Drug Dilution Research Articles

Ethnobotanical Exploration and Formulation Development of Cream Containing Ammi majus Linn and Portulaca oleracea Linn

Stearic acid served as the emulsifier in the preparation of an O/W emulsion-based cream that also included oil-soluble components and water-based extracts of Ammi majus Linn and Portulaca oleracea Linn. The cream was evaluated for color, appearance, presence of foreign particles/grittiness, pH, viscosity, phase separation, and extrudability. A skin irritation study was conducted on Wistar rats, with intact skin and hair removed three days earlier experiment. Cream-containing extracts were applied to test animals, and the backs of animals were scrutinized for erythema and edema. To study psoriatic skin cells in-vitro, researchers used the HaCaT cell line. Researchers also used the SRB assay to look for antipsoriatic effects in-vitro. Cultures of human keratinocyte cell lines HaCaT were carried out in a medium that included 10% fetal bovine serum and was otherwise identical to Dulbecco’s modified Eagle’s medium. In order to reach a concentration of 10%, 25 μL of 50% TCA was added to each well after 72 hours, creating a thin layer of ended drug dilutions. Phytochemical evaluation revealed that the extracts of A. majus Linn and P. oleracea Linn were soluble in water and had a yellowish solid color. The cream formulation showed good emulsionability, no foreign particles or grittiness, and no phase separation. The skin irritation test on Swiss albino rats showed that the standard drug (Retino A 0.05% cream) was free from irritation. The cream’s acceptability for topical use was also observed.

Comparative analysis of the effect of drugs lowering intraocular pressure on a primary culture of human corneal epithelium and A549 immortalized cell line

Background. Glaucoma as one of the most common eye diseases can be a comorbid condition of an epithelial corneal defect of various etiologies. Maintaining an optimal level of ophthalmotonus includes the prescription of antiglaucoma drugs, including benzalkonium chloride-preserved drugs.The aim of the study. To compare the effect of antiglaucoma drugs, as well as benzalkonium chloride (BC), on a primary culture of human corneal epithelium and A549 immortalized cell line.Methods. The effect of brimonidine, dorzolamide and timolol (1/100, 1/50, 1/20 and 1/10 dilutions; exposure 24 hours) on a monolayer of a human corneal epithelial primary culture and A549 immortalized cell line was assessed by structural changes in cells (phase-contrast microscopy) and MTT assay data. The cytotoxic effect of BC was studied in concentrations corresponding to its content in these dilutions of the antiglaucoma drug. Using a model of a linear defect in the monolayer of a corneal epithelial primary culture and A549 immortalized cell line, the effects of brimonidine, dorzolamide and timolol (1/100 and 1/20 dilutions; exposure 48 hours) were assessed by cell migration activity.Results. Among drugs (BC-free), dorzolamide (1/50, 1/20 and 1/10 dilutions) causes minor structural changes in human corneal epithelium and A549 immortalized cell line; timolol (1/100, 1/50, 1/20 and 1/10 dilutions) causes minor structural changes in A549 immortalized cell line. Structural changes in both types of cells, a decrease in their metabolic and migration activity occur under the influence of dorzolamide, brimonidine and timolol (BC-preserved) in 1/100, 1/50, 1/20 and 1/10 dilutions. BC at the studied concentrations exhibits a similar effect.Conclusion. The cytotoxic effect of antiglaucoma drugs is caused by the presence of BC in their composition. Despite similar morphofunctional changes in cells, A549 immortalized cell line is more resistant to the effects of drugs than the human corneal epithelial primary culture. When using it as a cellular model, it is advisable to change the experimental conditions (duration of exposure and concentration of the studied drug).

