Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human.

Validated analytical methods (HPLC, CE and GC-MS) for determining the amount of andrographolide (AND) in the blood plasma of rats and human volunteers following the oral administration of Andrographis paniculata extract (APE) and Andrographis paniculata fixed combination Kan Jang tablets were developed and used for the pharmacokinetic study. Andrographolide was quickly and almost completely absorbed into the blood following the oral administration of APE at a dose of 20 mg/kg body wt. in rats. Its bio-availability, however, decreased four-fold when a 10-times-higher dose was used. Since a large part (55 %) of AND is bound to plasma proteins and only a limited amount can enter the cells, the pharmacokinetics of AND are described well by a one-compartment model. Renal excretion is not the main route for eliminating AND. It is most likely intensely and dose dependently metabolized. Following the oral administration of four Kan Jang tablets (a single therapeutic dose, equal to 20 mg of AND) to humans, maximum plasma levels of approximately 393 ng/ml (approx. 1.12 microM) were reached after 1.5-2 hours, as quantified using a UV diode-array detection method. Half-life and mean residence times were 6.6 and 10.0 hours, respectively. AND pharmacokinetics in humans are explained well by an open two-compartment model. The calculated steady state plasma concentration of AND for multiple doses of Kan Jang (after the normal therapeutic dose regimen, 3 x 4 tablets/day, about 1 mg AND/kg body wt./day) was approximately 660 ng/ml (approx. 1.9 microM), enough to reveal any anti-PAF effect, particularly after drug uptake when the concentration of AND in blood is about 1342 ng/ml (approx. 3.8 microM, while for anti-PAF effect EC50 - 5 microM).     

A phase I clinical study of Andrographis paniculata fixed combination Kan Jang versus ginseng and valerian on the semen quality of healthy male subjects.

The safety of different doses of Kan Jang--a fixed combination of Andrographis paniculata special extract (SHA-10) and Acanthopanax senticosus--compared to two extensively used medicinal plants, Valeriana officinalis and Panax ginseng in the form of standardized extracts, has been examined. A phase I clinical study was designed to evaluate the effect on semen quality of healthy males in terms of spermatogenesis and quality of semen. The results of the study revealed no significant negative effect of Kan Jang on male semen quality and fertility, but rather a positive trend with respect to the number of spermatozoids in the whole ejaculate, the percentage of active (normokinetic) forms of spermatozoids, and fertility indexes, together with a decrease in the percentage of inactive (diskinetic) forms of spermatozoids. In the group receiving ginseng, no significant negative effects on the fertility parameters were revealed and there was a clear decrease in the percentage of diskinetic forms of spermatozoids. Subjects receiving valerian showed a temporary increase in the percentage of normokinetic spermatozoids and a decrease in diskinetic forms, but these changes had no effect on fertility indices. The results indicate that Kan Jang, ginseng and valerian are safe with respect to effects on human male sterility when administered at dose levels corresponding to approximately 3 times the human daily dose.     

Double-blind, placebo-controlled pilot and phase III study of activity of standardized Andrographis paniculata Herba Nees extract fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infection.

Two randomized double-blind, placebo-controlled parallel group clinical trials were performed to investigate the effect of a standardized extract (SHA-10) of Andrographis paniculata fixed combination (Kan jang) in the treatment of uncomplicated upper-respiratory tract infections. 46 patients in the pilot study and 179 patients in the phase III study completed the study according to the protocol. Medication was taken three times daily for a minimum of 3 days and a maximum of 8 days for the pilot study, and for exactly three days in the phase III study. The primary outcome measures in the patients self-evaluation were: related to pain in the muscle, cough, throat symptoms, headache, nasal symptoms and eye symptoms and temperature. The physician's fixed score diagnosis was based mainly on sign/symptoms: ears, nose, oral cavity, lymph glands-tonsils and eyes. The total symptom score showed a tendency toward improvement in the pilot study (p = 0,08), while both the total symptom score and total diagnosis score showed highly significant improvement (p < or = 0.0006 resp. 0.003) in the verum group as compared with the placebo. In both studies throat symptoms/signs, were found to show the most significant improvement.     

