Sterility and antibacterial activity of some antibiotics sterilized by irradiation

Sterility and antibacterial activity of several antibiotics (including some penicillins and their salts, gramicidin and neomycin) subjected to sterilization by irradiation has been studied. The compounds in solid phase have been exposed to gamma irradiation in air atmosphere at room temperature, with a dose of 25 kGy, and afterwards they have been subjected to tests recommended by FP V (volume I, 1990) checking their sterility and activity. The results have shown that the majority of initial compounds have been to a slight degree contaminated by bacteria from the genera Bacillus and Micrococcus, the number of bacteria did not exceed 10(2) CFU, and fungi up to 10 CFU in 1 g of the compound. All compounds subjected to sterilization with a dose of 25 kGy were sterile and preserved the activity required by FP V. The decrease in activity observed for some compounds was always within the limits of FP specification. The results have proved that the penicillins analysed, gramicidin and neomycin can be sterilized by irradiation with a dose of 25 kGy, without any detrimental effect on their properties and antibacterial activity.     

Antimycobacterial activity of some pyrido-1,2-thiazine derivatives

The 3-benzoylpyrido-1,2-thiazine-1,1-dioxides 1 and the related pyrazolopyrido-1,2-thiazine-5,5-dioxides 2 with a 4-arylpiperazin-1-ylpropyl side chained by the nitrogen atom of the thiazine ring were evaluated in vitro against Myobacterium tuberculosis H37Rv. Some of the tested compounds proved to be potent antimycobacterial agents and for the most active of them (1a,b) minimum inhibitory concentrations (MIC = 3.13 and 6.25 microg/ml, respectively) were determined. The correlation between mycobacterium growth inhibition and the lipophilicity (logPcalc.) within the series of derivatives 1 and 2 was studied.     

A comparative molecular surface analysis (COMSA). A new efficient technique for drug design

Several applications of the COMSA were discussed including a series of the potential anti-HIV drugs and a series of dyes.     

Comparative evaluation of safety and efficacy of pamidronate and zoledronic acid in multiple myeloma patients (single center experience)

Osteolytic bone destruction, caused by the aberrant production and activation of osteoclasts, results in significant morbidity for patients with multiple myeloma (MM). Pamidronate [(3-amino-1-hydroxypropylidene)-1,1-bis-phosphonate] inhibits osteoclastic activity and reduces bone resorption. A potency of zoledronic acid (2-[imidazol-1-yl]-1-hydroxyethylidene-1,1-bisphosphonic acid, a new third generation bisphosphonate, as inhibitor of resorption was 850-fold greater than pamidronate, as was shown in preclinical models of bone resorption. Randomized, double-blind study was conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating myeloma bone disease. Since March 1999 the efficacy and safety of pamidronate and zoledronic acid is evaluated in MM patients all receiving anti-myeloma chemotherapy acc. to VMCP/VBAP alternating regimen. Nine patients with stage III myeloma and osteolytic lesions (3 female, 6 male, median age 57 years, range 52-67, with monoclonal protein: IgG-7, IgA-2) were randomly assigned (1:1:1 ratio) to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. All patients have received 500 mg of calcium supplements and 500 IU of vit.D, orally, once daily, for the duration of administration of study medication. In extension phase of the study (June 2000-April 2002) patients did not received bisphosphonates. In 7 patients 18 cycles of assessed treatment was administered to each of them and one patient received 16 cycles. One patient died after receiving of 12 pamidronate therapy cycles at 11 month of the trial duration (and at 49 month since MM diagnosis and anti-tumour treatment). The patient's death occurred during the progression of plasma cell proliferation due to acute left ventricle cardiac failure. During the 12-month-period of bisphosphonate treatment skeletal related events (SRE) and progression of osteolysis occurred with the same frequency in 3 treatment groups. One patient experienced spinal cord compression and received radiation to bone and 2 patients experienced vertebral fracture. Time from study entry to the first SRE was 304 days in pamidronate and 366 and 392 days in 4 and 8 mg zoledronic acid group, respectively. The skeletal morbidity rate was identical in all treatment groups. Single hypocalcemic events occurred in 2 patients, mild hypertransaminasemia was observed in 3, worsening of renal function parameters in 2 patients (transient in one of them). Muscular pain and fever up to 39 degrees C (transient and self-limiting "flu-like" symptoms) occurred in 6 patients after several or some dozens of hours from study drug administration. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate and were experienced by a similar proportion of patients in each treatment group. Median time of patient's observation duration after completing of administered treatment with zoledronic acid and pamidronate amounts to 20 months. At present actual median survival time of analysed patients since MM diagnosis is 42 months, since the beginning of treatment with pamidronate and zoledronic acid--33 months, and since completing treatment--20 months and is similar in 3 treatment groups. As was shown in our single center study in MM patients the safety and efficacy of pamidronate 90 mg and zoledronic acid 4 mg and 8 mg in monthly i.v. infusion are comparable. Thus the recommended dosage of zoledronic acid is 4 mg administered as a 15 minute i.v. infusion at intervals of 3 to 4 weeks.     

