Reproducibility of the effects of homeopathically potentised Argentum nitricum on the growth of Lemna gibba L. in a randomised and blinded bioassay.

BACKGROUND: A previous study reported a significant statistical interaction between experiment date and treatment effect of Argentum nitricum 14x-30x on the growth rate of duckweed (Lemna gibba L.). The aim of the present study was to investigate the stability of the test system and intra-laboratory reproducibility of the effects found. METHODS: Duckweed was treated with A. nitricum potencies (14x-30x) as well as succussed and unsuccussed water controls. The outcome parameter area-related growth rate for day 0-7 was determined by a computerised image analysis system in two series of independent randomised and blinded experiments. Systematic negative control (SNC) experiments were carried out to investigate test system stability. Statistical analysis was performed with full two-way analysis of variance (ANOVA) and protected Fisher's Least Significant Difference (LSD) test. RESULTS: In the first repetition series we found a significant treatment effect (p = 0.016), while in the second series no effect was observed. The negative control experiments showed that the experimental system was stable. An a posteriori subgroup analysis concerning gibbosity revealed the importance of this growth state of L. gibba for successful reproduction of the statistically significant interaction in the original study; flat: no interaction (p = 0.762); slight gibbosity: no interaction (p = 0.356); medium gibbosity: significant interaction (p = 0.031), high gibbosity: highly significant interaction (p = 0.005). CONCLUSIONS: With the original study design (disregarding gibbosity status of L. gibba) results of the original study could not be reproduced sensu stricto. We conclude that the growth state gibbosity is crucial for successful reproduction of the original study. Different physiological states of the test organisms used for bioassays for homeopathic basic research must carefully be considered.

Adenosine A(2A) receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli.

1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 µmol/L), pancuronium (3 µmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 µmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 µmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade.

A Review: Prevention, Treatment and Management of Tuberculosis through Combinational Approaches of Different Indian Systems of Medicine.

Tuberculosis (TB) is one of the oldest fatal diseases of history. Multidrugresistant tuberculosis (MDRTB) is a major public health issue in the world. In India, the incidence is getting up despite the Indian revised National Tuberculosis Control Programme. India has six recognize medicine systems in this category, namely Ayurveda, Siddha, Unani and Yoga, Naturopathy and Homoeopathy. This review study was undertaken to evaluate the efficacy of different drug treatments based on Indian Systems of Traditional Medicines to the standard MDR-TB regimen. This review mainly focuses on the combinational approaches towards treatment protocols, prevention strategies, and management of tuberculosis in different established systems of medicine in India. Along with allopathic drugs, these AYUSH based drugs work in synergistic manner. Recent research suggests that Homeopathic treatment along with the antibiotics synergise the effect of antibiotics while reaching to its site of action. Additionally in Siddha system, formulation of medicinal herbs showing significant activity against TB bacteria. Furthermore, adopting the management or principles of Unani system would be beneficial in health and disease. Similarly, Unani and Naturopathy through natural healing are equally effective. On the other hand, medicinal plants from the Ayurveda that have been successfully employed to treat TB because of less toxicity and side effect in comparison with existing antibiotics. The findings in this review have provided scientific support for anti-TB activity of different medicinal system of India via numerous underlying mechanisms.

Site selectivity of competitive antagonists for the mouse adult muscle nicotinic acetylcholine receptor.

The muscle-type nicotinic acetylcholine receptor has two nonidentical binding sites for ligands. The selectivity of acetylcholine and the competitive antagonists (+)-tubocurarine and metocurine for adult mouse receptors is known. Here, we examine the site selectivity for four other competitive antagonists: cisatracurium, pancuronium, vecuronium, and rocuronium. We rapidly applied acetylcholine to outside-out patches from transfected BOSC23 cells and measured macroscopic currents. We have reported the IC(50) of the antagonists individually in prior publications. Here, we determined inhibition by pairs of competitive antagonists. At least one antagonist was present at a concentration producing > or =67% receptor inhibition. Metocurine shifted the apparent IC(50) of (+)-tubocurarine in quantitative agreement with complete competitive antagonism. The same was observed for pancuronium competing with vecuronium. However, pancuronium and vecuronium each shifted the apparent IC(50) of (+)-tubocurarine less than expected for complete competition but more than expected for independent binding. The situation was similar for cisatracurium and (+)-tubocurarine or metocurine. Cisatracurium did not shift the apparent IC(50) of pancuronium or vecuronium, indicating independent binding of these two pairs. The data were fit to a two-site, two-antagonist model to determine the antagonist binding constants for each site, L(alphaepsilon) and L(alphadelta). We found L(alphaepsilon)/L(alphadelta) = 0.22 (range, 0.14-0.34), 20 (9-29), 21 (4-36), and 1.5 (0.3-2.9) for cisatracurium, pancuronium, vecuronium, and rocuronium, respectively. The wide range of L(alphaepsilon)/L(alphadelta) for some antagonists may reflect experimental uncertainties in the low affinity site, relatively poor selectivity (rocuronium), or possibly that the binding of an antagonist at one site affects the affinity of the second site.