Antitussive effect of a fixed combination of Justicia adhatoda,Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative,randomized, double-blind,placebo-controlled study

BackgroundKan Jang® oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment.PurposeThe present clinical trial aimed to compare the antitussive effect of KJ with placebo (PL) and bromhexine (BH) among patients of 18–65 years old with non-complicated upper respiratory infections (URI; i.e., common cold).Study designWe performed a parallel-group, randomized, double-blinded, placebo-controlled trial in in 177 patients with acute URI over a 5 day period.MethodsWe investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with standardized contents of 0.2 mg/ml vasicine, 0.8 mg/ml chicoric acid, and 0.03 mg/ml eleutherosides B and E), bromhexine hydrochloride (24 mg/30 ml/day) and PL on cough and blood markers. The primary outcome was cough relief, which was assessed as the change of cough frequency from baseline (cough index). Secondary outcomes were safety with regards to reported adverse events (AEs) and hematological data.ResultsBoth KJ and BH relieved cough more effectively than placebo. On the third and fourth days of treatment, we observed faster improvement in the group receiving KJ compared to in the groups receiving BH (100%) or PL (100%), indicating a slightly shorter recovery time in the KJ group. KJ showed a good tolerability and safety profile.ConclusionKJ exerted significant antitussive effects in URI. The present data further support the therapeutic use of KJ in upper respiratory tract infections.     

A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers

Background and Rationale

Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.

Methodology/Principal Findings

A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.

Conclusions/Significance

Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00741026","term_id":"NCT00741026"}}NCT00741026     

Randomized trial of a fixed combination (KanJang) of herbal extracts containing Adhatoda vasica, Echinacea purpurea and Eleutherococcus senticosus in patients with upper respiratory tract infections.

The clinical efficacy of KanJang oral solution, a fixed combination of standardised extracts of Echinacea purpurea, Adhatoda vasica and Eleutherococcus senticosus, was compared with the combined extracts of Echinacea purpurea and Eleutherococcus senticosus alone (Echinacea mixture) in a controlled, double blind, randomized trial, and with Bromhexine (a standard treatment) in a controlled, open, randomized clinical trial on patients with non-complicated acute respiratory tract infections. Many of the parameters evaluated, such as severity of coughing, frequency of coughing, efficacy of mucus discharge in the respiratory tract, nasal congestion and a general feeling of sickness, showed significantly greater improvement in patients treated with KanJang compared with those receiving the standard treatment. However, no significant differences in the improvement of these symptoms (except in a reduced frequency of coughing) were observed between patients treated with the Echinacea mixture and those receiving the standard treatment. The only explanation is that the lack of extract of A. vasica in the Echinacea mixture reduces its efficacy compared with the complete KanJang oral solution even though direct double-blind comparison yielded no significant differences between these two groups of patients. The recovery time of patients being treated with KanJang or Echinacea mixture was 2 days shorter than that of patients receiving the standard treatment. None of the patients completing the study reported adverse reactions to the medication taken. The significance of the results obtained in this study is discussed with respect to the efficacy of KanJang in the treatment of acute respiratory infection and to the concept that multi-drug therapy offers higher efficacy compared with mono-drug treatment of such infections.     

Are antibiotic drugs needed for the treatment of upper respiratory tract infections in infants?

Much confusion exists about the necessity of using antibiotic drugs to treat upper respiratory tract infections in children, especially infants. In this study the frequency of bacterial causes of such infections was studied in 4746 children under three years of age. Clinical evidence of infection was absent in half of these children and present in the others. There was no practical difference between the frequency of positive cultures from infected and non-infected children, suggesting that antibiotics were not required.     