Pharmaceutical availability of betamethasone dipropionate and gentamicin sulfate from cream and ointment

Kinetics of drug release from both compared preparations occuring as a cream and ointment, was in vitro studied. A reversed-phase HPLC method was developed for the determination of betamethasone dipropionate in lipophylic bases. Analyses were performed using a PLRP column with a mobile phase of methanol-acetonitrile-water and ultraviolet detection at lambda = 254 nm. The calibration curve was constructed for concentration (.0-50.0 microg/ml. The method is simple, accurate and precise. For the determination of gentamicin sulfate the FPIA method was used.     

Determination of active substances in antiallergic and antiphlogistic multicomponent preparations by high performance liquid chromatography (HPLC)

The aim of the present study was the elaboration of an HPLC method enabling the identification and determination of the content of selected compounds occurring in multicomponent preparations applied in allergic and non-allergic diseases of upper respiratory tracts. These compounds include: buzepide methyl iodide, clocinizine dihydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine sulfate and dexbrompheniramine maleate. The elaborated HPLC method shows that a good separation of the mentioned compounds is feasible. The regression analysis has demonstrated linearity of the method in concentration range suitable for the intended experiments. The determination of the compounds in pharmaceutical preparations and the statistical evaluation of the results indicate that both the selectivity and precision of the method are good.     

The effect of cryoprotectants on the physical properties of large liposomes containing sodium diclofenac

Large liposomes (1-10 microm) containing sodium diclofenac were prepared and lyophilized using lactose or mannitol (7.5% in respect to the lipid content) as cryoprotectants. The physical studies of liposomes were performed during 30 days of storage in a dry or resuspended form. Lyophilization of large liposomes and storage in the dry form at 5 degrees C increases their physical stability. Lactose is a cryoprotectant which does not influence changes of properties of liposomes regarding their size, encapsulation efficacy and release rate. Large liposomes lyophilized in the presence of mannitol tend to increase in size and encapsulation efficacy, but the lipid bilayers are stabilized and less permeable to the drug.     

Effect of various vehicles on diclofenac sodium and indomethacin pharmaceutical availability

The aim of the study was to determine the pharmaceutical availability of various ointment systems containing antirheumatic substances and to establish an optimal system for cutaneous application. Topical application permits elimination or at least reduction of side effects connected with oral administration. Three systems were evaluated: emulsion W/O (ointment), emulsion O/W (cream) and gel, all of them containing diclofenac sodium or indomethacin. The investigated systems are characterized by proper rheological parameters and long physicochemical stability. Studies on diclofenac and indomethacin pharmaceutical availability show a good release of the substances from cream and hydrogel bases, but a very poor release from the ointment base.     

Quantitative determination of coumarins,flavonoids and chlorogenic acid in the leaves and underground parts of some species of genus Scopolia Jacq

The quantitative determination of coumarins, flavonoids and chlorogenic acid in the leaves and underground parts of Scopolia carniolica Jacq., S. lurida Dun. and S. sinensis Hemsl. using the RP-HPLC method has been described.     

Intrathecal bradykinin administration: opposite effects on nociceptive transmission

Injected intrathecally, bradykinin (BK) produced either hyperalgesia (0.15 microg) or antinociception (6.0 microg) in rats when thermal noxious stimuli were used. Similarly, des-Arg(9)-BK at the lower dose (0.15 microg) decreased, whereas at the higher dose (6.0 microg) it increased the threshold to thermal noxious stimuli; however, these effects were less pronounced than those of BK. The antinociception induced by BK was abolished by HOE 140, a B(2) receptor antagonist, injected intrathecally at a dose of 1.3 ng and was markedly attenuated by des-Arg(10)-HOE 140, a B(1) receptor antagonist (1.15 ng i.t.). The results obtained in this study showed that--depending on the dose used--BK and des-Arg(9)-BK could produce pro- as well as antinociceptive actions. Both B(2) and B(1) receptors are involved in the action of intrathecally applied BK.