COMPLEX RESEARCH HERB OF THE FRAGRANT VIOLET GROWING IN THE NORTH CAUCASUS AND WAYS OF ITS USE

Introduction. Fragrant violet (Viola odorata L., family Violaceae) is a perennial herbaceous plant, widespread in the North Caucasus and the European part of Russia. The aerial part of the plant contains various active biologically active substances, such as phenolic and triterpene glycosides, polysaccharides, phenolic compounds, coumarins and flavonoids, ascorbic acid, macro and microelements, which are responsible for its medicinal properties. In modern herbal medicine, fragrant violet is used as an anti-inflammatory, analgesic, antioxidant, diuretic, antihypertensive and antibacterial agent. However, further research is needed to confirm these medicinal properties. Objectives. Preparation of a dry extract from the herb violet fragrant and evaluation of its antibacterial activity against the clinical strain of Staphylococcus aureus III. Material and methods. The object of the study was a dry extract from the herb of fragrant violet, collected on the territory of three municipalities of the Stavropol Territory in the flowering phase of 2020-2022, obtained by exhaustive extraction with 70% ethyl alcohol. For microbiological studies, the serial dilution method was used. Meat-peptone broth (MPB) was used as a control, without adding a suspension of microorganisms to control the sterility of the environment and with the addition of microorganisms to control the growth of the microorganism, as well as a number of serial dilutions of the reference drug: “Ceftriaxone”. Results. It was established that the studied extract from fragrant violet has antibacterial properties, which is confirmed by the identified bacteriostatic effect (reduction in the number of colonies formed compared to the control) and a change in the cultural properties of the colonies relative to the control. Conclusions. The obtained screening results actualize further study of the extract from the herb violet fragrant in relation to representatives of opportunistic flora and the prospects of its use as an antimicrobial and anti-inflammatory agent of plant origin.

A Research Work on Design, Development and In-Vitro Evaluation of Losartan Potassium Loaded Pectinate Microspheres

One of the special and innovative drug delivery strategies is the use of microspheres, which can increase a drug's effectiveness by preventing drug dilution in bodily fluids, allowing drug localization and targeting at a specific site, and maintaining drug concentration between MEC and MTC levels.Microspheres are characterized as roughly spherical, solid particles with sizes between 1 to 1000 μm that are intended to be covered in protective materials such as polymeric or waxy coatings. One of the more innovative methods in the field of oral controlled drug delivery systems is the use of microsphere dosage forms, which target a specific area of the body for a prolonged period of time, allowing for more effective local drug delivery as well as improved systemic drug. The % yield of all the losartan potassium loaded pectinate microsphere formulations (LM1 to LM5) was found within the range from 76.74 ± 3.79 % to 89.06 ± 2.67 %.The % entrapment efficiency and particle size of the prepared losartan potassium loaded pectinate microsphere formulations (LM1 to LM5) was found within the range from 63.68 ± 3.55 % to 84.78 ± 2.27 % and 0.78 ± 0.14 mm to 0.91 ± 0.05 mm respectively. Formulations LM1 to LM5 showed 2.12 % to 12.46 % mucoadhesion up to 6 hours in simulated gastric fluid (pH 1.2, 0.1N HCl) and 74.28 % to 96.04 % mucoadhesion up to 6 hours in simulated intestinal fluid (phosphate buffer, pH 6.8).

Testing the test strips: laboratory performance of fentanyl test strips

BackgroundThe overdose crisis driven by synthetic opioids continues to escalate in the USA. We evaluated the efficacy of multiple manufacturing lots of a fentanyl test strip (FTS) to detect fentanyl and fentanyl analogs and assessed cross-reactivity with possible interferences.MethodsDrug standards were dissolved in water in a laboratory setting and serially diluted. Drug dilutions were tested using five different manufacturing lots of BTNX Rapid Response (20 ng/mL cutoff) lateral flow chromatographic immunoassay strips to assess lot-to-lot variability for FTS sensitivity and cross-reactivity for the analytes of interest.ResultsAll five manufacturing lots cross-reacted with fentanyl and eleven fentanyl analogs. Diphenhydramine, lidocaine, MDMA, and methamphetamine were found to cause false positives with the strips. There was notable lot-to-lot variability in the sensitivity of the strips for fentanyl, fentanyl analogs, and known interferences.DiscussionFTS remains an important overdose prevention tool, but lot-to-lot variability in performance complicates robust instructions that balance the prevention of false positives and false negatives. Continued lot-to-lot performance assessment is recommended to ensure health education for FTS remains accurate. More sophisticated drug checking technologies and services are needed in the community landscape to augment personal FTS use to facilitate informed consumption and overdose risk mitigation.

Hydrogel: a new material for intravesical drug delivery after bladder cancer surgery.