[Anticoagulative effect and antiplatelet aggregation effect of combination of Hirudo and Tabanus on rat model of blood stasis syndrome].

OBJECTIVE: To observe anticoagulative effect and antiplatelet aggregation effect of the combination of Hirudo and Tabanus with different dose-ratio on rat model of blood stasis syndrome. METHODS: The rat model of blood stasis syndrome was established by subcutaneous injection of adrenaline combined with stimulation of icy water. Then prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) contents and inhibition rate of blood platelet aggregation were determined. RESULTS: Platelet aggregation increases, APTT and PT reduced, and FIB contents increased in model control group significantly (P<0.001). Hirudo, Tabanus and the combination of Hirudo and Tabanus had antiplatelet aggregation effect in varying degrees. APTT and PT were prolonged significantly (P<0.05 and P<0.01, respectively) in Hirudo group, Tabanus group and combination groups, especially in the group with dose-ratio of Hirudo to Tabanus being 4:3. FIB contents decreased significantly in combination group with dose-ratio being 3:1 (P<0.05). CONCLUSIONS: The combination groups of Hirudo and Tabanus have better effect of anticoagulation and antiplatelet aggregation than Hirudo group and Tabanus group. While in the four combination groups, the group recommended by classical TCM monograph with dose-ratio of Hirudo to Tabanus being 4:3, has the best anticoagulation effect.

Potentiation of neostigmine and pyridostigmine by 4-aminopyridine in the rat.

The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 microgram kg(-1) respectively. The addition of 100 microgram kg(-1) of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7.4 microgram kg(-1). The addition of 200 microgram kg(-1) of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 microgram kg(-1). We conclude that both neostigmine and pyridostigmine interact with 4-aminopyrine synergistically.

The effect of nizatidine on neuromuscular transmission.

The effect of the H2-receptor antagonist, nizatidine, on neuromuscular transmission was investigated using sciatic nerve-gastrocnemius muscle preparations of rat in vivo. Nizatidine, administered by i.v. injection, potentiates the neuromuscular blockade induced by d-tubocurarine, pancuronium and the aminoglycoside antibiotic, kanamycin. Moreover, the drug alone is capable of producing a blockade on preparations stimulated at high frequency. The neuromuscular blockade induced by nizatidine is reversed by 4-aminopyridine but not by dimaprit.

The effect of famotidine on neuromuscular transmission.

We have investigated the effects of the H2 receptor antagonist famotidine on the neuromuscular transmission by using the sciatic nerve--gastrocnemius muscle preparation of rat in vitro. Famotidine, administered by I.V. injection, potentiates the neuromuscular blockade induced by d-tubocurarine, pancuronium and aminoglycoside antibiotics. Moreover, the drug alone is capable of producing a blockade on the preparation stimulated at high frequency. The neuromuscular blockade induced by famotidine is reversed by 4-aminopyridine but not by dimaprit. Similar results have previously been obtained with cimetidine.

Interaction of sevoflurane, isoflurane, enflurane and halothane with non-depolarizing muscle relaxants and their prejunctional effects at the neuromuscular junction.

The interaction of four inhalational anesthetics (sevoflurane, isoflurane, enflurane and halothane) with pancuronium and vecuronium and also their prejunctional actions at the neuromuscular junction were quantitatively studied using rat phrenic nerve-hemidiaphragm preparations. To investigate the prejunctional effects of inhalational anesthetics, a train-of-four ratio (T4/T1) and the tetanus ratio (the ratio of the final response to the initial response during tetanus) were evaluated. All four inhalational anesthetics markedly potentiated the neuromuscular blockade of twitch response caused by either pancuronium or vecuronium with halothane and enflurane being the most potent both on a % concentration basis and on a MAC (minimum alveolar concentration) basis. Although none of the four inhalational anesthetics had any effects on the T4/T1 ratio, they produced variable effects on the tetanus ratio. Sevoflurane had little effect on the tetanus ratio, whereas 1 and 2% isoflurane and 1, 2 and 3% enflurane increased the tetanus ratio and 5% halothane and 5% enflurane significantly reduced the tetanus ratio. Halothane and enflurane had the most potent depressant action of the four inhalational anesthetics both on the % concentration basis and on the MAC basis. These results indicate that the main site of action of inhalational anesthetics is a postjunctional site at the neuromuscular junction and that they do not seem to act on prejunctional sites at the concentrations used in clinical situations.

