Carboxymethylated and acetylated xerogel derivatives of Plectranthus esculentus starch protect Newcastle disease vaccines against cold chain failure.

Developing vaccine stabilizers from local natural sources is desirable especially if the stabilizer would enhance the ability of the antigen to withstand frequent failures in cold chains. The study was undertaken to formulate immunogenic live Newcastle Disease (ND) LaSota vaccines stabilized with modified native starches for use at cold and ambient temperatures and to assess the immunogenicity of the starch stabilized vaccines in vaccinated chickens. Native starch extracted from the tubers of Plectranthus esculentus (Family, Lamiaceae) was modified by carboxymethylation and acetylation/xerogel formation and used as vaccine stabilizers of ND LaSota virus with/without buffers/bulking excipients. Cold Chain Failure (CCF) was simulated by storing the vaccines at 5 ± 2 °C for one month then at 37 ± 1 °C for 96 h. The stability of the samples were evaluated in comparison with peptone stabilized ND vaccines using pH, residual moisture, XRD, reconstitution time, mean embryo infective dose (EID50) and haemagglutination (HA) tests. Haemagglutination inhibition was used to evaluate the efficacy of the vaccines in conferring positive serum antibody titers (≥23 log2) in vaccine-naïve 2-week old broilers that were orally administered a single dose of the vaccines kept at 37 ± 1 °C for 96 h and bled weekly over four weeks. Temperature, pH, moisture content and amorphousness impacted vaccine stability. Peptone stabilized vaccines were significantly less stable and most affected by temperature changes with 1.2log10EID50 loss while buffered/bulked trehalose, carboxymethylated and acetylated/xerogelized starch stabilized vaccines were most stable (0.2-0.5log10EID50 loss in titer) after 96 h in CCF. Buffered trehalose stabilized vaccine (TVB) had lower HA titres than peptone and starch stabilized vaccines containing D-mannitol and Na2HPO4. Antibody titres of vaccinated broilers were between 3.3 ± 1.398 and 8.35 ± 2.678. All the vaccines were immunogenic (HI ≥ 23) and developed HI titres (≥24) considered to be protective. Carboxymethylated and acetylated/xerogel derivatives of P. esculentus starch have a great potential as vaccine stabilizers especially in areas prone to CCF.

Mefloquine pharmacokinetics in healthy subjects and in peptic ulcer patients after cimetidine administration.

The pharmacokinetics of orally administered mefloquine were determined in six healthy male subjects and in six ulcer patients before and after a 3-day course of cimetidine (400 mg morning and evening). Peak plasma concentrations Cmax and AUC0-infinity were similarly and significantly (P < 0.05) increased after cimetidine pretreatement in both healthy subjects and peptic ulcer patients Cmax was increased by 42.4% and 20.5% while AUC0-infinity was increased by 37.5% in healthy and peptic ulcer subjects respectively. The values of t1/2ab absorption and t1/2 beta elimination, total crearance CLT/F and volume of distribution were altered to varying levels after cimetidine treatment but the changes were not statistically significant in both healthy and peptic ulcer subjects. The established long t1/2 beta and this apparent interaction between mefloquine and cimetidine which resulted in increased mefloquine plasma concentration might be of clinical significant in patients with neurological/psychiatric history.

Effects of cimetidine on the pharmacokinetics of proguanil in healthy subjects and in peptic ulcer patients.

The pharmacokinetics of orally administered proguanil and its metabolites were determined in six healthy volunteers and in six peptic ulcer patients, before and after a 3-day course of cimetidine (400 mg given two times daily for 2 days and 400 mg on the third day 1 h before proguanil). Cimetidine significantly increased Cmax (P < 0.05), AUCo-alpha (P < 0.005) and elimination half-life t 1/2b of proquanil in plasma of healthy subjects. In ulcer patients, cimetidine significantly increased, AUCo-alpha (P < 0.05), elimination half life (P < 0.005) and Cmax. Cimetidine significantly reduced (P < 0.05) Total body clearance in both healthy subjects and in peptic ulcer patients. The Cmax and AUCo-alpha of the active metabolite cycloguanil was significantly decreased (P < 0.05) in both the healthy subjects and in the peptic ulcer patients. The Cmax of the inactive metabolite, 4-CPB was significantly decreased in healthy subjects and AUCo-alpha significantly decreased in peptic ulcer patients.

Effect of temperature on chlorproguanil and proguanil hydrochloride solutions: a chemical stability study.

Chlorproguanil and proguanil hydrochloride solutions in 0.5 M hydrochloric acid, water and 1 M ammonium hydroxide were subjected to different temperatures (22-80 degrees C) for 68 h. The decomposition rate constants for chlorproguanil ranged from 1.60 to 47.6 x 10(3) h-1 in acid, 3.5 to 18 x 10(3) h-1 in water and 3.87 to 32.5 x 10(3) h-1 in base, between 50 degrees C and 80 degrees C. The activation energy Ea was 96.5, 52.12 and 62.1 kJ mol-1 in acid, water and base respectively. The proguanil decomposition rate constant ranged from 1.72 to 18.5 x 10(3) h-1 in acid, 1.58 to 9.67 x 10(3) h-1 in water and 2.34 to 15.77 x 10(3) h-1 in base, between 50 degrees C and 80 degrees C, with Ea values of 54.7, 73.3 and 62.5 kJ mol-1. Three unidentified degradation products were separated in the acid solution for each of the compounds. Chlorproguanil and proguanil are stable (t1/2 values over 30 days and up to 287 days respectively) in acid, water and base at temperatures below 22 degrees C.

Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

1. Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg. 2. Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2-4 h). 3. Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml-1 compared with 12 to 69 (median 41) ng ml-1 for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml-1 for CPB. Peak (mean +/- s.d.) plasma CG concentrations occurred 5.3 +/- 0.9 h and peak CPB concentrations occurred 6.3 +/- 1.4 h after oral administration of proguanil. 4. Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5. A triexponential function was fitted to these data; mean (+/- s.d.) values for the AUC were 3046 +/- 313 ng ml-1 h for proguanil, 679 +/- 372 ng ml-1 h for CG and 257 +/- 155 ng ml-1 h for CPB. 6. Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half-lives estimated as 16.1 +/- 2.9 h and 15.7 +/- 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 +/- 4.9 and 19.3 +/- 2.4 h.