Microbiocenosis of the mucous membranes of the upper respiratory tract and its correction with acipol in the treatment of patients with acute respiratory virus infections

Clinical and laboratory evaluation of the preparation Acipol in 45 children greatly susceptible to acute respiratory virus infections (ARVI) was carried out. Simultaneously with the clinical analysis, the study of the microflora of the mucous membranes of the upper respiratory tracts and intestine, as well as the levels of secretory IgA in saliva and coprofiltrates before and after treatment, was made. The inclusion of Acipol into the therapy of ARVI patients facilitated their clinical convalescence, uncomplicated course of the disease, correction of disturbances in the biocenosis of the upper respiratory tracts and increased infectious resistance.     

Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever.

Double blind, randomized, placebo controlled pilot study of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees., Eleutherococcus senticosus Maxim., Schizandra chinensis Bail., and Glycyrrhiza glabra L. special extracts standardized for the content of Andrographolide (4 mg/tablet), Eleuteroside E, Schisandrins and Glycyrrhizin, was carried out in two parallel groups of patients. The study was conducted in 24 (3-15 years of both genders) patients with Familial Mediterranean Fever (FMF), 14 were treated with tablets of series A (verum) and 10 patients received series B product (placebo). The study medication was taken three times of four tablets daily for 1 month. Daily dose of the andrographolide--48 mg. The primary outcome measures in physician's evaluation were related to duration, frequency and severity of attacks in FMF patients (attacks characteristics score). The patient's self-evaluation was based mainly on symptoms--abdominal, chest pains, temperature, arthritis, myalgia, erysipelas-like erythema. All of 3 features (duration, frequency, severity of attacks) showed significant improvement in the verum group as compared with the placebo. In both clinical and self evaluation the severity of attacks was found to show the most significant improvement in the verum group. Both the clinical and laboratory results of the present phase II (pilot) clinical study suggest that ImmunoGuard is a safe and efficacious herbal drug for the management of patients with FMF.     

Randomised,double blind,placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults.

OBJECTIVES--To compare the effectiveness of penicillin V and amoxycillin with placebo in treatment of adult patients with acute sinusitis. DESIGN--Randomised, double blind, placebo controlled trial. SETTING--Norwegian general practice. SUBJECTS--130 adult patients with a clinical diagnosis of acute sinusitis confirmed by computed tomography. MAIN OUTCOME MEASURES--Subjective status after three and 10 days of treatment, difference in clinical severity score between day 0 and day 10 as evaluated by the general practitioner, difference in score from computed tomography on day 0 and day 10, and duration of sinusitis. RESULTS--Amoxycillin and penicillin V led to significantly faster and better recovery than placebo. By day 10, 71 patients receiving antibiotic treatment- (86%) considered themselves to be recovered or much better compared with 25 (57%) receiving placebo. The mean (95% confidence interval) reductions in clinical severity scores by day 10 were 5.4 (5.0 to 5.8) for penicillin V, 5.5 (4.9 to 6.0 for amoxycillin, and 3.4 (2.8 to 4.0) for placebo. For the antibiotic groups combined the number of patients with the greatest degree of improvement on computed tomography (scale 0-16)-that is, score 5-16 on day 10-was 31/83 (37%) compared with 10/44 (23%) receiving placebo. The median duration of the sinusitis was nine days in the amoxycillin group, 11 days in the penicillin V group, and 17 days in the placebo group. CONCLUSION--Penicillin V and amoxycillin are significantly more effective than placebo in the treatment of acute sinusitis.     

Netilmicin in the treatment of bacterial respiratory tract infections

Netilmicin - a semisynthetic aminoglycoside - was administered to 33 patients with the acute or chronic lower respiratory tract or pulmonary infections in a daily dose of 5 mg/kg body weight for 10 days. A principle criterium of patients classification to netilmicin therapy were sensitive bacterial strains either in sputum or in BAL liquid. A significant clinical improvement was noted in 88% of the treated patients. However, elimination of pathogens from the sputum was achieved only in 52% of these patients. No improvement was observed in 4% of the treated patients. No adverse reactions were noted. Netilmicin proved safe and effective antibacterial agent in patients with respiratory infections.     