The standard treatment for non-muscle invasive bladder cancer (NMIBC) is transurethral resection of bladder tumor (TURBT). However, this procedure may miss small lesions or incompletely remove them, resulting in cancer recurrence or progression. As a result, intravesical instillation of chemotherapy or immunotherapy drugs is often used as an adjunctive treatment after TURBT to prevent cancer recurrence. In the traditional method, drugs are instilled into the patient's bladder through a urinary catheter under sterile conditions. However, this treatment exposes the bladder mucosa to the drug directly, leading to potential side effects like chemical cystitis. Furthermore, this treatment has several limitations, including a short drug retention period, susceptibility to urine dilution, low drug permeability, lack of targeted effect, and limited long-term clinical efficacy. Hydrogel, a polymer material with a high-water content, possesses solid elasticity and liquid fluidity, making it compatible with tissues and environmentally friendly. It exhibits great potential in various applications. One emerging use of hydrogels is in intravesical instillation. By employing hydrogels, drug dilution is minimized, and drug absorption, retention, and persistence in the bladder are enhanced due to the mucus-adhesive and flotation properties of hydrogel materials. Furthermore, hydrogels can improve drug permeability and offer targeting capabilities. This article critically examines the current applications and future prospects of hydrogels in the treatment of bladder cancer.

A Cantharis potency acts on heat exposed bovine serum albumin as revealed by FT-IR spectroscopy

In a series of experiments we have demonstrated that high dilution of homeopathic drugs produces distinct effects on plants and animals in-vivo through the medium of water. High dilutions (HDs) of a drug prepared by serial dilution with a solvent medium 1:100, followed by mechanical agitation in several steps are called potencies. Water molecules play an important role on protein structure and function. We focused our observation on water molecules associated with BSA. High dilution (HD) of a homeopathic drug is thought to be specific water structure which produces therapeutic effects on man. HDs also produce effects on animals, plants and even proteins in aqueous solution. What is the primary target of HDs on organisms or on protein? The present study addresses this question. Cantharis 30 cH, a homeopathic potency used for burn injuries, has been tested on bovine serum albumin (BSA) in-vitro. The protein has been exposed to heat at 750C for 10 mins, cooled down to room temperature and then treated with Cantharis 30 cH. The treatment was done by two methods, direct and indirect through water. The results from both the methods are almost similar. The treated and untreated protein solutions were analysed by Fourier Transform Infra-Red (FT-IR) spectroscopy. The treatment effect was evident on water molecules associated with BSA. The results indicate that Cantharis 30 cH interacts with water molecules which in turn influence BSA. It is concluded that the homeopathic potency converts first water structure which then affects the protein. Based on the results on this experiment we can assumes that the primary target of all homeopathic potencies is water which constitutes the major component of all living organisms. All biomolecules are suspended in water.

Fosfomycin activity in vitro against Escherichia coli strains isolated from urine specimens

Abstract Urinary tract infections are caused mostly by uropathogenic Escherichia coli strains. The aim of this paper was to assess the activity of fosfomycin in vitro against 74 E. coli strains isolated from urine samples of outpatients with acute cystitis. Minimum inhibitory concentration (MIC) was determined by the recommended method of serial drug dilution in Mueller-Hinton agar supplemented with glucose-6-phosphate (25 mg/L). The estimated MIC values were in the range of 1-32 mg/L. The prevalence of fosfomycin-sensitive strains was 45.9%, while that of fosfomycin-resistant strains – 54.1%. The time-kill assay was performed for a chosen clinical strain (MIC = 1 mg/L) in Mueller-Hinton broth also supplemented with glucose-6-phosphate in the presence of various concentrations of fosfomycin (0.5-64 mg/L). The bacterial population density was expressed as log CFU (colony forming units)/mL. The decrease of the bacterial population viability after 6h incubation was found with ∆log CFU/mL = 1.05-5.02, depending on fosfomycin concentration. However, bactericidal effect of this antibiotic (∆log CFU/mL >3) was observed only at the highest concentrations (32-64 mg/L). Moreover, after prolonged incubation (24 h), the re-growth of bacterial population revealed as the increase of its viability (∆log CFU/mL = 1.03-3.03) was observed at fosfomycin concentration in the range 0.5-32 mg/L, but not at 64 mg/L. This phenomenon may be due the presence of subpopulations of spontaneous mutants sensitive only to higher concentrations of this antibiotic comparing to MIC. The presented data confirm a need to monitor the sensitivity of uropathogenic E. coli strains to fosfomycin.