Effects of enflurane and isoflurane anesthesia on the pharmacokinetics of pancuronium in adult patients.

OBJECTIVE: To evaluate the effects of 1 MAC of enflurane or isoflurane anesthesia on the pharmacokinetics of pancuronium. METHODS: Eighteen adult patients undergoing the elective plastic surgery were randomly divided equally into 3 groups, namely, Group 1 (control group), Group 2 (enflurane group) and Group 3 (isoflurane group). Anesthesia was maintained with thiopental and 67% N2O-O2 in Group 1, 1 MAC enflurane in Group 2 and 1 MAC isoflurane in Group 3. After administration of a bolus of pancuronium 100 micrograms/kg, an improved fluorimetric assay was used to determine the serum concentrations of pancuronium and the pharmacokinetic variables of pancuronium were calculated with a 3P87 program. RESULTS: The disposition of pancuronium may be well described mathematically by a two-compartment open model. The results showed that in comparison with the control group, patients in Group 2 and Group 3 had a longer T1/2 beta and MRT. The patients in Group 2 had the slower K10 and lower CL than those in the control group. There were no significant differences among the three groups in T1/2 alpha, V1, V2, Vdss, V beta, K21, K12 and AUC. CONCLUSION: During enflurane and isoflurane anesthesia, CL of pancuronium decreased, and T1/2 beta and MRT of pancuronium were prolonged in our patients, so duration of the effective plasma concentrations of pancuronium was much longer. As a result, the effects of enflurane and isoflurane of the pharmacokinetics of pancuronium may be part of reason why two drugs extended the duration of neuromuscular depression produced by pancuronium.

The synergistic effect of two different nondepolarizing muscle relaxants on intraocular pressure.

STUDY OBJECTIVES: To evaluate the synergistic effect of neuromuscular blockade, produced by administering a priming dose of d-tubocurarine before or after pancuronium bromide, on endotracheal intubating conditions, intraocular pressure (IOP), and hemodynamic changes 1 minute following injection of intubating doses. To compare the results with equipotent doses of the individual muscle relaxants administered as a single bolus dose or in divided doses. DESIGN: Randomized study. SETTING: University medical center. PATIENTS: Ninety ASA physical status I and II inpatients (45 males, 45 females) assigned to one of six comparable groups (A-F). INTERVENTIONS: One hour after premedication, either normal saline (Groups A and B) or a priming dose of either d-tubocurarine (Groups C and F) or pancuronium (Groups D and E) was given intravenously (IV). Three minutes later, anesthesia was induced with 6 mg/kg of 2.5% thiopentone i.v. Then an intubating dose of pancuronium (Groups A, C, and E) or d-tubocurarine (Groups B, D, and F) was administered. The total dose given was equal to d-tubocurarine 0.4 mg/kg or pancuronium 0.07 mg/kg. Patients were intubated 1 minute after injection of an intubating dose of either relaxant. MEASUREMENTS AND MAIN RESULTS: IOP was measured with a Perkins applanation tonometer and blood pressure (BP) by a sphygmomanometer. Heart rate was derived from the electrocardiogram. Intubating conditions were scored according to given intubation criteria. Measurements were obtained at different times before and after intubation. In those patients given only one muscle relaxant for intubation either divided into priming and intubating doses or preceded by normal saline (Groups A, B, E, and F), there was a significant increase in IOP in response to intubation as compared with baseline (p < 0.05). In contrast, when d-tubocurarine was used as the priming drug for pancuronium blockade (Group C), IOP was significantly reduced in response to intubation, despite a concomitant increase in BP (p < 0.05). No significant change in IOP was observed when pancuronium was used as the priming drug for d-tubocurarine blockade (Group D). Although good to excellent intubating conditions were reported in Groups C and D, poor intubating conditions were reported when the priming muscle relaxant was the same as the relaxant used to intubate. CONCLUSIONS: A smooth, rapid-sequence intubation with a concomitant reduction in IOP as required for open-eye, full-stomach patients can be achieved with a judicious mixture of nondepolarizing muscle relaxants as described for d-tubocurarine and pancuronium in Groups C and D.

Effects of neostigmine, edrophonium, 4-aminopyridine and their combinations.

