Fast-release orodispersible tramadol as analgesia in hysterosalpingography with a metal cannula or a balloon catheter.

BACKGROUND: This study aimed to evaluate the potential benefit, in terms of pain relief, of the new oral fast-release orodispersible galvanic form of tramadol in women undergoing hysterosalpingography (HSG) with either a metal cannula or a balloon catheter. METHODS: In a randomized, double-blind, placebo-controlled, 2 x 2 factorial-design trial, conducted at a single academic centre, 128 women were assigned into groups: (I) tramadol and a metal cannula, (II) tramadol and a balloon catheter, (III) placebo and a metal cannula or (IV) placebo and a balloon catheter. The primary end-point was pain registered by the patients on 10-cm visual analogue scales (VASs) at various times during and after the procedure. Secondary end-points included side effects and pain as assessed by the same physician during HSG. RESULTS: The main effect of tramadol versus placebo medication (i.e. I and II versus III and IV) was a statistically significant difference (P < 0.001) in self-reported VAS of -0.91 (-1.35 to -0.47) on the absolute and -33% (-48% to -17%) on the relative scale in favour of tramadol. Likewise, there was a significant benefit for tramadol against placebo medication for physician-perceived VAS pain scores (39% relative reduction; P < 0.001). The main effect of the balloon catheter versus metal cannula (i.e. II and IV versus I and III) was a non-significant (P = 0.82) difference in patient-reported VAS of -0.05 (-0.49 to +0.39) and -2% (-21% to +17%). There were no medication-HSG device interactions and no differences in side effects. CONCLUSIONS: During and after HSG, fast-release orodispersible tramadol significantly reduces pain without increasing side effects.

Association of aplastic anaemia and Fanconi's disease with HLA-DRB1 alleles.

One of the most fascinating areas of research within the field of histocompatibility at present time concerns an observation that a major human histocompatibility system, human leucocyte antigen (HLA), is deeply involved in the development of a great number of diseases. Major histocompatibility complex is the most polymorphic system in the genome of different species. Recognition of HLA alleles could be useful in transplantation and disease studies. Genetic construct of HLA DRB1 was studied in Iranian normal populations and patients with aplastic anaemia and Fanconi's disease. DNA was extracted from the whole blood of 466 normal, 35 aplastic anaemia and 10 Fanconi's individuals. Then DRB1 gene polymorphism was studied by polymerase chain reaction-sequence-specific primer method. The HLA DRB1 gene analysis showed increase of DRB1*07 in aplastic anaemia patients compared to normal population (P = 0.02). According to this study, the frequency of DRB1*07 in normal individuals was 8.3, and in aplastic anaemia patients, 15.7%. Additionally, the frequency of DRB1*04 in normal, aplastic anaemia and Fanconi's individuals was 10, 5.7 and 20%, respectively. Our results of investigation showed correlation between some HLA alleles with the studied diseases. We reported the frequency of various DR types in aplastic and Fanconi's patients. This study could imply the possible role of HLA-DRB1*07 in the incidence of aplastic anaemia. Moreover, the frequency of DRB1*04, DRB1*03 and DRB1*15 alleles showed intermediate correlation with Fanconi's anaemia.

A randomized crossover study of bee sting therapy for multiple sclerosis.

BACKGROUND: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. METHODS: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). RESULTS: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. CONCLUSIONS: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

In vitro antineoplastic activity of C7-substituted mitomycin C analogues MC-77 and MC-62 against human breast-cancer cell lines.

Mitomycin C (MIT-C) is one of the most potent antineoplastic agents used for the treatment of breast cancer and a wide variety of malignant tumors. However, administration of MIT-C is frequently accompanied by the delayed onset of severe myelosuppression We have synthesized a new series of MIT-C analogues that are predicted on a structure/function basis to retain cytotoxicity but exhibit decreased toxicity. These new compounds feature a sugar substitution at the N7 position. Using a series of human breast-cancer cell lines growing in vitro, we determined the structure/activity relationship of two independent N7-substituted spacers displaying the same glucopyranose moiety. N-( [(2-acetamide-3,4,6-tri-O-acetyl-2-deoxy-beta- D-glucopyranosyl)amino]carbonyl] propylmitomycin C (MC-62) contains the sugar moiety linked to MIT-C through a butanoic acid spacer. MC-62 exhibits significantly less biological potency as compared with the parent drug. In contrast, N-[4-(tetra-O-acetylglucopyranosyl)oxy]phenylmitomycin C (MC-77) contains the glucopyranose moiety linked to MIT-C through a phenolic spacer. This analogue generally exhibits greater antitumor activity in vitro as compared with either MC-62 or MIT-C. Thus, N7-substituted analogues containing sugar moieties exhibit altered biological activity, the degree of which is related to the properties/structure of the spacer.