Transcriptomic Features Influencing Anti-Myeloma Drug Resistance in Human Multiple Myeloma Cell Lines

Despite increasing number of new drugs, multiple myeloma (MM) remains a significant challenge in hematology. This problem primarily arises from the emergence of drug resistance, which could either result from pre-existing drug-resistant clones, or from the development of secondary genomic and phenotypic drug resistance features upon drug exposure. The use of primary MM patient-derived samples, while considered the gold standard in preclinical MM research, presents challenges due to notoriously low plasma cell yields and short ex vivo lifespan. Moreover, these cells often fail to survive cryopreservation, making them difficult to use in reproducible drug sensitivity screens. To address this issue, the MM research community has established numerous culture-adapted MM cell lines (HMCLs), representative of all cytogenetic MM subtypes and characterized by DNA and RNA sequencing. However, a comprehensive evaluation of their drug sensitivity has been lacking. In this study, we sought to bridge this gap by profiling the sensitivity of over 30 HMCLs to both established and novel drugs relevant to MM treatment. We explored the transcriptomic and genomic features that correlate with drug sensitivity of these cell lines, and investigated whether these features were associated with the outcomes of patients enrolled in the MMRF CoMMpass study. Our initial results suggest potential pathways universally implicated in MM drug resistance, which could be targeted therapeutically. We performed drug sensitivity screening in 96-well plates, testing established drugs such as proteasome inhibitors, immunomodulatory drugs, dexamethasone, and melphalan, alongside novel treatment modalities including the BCL2 inhibitor venetoclax, XPO1 inhibitor selinexor, and histone deacetylase inhibitor panobinostat. Optimal cell density and drug dilutions were ensured to capture the full spectrum of drug response. After 4 days of incubation, cell proliferation was measured using a metabolic MTS assay, and EC50 values were computed using four-parameter logistic regression. Genomic and transcriptomic data were obtained from HMCL66 dataset from the Keats laboratory. Drug sensitivity was analyzed using a log-transformed EC50 matrix, which was used for unsupervised hierarchical clustering of cell lines, revealing two primary clusters: multi-drug resistant (MDR) and multi-drug sensitive (MDS) cell lines. Gene set enrichment analysis revealed that MDR cell lines showed positive enrichment for KEAP1/NFE2L2 (Figure 1A), UPR/PERK pathways, and type I interferon signaling. Negative enrichment in MDR cell lines was observed for TP53-regulated transcription of cell death genes, with the top leading edge genes being key apoptosis inducers such as BAX, BID, APAF1, and FAS. We used the obtained leading edge gene lists to assign respective pathway activation scores to the CoMMpass patients, based on their transcriptomic profile, using the ssGSEA singscore package. High activation score of KEAP1/NFE2L2 was associated with shorter overall survival (HR = 1.57, p = 0.016), irrespective of type of first-line therapy (Figure 1A). Our study represents a significant milestone in characterizing the HMCL drug sensitivity landscape, suggesting that MDR cell lines inherently exhibit transcriptional features associated with high activity of the KEAP1/NFE2L2 and PERK pathways. These pathways have been previously associated with PI and IMiD resistance, but interestingly, our findings also link these signatures with the sensitivity to a variety of other anti-MM drugs. Conversely, MDS cell lines displayed enhanced basal activity of TP53-regulated pro-apoptotic genes, which might increase their apoptotic priming and consequently increase their susceptibility to drug-induced apoptosis. With the rapid evolution of protein-protein interaction inhibitors, future exploration of KEAP1-NRF2 or MDM2-TP53 interaction inhibitors could potentially enhance myeloma cell sensitivity. In the future, our team plans to expand the drug panel used in the screen and provide this enriched dataset as a public resource, thereby facilitating wider access and collaborative advancements in the field. Study supported by National Science Centre Grants PRELUDIUM 2018/31/N/NZ5/03214, ETIUDA 2020/36/T/NZ5/00610 and Polish Stem Cell Bank ExCELLent grant.