A study was carried out in the in-vitro rat phrenic nerve hemidiaphragm preparation to find a fast and strong working antagonist of non-depolarizing muscle relaxants. We studied neostigmine, edrophonium, 4-aminopyridine and their combinations from the cumulative concentration response curves of pancuronium. Neostigmine, edrophonium and 4-aminopyridine all antagonized the effect of pancuronium. Neostigmine and 4-aminopyridine did potentiate each other as did neostigmine and edrophonium. The combination of edrophonium and 4-aminopyridine showed less total effect than the addition of their individual effect. We conclude that the mechanisms of action of neostigmine and edrophonium are different.

The neuromuscular blocking action of vecuronium in normal patients and in patients with no renal function and interaction vecuronium-tobramycin in renal transplant patients.

The new short acting steroid muscle relaxant vecuronium was tested clinically in 42 surgical patients and compared in three different groups of patients: normal patients, renal graft patients who received tobramycin preoperatively and other anephric patients undergoing surgery. Twenty-five percent recovery of initial twitch height as measured by NTM was significantly longer in the renal graft group than in the two other groups where recovery time is normal. Cardiovascular parameters were recorded before and after the injection of vecuronium. Reversal of the neuromuscular block was spontaneous or pharmacologically evoked by neostigmine. Clinical recovery was complete in all patients and there was no residual block.

The comparative influence of gamma-hydroxy butyric acid, althesin and etomidate on the neuromuscular blocking potency of pancuronium in man.

The potentiating effect of gamma-hydroxy butyric acid (GHB), Althesin and etomidate on pancuronium was studied in man. GHB proved to influence pancuronium the least whereas Althesin and etomidate potentiate considerably. It is concluded that the amount of non-depolarizing relaxant needed depends on the type of anesthesia given. For neuromuscular blocking studies, GHB and/or thiopentone anesthesia seem to be preferable.

The comparative neuromuscular blocking effects of some aminoglycoside antibiotics.

The neuromuscular blocking effects of aminoglycoside antibiotics were tested in the isolated phrenic nervediaphragm preparation of the rat. The neuromuscular blocking potencies were netilmicin equals sisomicin much greater than neomycin much greater than gentamicin much greater than tobramycin. The EC 50's (concentration resulting in 50 percent depression of the original twitch tension) were respectively 13.3 x 10(-4); 13.4 x 10(-4); 13.6 x 10(-4); 15.1 x 10(-4); and 95.3 x 10(-4) Mol/l for netilmicin, sisomicin, neomycin, gentamicin and tobramycin. When a threshold dose of pancuronium was added to the bathing fluid the EC 50's were diminished respectively by a factor of 0.4 (sisomicin and neomycin) 0.5 (tobramycin) and 0.6 (netilmicin and gentamicin). Addition of a threshold dose of Org-NC45, a new steroidal non-depolarizing muscle relaxant, diminished the EC 50's to the same extent. The neuromuscular blocking effects of pancuronium and Org-NC45 themselves were potentiated by pretreatment of the preparations with a threshold dose of the aminoglycoside. Comparison of the results demonstrated the following potentiating effects: netilmicin equals sisomicin much greater than neomycin much greater than gentamicin greater than tobramycin. Which is in the same sequence s the neuromuscular blocking potencies of these drugs.

Potentiation of atracurium by pancuronium during propofol-fentanyl-N2O anesthesia.

At the end of abdominal surgery deep neuromuscular blockade is required for peritoneal closure. Ideally injecting an intermediate acting drug like atracurium after a long acting drug such as pancuronium should deepen the neuromuscular block without the fear of an inadequate reversal at the completion of surgery. Thirty patients ASA I or II status, without known allergy to myorelaxant and without neuromuscular, hepatic or renal failure were included in this study. Anesthesia was induced and maintained with propofol, fentanyl, and N20. Normal core temperature was maintained by active warming of the upper part of the body. Blood electrolytes and the acid-base status were within the normal range. The accelerographic responses to Train-Of-Four supramaximal stimulation (TOF) of the ulnar nerve was monitored at the thumb. After obtaining a stable response with the accelerograph, the patients randomly received pancuronium (0.10 mg.kg-1, group I, n = 10 and group II, n = 10) or atracurium (0.50 mg.kg-1, group III, n = 10). An additional dose of atracurium (0.16 mg.kg-1, group I and III) or pancuronium (0.03 mg.kg-1, group II) was injected when the first response of TOF stimulation (T1) reached 25% of its initial value. Then the time to obtain a 25% twitch height of T1 (T25), the recovery index (RI 25-75), the delay to obtain 4 responses to TOF and an adequate recovery [TOF ratio of 0.70 (TOF70)] were monitored. Injection of 60% ED95 of atracurium after pancuronium resulted in a similar recovery of neuromuscular function as after 45% ED95 of pancuronium as shown by the same recovery of T25 (66.5 +/- 4.2 min versus 71.4 +/- 7.8 min, group I versus group II, p > 0.05) and TOF70 (131.6 +/- 15.7 min versus 144.0 +/- 17.5, group I versus II, p > 0.05). Nevertheless the RI 25-75 of group I was of intermediate duration between those of group II and III. Electrolytes and acid-base status were similar between groups at the beginning of surgery. Thus this study shows a synergistic effect of the combination of atracurium after pancuronium occurring in non hypothermic patients anesthetized without halogenated agents. Because the duration of action of the drug administered first governs the duration of action of the subsequent neuromuscular myorelaxant, the neuromuscular function should be closely monitored at the end of surgery if neuromuscular drugs are used in combination.

