emptying in the first 30 min after meal ingestion from a baseline rate of 0.072±0.06%/min to 0.96±0.31%/min after erythromycin ( P =0.028). For each of the subsequent 30 minute time periods, erythromycin had no significant effect on the rate of gastric emptying.
Conclusion : Intravenous erythromycin significantly improves the initial phase of solid meal gastric emptying in patients with chronic symptomatic post-antrectomy–vagotomy gastroparesis.