Dissolution Enhancement of Ketoconazole by Melt Granulation Co-Processing

Background: Melt granulation (MG) is a simple operation involving a uniform mixture of active ingredients with a melted polymeric carrier. However, this process can also enhance a drug's biopharmaceutical properties by augmenting its dissolution rate and, thus, its absorption. Purpose: By applying MG technology, current research focuses on developing co-processed ketoconazole with a higher aqueous dissolution rate than its pure form. Methods: A measure of how the type and proportion of polymeric carriers affect the crystallinity and dissolution rate of co-processed ketoconazole materials was performed. MG prepared materials in a high-shear mixer using co-povidone (Kollidon®) VA 64, HPMCAS HF as polymeric carriers, PEG 1450 (Kollisolv®) and triethyl citrate as plasticizers. Results: The co-processed ketoconazole materials exhibited miscibility in the polymeric systems, as indicated by the reduction in the enthalpy of fusion. Drug crystallinity was significantly reduced in the HPMCAS HF polymeric system, confirmed by XRPD and ATR-FTIR studies. The dissolution rate was enhanced by using a higher drug concentration in a co-povidone VA 64 environment; contrarily, for HPMCAS HF, a higher drug dilution was observed to favor the dissolution rate. Conclusions: MG is a handy, low-cost technology that develops dissolution-enhanced co-processed active pharmaceutical ingredients, spotting specific carrier-drug interactions. MG yields scalable, proven processes, raising interest in its applications in optimizing drug therapeutic efficacy. Ultimately, this technology for dissolution enhancement could bring lower-cost, high-efficiency drugs to improve patients' quality of life.

ВОЗМОЖНОСТИ ОПТИМИЗАЦИИ ЗАТРАТ НА ЛЕКАРСТВЕННОЕ ОБЕСПЕЧЕНИЕ ПАЦИЕНТОВ ЗА СЧЕТ ЦЕНТРАЛИЗОВАННОГО РАЗВЕДЕНИЯ ПРОТИВООПУХОЛЕВЫХ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ

The high level of costs for chemotherapy of malignant neoplasms requires the search for new solutions to reduce the cost of treatment. Centralized dilution of drugs is one of the most optimal solutions to this problem. But making such a decision requires a rather laborious calculation of the expected economic effects. The purpose of the study was to substantiate the economic benefits of centralized dilution of chemotherapeutic drugs in the regional oncological hospital. As materials, we took into account the number of spent 62 injectable forms of antitumor drugs in the departments of the Sverdlovsk Regional Oncological Dispensary, information on the implementation of 2098 chemotherapy regimens, acts on the disposal of unused drug residues, state contracts for the supply of drugs in 2022-2023. Methods of economic and mathematical analysis, modeling of economic situations with calculation of economic indicators were used to determine direct absolute and relative losses during the disposal of drug residues, as well as calculation of prevented economic damage. As a result, indicators were developed to determine the economic efficiency of the centralized drug dilution: the specific drug weight in the prescribing lists, absolute and relative financial losses, loss reduction coefficient. The relationship between the frequency of prescriptions and the potential for possible savings due to rational utilization of drug residues has been established. The average level of relative drug losses after the introduction of centralized drug dilution was 0.09% in 2023 against 5.54% of losses in 2022. The economic feasibility of using centralized drug dilution in large medical organizations is substantiated. The introduction of a centralized drug dilution in the Sverdlovsk Regional Oncology Dispensary prevented more than 20 million rubles of economic damage per month.

Development and Evaluation of Polymeric Mixed Micelles Prepared using Hot-Melt Extrusion for Extended Delivery of Poorly Water-Soluble Drugs

The poor aqueous solubility is a well-recognized restriction for the clinical application of many drug molecules. Micelles delivery system provides a promising strategy for the solubility enhancement of hydrophobic drugs. This study developed and evaluated different polymeric mixed micelles prepared using hot-melt extrusion coupled hydration method to improve the solubility and extend the release of the model drug ibuprofen (IBP). The physicochemical properties of the prepared formulations were characterized in terms of particle size, polydispersity index, zeta potential, surface morphology, crystallinity, encapsulation efficiency, drug content, in vitro drug release, dilution stability, and storage stability. Soluplus®/poloxamer 407, Soluplus®/poloxamer 188, and Soluplus®/TPGS mixed micelles had average particle sizes of 86.2 ± 2.8, 89.6 ± 4.2, and 102.5 ± 3.13 nm, respectively with adequate encapsulation efficiencies of 80% to 92%. Differential scanning calorimetry studies confirmed that the IBP molecules were dissolved in the polymers in an amorphous state. The in vitro release results revealed that the IBP-loaded mixed micelles presented extended-release behavior compared to the free drug. In addition, the developed polymeric mixed micelles remained stable upon dilution and one-month storage. These results demonstrated that the hot-melt extrusion coupling hydration method could be a promising, effective, and environment-friendly manufacturing technique for the scale-up production of polymeric mixed micelles to deliver insoluble drugs.