Pinimenthol ointment in patients suffering from upper respiratory tract infections – A post-marketing observational study

In order to gain further experience regarding the tolerability of Pinimenthol^® ointment¹ in adolescents (⩾12 years) and adults suffering from upper respiratory tract infections, a post-marketing observational study was performed. In this study, data of 3060 patients were collected (64.9% prospectively over an individual observation period of 5–14 days, 35.1% retrospectively). The prospective documentation also comprised data concerning treatment effects.Sample size of the post-marketing observational study was calculated in the way that adverse drug reactions with an event probability of at least 1:1000 would occur within the study at least once with a probability of 95%.Most patients suffered from cold, acute or chronic bronchitis, bronchial catarrh or hoarseness. Pinimenthol^® ointment was prescribed to inunction (29.6%), inhalation (17.3%) or inunction and inhalation (53.1%), respectively. The mean duration of study participation was 8.0±3.4 days.The tolerability was rated as excellent or good by 96.7% of physicians and 95.7% of patients. A total of 22 patients (0.7%) reported adverse drug reactions which mostly affected the skin or mucus membrane and therefore correspond to the expected adverse effects profile of Pinimenthol^® ointment. The treatment effect was mostly judged as excellent or good (physicians: 88.3%; patients: 88.1%).In conclusion, the study confirms Pinimenthol^® ointment as a well tolerated therapy option for upper respiratory tract infections in both adolescents and adults.     

Risk of acute non-specific upper respiratory tract infections in healthy men taking dapsone-pyrimethamine for prophylaxis against malaria

The relative risks of non-specific upper respiratory tract infections were studied in two well matched groups of military recruits to see whether dapsone-pyrimethamine (Maloprim) given as antimalarial prophylaxis was associated with immunosuppression. Mean risks of upper respiratory tract infection were 64% higher in the study group than in the controls, the largest monthly differences being recorded in the months of harder training. These findings were unlikely to have been due solely to harder training in the study group, as concurrently measured sprains (arguably more likely to have been affected) were increased by only 19%. A more likely explanation was some degree of immunosuppression, physical stress possibly having a synergistic effect.These findings suggest that travellers taking dapsone-pyrimethamine as antimalarial prophylaxis may be rendered more susceptible to commoner infections, especially when engaged in increased physical activity.     

Aetiology of upper respiratory tract infections in children in Arak city: a community based study

Viruses are frequent causes of upper respiratory tract infections in children. We investigated the viral aetiology of community-acquired upper respiratory tract infections (URIs) in young children treated as outpatients in community settings. During November 2008, nasal swab specimens were taken from children with recent onset of upper respiratory tract infections. The patients attended day care or primary schools; the specimens were randomly obtained by pediatricians from schools and childcare institutions and sent for identification by PCR method. A total of 300 specimens were collected. From all samples, 40.67% were positive for at least 1 virus, viz. adenovirus 11.76%, rhinovirus 9.8%, respiratory syncytial virus 6.08%, influenza virus 5.56%, parainfluenza virus 4.9%, enterovirus 2.94% and a combination of 2 viruses 2%. Clinical manifestations of the respiratory infections were as follows: 70.7% of the patients had coryza, 69.3% cough, 26% sneezing, 19.7% sore throat, 2.7% headache, 7.7% fever, 2.3% conjunctivitis, 1.3% abdominal pain and 1% hoarseness. The results of this study demonstrate that adenoviruses and rhinoviruses are the two most common viral agents isolated from pediatric outpatients with acute URIs in autumn in Arak City. Coryza and cough were the most common symptoms in children. Sore throat and hoarseness were more prevalent in infections caused by influenza virus, conjunctivitis in parainfluenza, and coryza in rhinovirus infections.