[Nitroglycerin reduces requirement of pancuronium in surgical patients].

We performed a study on 34 adult surgical patients between 15 and 56 years of age, to evaluate whether synergism between nitroglycerin and pancuronium exists or not. Neuromuscular (NM) transmission was measured by electromyography of the thenar muscle using transcutaneous electrodes. Anesthesia was induced by droperidol 0.2 mg.kg-1, fentanyl 50 micrograms, thiamylal 150-250 mg, and succinylcholine 1 mg.kg-1, and maintained with nitrous oxide and O2 (67:33) supplemented with repeated i.v. doses of fentanyl (within 15 micrograms.kg-1). Pancuronium 4 mg was given at the 20% recovery from succinylcholine induced NM block. Sequential i.v. doses of pancuronium 1 mg were injected repeatedly at the every 20% recovery until the end of operation. To control blood pressure, nitroglycerin, ranging from 0 to 5 micrograms.kg-1.min-1, was given intravenously. The linear multiple regression analysis was performed between the dose of pancuronium (micrograms.kg-1.hr-1) and the dose of nitroglycerin (micrograms.kg-1.min-1), the age, sex, or body weight of the patients. The results show that the dose of pancuronium decreases with increasing dose of nitroglycerin. No relationship was found between the dose of pancuronium and the age, sex, or body weight of the patients. In conclusion, nitroglycerin reduces requirement of pancuronium in surgical patients.

[The effect of succinylcholine on vecuronium and pancuronium].

In 105 adult patients under halothane anesthesia, the neuromuscular blocking effects of vecuronium and pancuronium were determined with prior succinylcholine 1 mg.kg-1 administration and without. Force of the evoked twitch increased 123.7% of control after recovery from succinylcholine-induced block. Prior administration of succinylcholine was associated with a leftward shift of dose-response curve of vecuronium or pancuronium. Onset of the force reduction from initial dose (0.08 mg.kg-1) was faster and recovery from initial and maintenance doses (0.02 mg.kg-1) were slower. This potentiating effect persisted at least 2 hours.

[Potentiation of pancuronium induced neuromuscular blockade by nitrous oxide].

To evaluate in man the potentiation by nitrous oxide of the neuromuscular blockade produced by pancuronium, pancuronium 0.025, 0.035, 0.049 or 0.068 mg.kg-1 was given during thiamylal-fentanyl anesthesia with and without nitrous oxide, and the evoked electromyography (EMG) of hypothenar muscle was measured. In the group receiving nitrous oxide the ED50 and ED95 were 0.0359 and 0.0691 mg.kg-1. In the group not receiving nitrous oxide, these values were 0.0389 and 0.0849 mg.kg-1. The dose-response curve (DRC) constructed from log-probit transformation for the group not receiving nitrous oxide shifted to the right for 10.3% (P < 0.05). It was also revealed that the magnitude of the blockade was influenced by dose, gender, nitrous oxide, lean body mass and body surface area by the multiple regression analysis. DRS for the female patients shifted to the left, and the differences between both sexes seemed to decrease in the group receiving nitrous oxide. It is concluded that the results of the present study appears to be similar to those obtained in the previous study on vecuronium using EMG.

[Synergy and attenuation of cyclophosphamidum (CTX) activities by abalone polysaccharide].

Abalone polysaccharide (AP) was extracted from Haliotis discushannai Ino. The combined effects of AP and CTX against tumor-bearing mice were investigated. The results showed that AP could markedly promote the inhibition effects of CTX on S180 and HepA tumor, enhance protection against leukocytopenia, decrease of spleen and thymus weight and hemolysin in serum, and bone marrow supression induced by CTX.