Determination of fungicidal effect of disinfectant ‘SanDezVet’ on sanitary significant test cultures of mold micromycetes of the genus Aspergillus Mich.

Studying the properties of new disinfectants is a crucial aspect of disinfectology research. During the investigation of the fungicidal properties of the ‘SanDezVet’ disinfectant, it was discovered that the recommended concentrations of 0.1% and 0.5%, at a temperature of 20.0 ± 0.5 °C and an exposure time of 60, 120, and 180 minutes, do not inhibit the growth of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger test cultures. This conclusion was reached as continuous growth of micromycetes was observed in all drug dilutions. The disinfectant ‘SanDezVet’ at a concentration of 3.0% displayed fungistatic properties by significantly delaying the growth of experimental test cultures. A 5.0% solution of the disinfectant resulted in a complete delay in growth of museum strains of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger. This indicates fungicidal properties when compared to the positive control. Based on the obtained results, it was observed that the optimal exposure times for disinfection measures with ‘SanDezVet’ are 60 and 120 minutes. ‘SanDezVet’ can be effectively used for fungal infections at different veterinary facilities

Sprayable Berberine-Silk Fibroin Microspheres with Extracellular Matrix Anchoring Function Accelerate Infected Wound Healing through Antibacterial and Anti-inflammatory Effects.

The conventional method of applying local medications for treating wound infections is often ineffective because of the dilution of drugs by the excess wound exudate. In addition, there have been insufficient studies investigating the adhesion between drug-loaded nanomaterials and cells or tissue. To address this intractable problem, berberine-silk fibroin microspheres (Ber@MPs) with an extracellular matrix-anchoring function were developed in this study. The microspheres were prepared from silk fibroin using the polyethylene glycol emulsion precipitation method. Subsequently, berberine was loaded onto the microspheres. Our results revealed that Ber@MPs firmly anchored to cells, continuously releasing berberine in the microenvironment. Moreover, both Ber@MPs and Ber@MPs-cell complexes exerted a strong and long-lasting antibacterial effect against Staphylococcus aureus and Staphylococcus epidermidis in the microenvironment, despite the large amount of wound exudate. In addition, Ber@MPs effectively resisted the inflammatory response induced by lipopolysaccharides and accelerated the migration of fibroblasts and neovascularization of endothelial cells cultured in inflammation-induced media. Finally, the in vivo experiments confirmed that the Ber@MP spray accelerated the healing of infected wounds via its antibacterial and anti-inflammatory effects. Therefore, this study provides a novel strategy for treating infected wounds in the presence of excess exudate.

Effect of potentised homoeopathic medicines on the germination and growth of Pisum sativum L.

The study is to know about the possible effects of arsenicum album on germination of the Pisum sativum (pea seed). The pea seed were treated with three different potencies of arsenicum album (30C, 200C, 1M).with the increase in potencies the possible changes in the root can be seen. Hence the effect on growth was obtained on medicines when its compared to untreated one after the dilution of drug beyond the avogadro’s number.

In Vitro-In Vivo Correlation of Posaconazole-Amphotericin B Combination against Candida albicans: In Vitro Interacting Concentrations Are Associated with In Vivo Free Drug Levels.