New sugar mitomycin C analogues: preparation, murine P388 antitumor activity, and leukopenia induction.

Four new sugar:mitomycin C derivatives were synthesized by coupling of N-1 of mitomycin C with tetra-O-acetylglucopyranosyl isothiocyanate and 3,4,6-tri-O-acetyl-2-(N-acetylamino)-2-deoxyglucopyranosyl isothiocyanate. Conversion of each derivative to its water-soluble analogue was achieved by deacetylation, using saturated NH3:CH3OH. Antitumor activity, assessed using the in vivo murine P388 ascitic leukemia system, demonstrated efficacy comparable with the parent mitomycin C. However, unlike the highly myelosuppressive parent drug, optimal antitumor activity is achieved at doses which produce only limited leukopenia.

Murine anti-tumor activity of new water soluble platinum(II) complexes with reduced toxicity.

A series of new water soluble sugar and non-sugar containing platinum(II) complexes was synthesized and evaluated for effects of the sugar moiety on water solubility, anti-tumor activity, and acute leukopenia. When tested in vivo against the murine P388 and L1210 leukemias at LD10/maximally effective doses, the compound cis-[(gluconylamino)malonato-O,O'](1R,2R-cyclohexanediami ne-N,N')platinum (II), R,RG-AMP produced comparable or superior anti-tumor activity to cisplatin, carboplatin, and tetraplatin. Efficacy was also demonstrated for the L1210/DDP (cisplatin-resistant) leukemia. Further, R,R-G-AMP is non-nephrotoxic and produces less leukopenia than cisplatin, carboplatin, and tetraplatin.

6-bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride: synthesis, chemical characterization, murine P388 antitumor activity, and bone marrow toxicity.

6-Bis-(2-chloroethyl)amino-6-deoxy-D-galactopyranose hydrochloride has been synthesized, characterized, and evaluated for antitumor activity and bone marrow toxicity in mice. The 1D- and 2D-NMR studies show the compound to exist as a beta-anomer chair conformation (23%), alpha-anomer chair conformation (22%), and several equilibrating boat conformations or furanose forms (55%). A single ip LD10 dose of 15.0 mg/kg produced antitumor activity against the murine P388 leukemia superior to that achieved with an equitoxic dose of nitrogen mustard. In normal mice, this 15.0-mg/kg dose produced minimal depression of peripheral white blood cells and no significant decrease in absolute neutrophil counts. A reduction in toxicity was also demonstrated for human bone marrow CFU-GM, as compared with nitrogen mustard and L-PAM. This and other sugar-containing mustard compounds may represent a class of antineoplastic alkylating agents with reduced bone marrow toxicity.

A homogeneous immunoassay for the mycotoxin T-2 utilizing liposomes, monoclonal antibodies, and complement.

The trichothecene mycotoxin T-2 is a fungal metabolite known to contaminate agricultural products and cause intoxication of humans and animals. We have developed a homogeneous competition inhibition assay for T-2 mycotoxin based on complement-mediated lysis of liposomes. The T-2 mycotoxin was converted to an acid chloride derivative, subsequently coupled to the amino group of phosphatidylethanolamine, and incorporated with the phospholipid into unilamellar liposomes. Carboxyfluorescein, which is self-quenched at high concentrations, was entrapped in the liposomes as a release marker. We used a monoclonal IgG1 antibody specific for T-2 mycotoxin and a polyclonal anti-mouse Ig as a secondary antibody since the anti-T-2 IgG1 does not activate complement. In the absence of free T-2, the liposomes were lysed within 30 min after the addition of complement, releasing carboxyfluorescein into the surrounding buffer. In the presence of free T-2 toxin, the binding of antibodies to the liposomes was reduced, causing a corresponding decrease in lysis. This assay proved to be sensitive to T-2 toxin levels as low as 2 ng, which is 10-fold more sensitive than the present enzyme immunoassay using the same antibodies.