The in vitro/in vivo correlation of antifungal combination testing is necessary in order to assess the efficacy of combination regimens. We, therefore, attempted to correlate in vitro chequerboard testing of posaconazole (POS) and amphotericin B (AMB) with the in vivo outcome of combination therapy against experimental candidiasis in a neutropenic murine model. The AMB + POS combination was tested against a Candida albicans isolate. In vitro, a broth microdilution 8 × 12 chequerboard method with serial two-fold drug dilutions was used. In vivo, CD1 female neutropenic mice with experimental disseminated candidiasis were treated with i.p. AMB and p.o. POS alone and in combination at three effective doses (ED20, ED50 and ED80 corresponding to 20%, 50% and 80% of maximal effect, respectively). CFU/kidneys after 2 days were determined. The pharmacodynamic interactions were assessed based on Bliss independence interaction analysis. In vitro, a Bliss antagonism of -23% (-23% to -22%) was observed at 0.03-0.125 mg/L of AMB with 0.004-0.015 mg/L of POS, while a Bliss synergy of 27% (14%-58%) was observed at 0.008-0.03 mg/L of AMB with 0.000015-0.001 mg/L of POS. In vivo, Bliss synergy (13 ± 4%) was found when an AMB ED20 of 1 mg/kg was combined with all POS ED 0.2-0.9 mg/kg, while Bliss antagonism (35-83%) was found for the combinations of AMB ED50 2 mg/kg and ED80 3.2 mg/kg with POS ED80 of 0.9 mg/kg. Free drug serum levels of POS and AMB in in vivo synergistic and antagonistic combinations were correlated with the in vitro synergistic and antagonistic concentrations, respectively. Both synergistic and antagonistic interactions were found for the AMB + POS combination. POS compromised the efficacy of high effective AMB doses and enhanced low ineffective AMB doses. In vitro concentration-dependent interactions were correlated with in vivo dose-dependent interactions of the AMB + POS combination. In vivo interactions occurred at free drug serum levels close to in vitro interacting concentrations.

High Dilutions of Homeopathic Drugs Interact with Human Serum Albumin as Revealed by Electronic Spectroscopy

Homeopathy uses drugs in extreme dilutions that are mostly devoid of the original drug molecules. Drug-induced water structures are thought to be responsible for their therapeutic effect. We have already observed that homeopathic potencies first interact with serum albumin, which is present in the oral mucosa. In this experimental study, we have shown that the homeopathic potencies of three drugs, Bryonia alba (Br), Rhux toxicodendron (Rt), and Thuja occidentalis (Th), initiate their action on Human Serum Albumin (HSA). The potency-HSA complexation has been observed by electronic spectroscopy. The control, HSA plus water, shows only one peak at 216 nm, but the potencies plus HSA show two peaks, one at 205 nm and another around 265 nm. The first peak is due to the peptide bond. The first peak in the control shows a marked red shift. The second peak at higher wavelength is due to the aromatic amino acids. The first peak with the potencies shows a marked blue shift, possibly due to a change induced by the potencies on the peptide bond. Unlike water control the potencies interact with aromatic amino acids. It is evident that the complexes made up of HSA and potency are different from those of the control. This means that homeopathic potencies are not ordinary water. It is concluded that water control interacting with HSA shows a single peak in UV-spectra at lower wavelength, but homeopathic potencies show one additional peak at a higher wavelength besides the peak at the lower wave length. HDs can produce effects on aromatic amino acids. The mother tinctures and their HDs show marked differences from each other in their electronic spectra.

Antibacterial efficacies of brown sea weed Sargassum Wightii on Periodontal Pathogens: An In-Vitro Microbiological Analysis

Objective: Sargassum wightii is brown algae available across the south east coast of India which can produce many secondary metabolites and are opulent sources of potential plant derived by-products with antiviral, antihelminthic, antifungal and antibacterial activities. The objective of the current study was to assess minimal inhibitory concentration MIC and minimum bactericidal concentration MBC of whole leaf extract of Sargassum wightii on P.Gingivalis (Pg), F.Nucleatum (Fn), T.Forsythia (Tf) and A. Actinomycetemcomitans (Aa). Methods: The method executed out by serial dilutions of the test drug with thioglycollate broth nine times. Cultures of chosen pathogens were added to obtain culture suspension up to 10-9. Their turbidity has monitored to assess MIC after incubating in oxygen independent container. The First 3 or 5 dilutions tubes which were MIC sensitive were removed and incubated one complete day. To determine whether there was bacterio-static or bactericidal effect of the extract on selected organisms, colony numbers were assessed the day after. Results: Outcome for MIC was in the span of 0.2μg/ml to 0.4μg/ml and for MBC from 0.2μg/ml to 3.12μg/ml. Conclusion: Positive pharmacological effect does exists against tested microorganisms of whole leaf extract of Sargassum Wighitti & demands more extensive research for treating multi-factorial periodontal disease.

Evaluation in pig of an intestinal administration device for oral peptide delivery

The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5-3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.

Standardisation of intravenous infusion therapy for paediatrics: big challenges for the little patients

BackgroundWorldwide organisations advocate standardising the management of intravenous drugs as an essential strategy to increase safety in paediatric healthcare settings. Intravenous administration is a route associated with some potential complications....