The 2.0-Å resolution crystal structure of a trimeric antibody fragment with noncognate VH–VL domain pairs shows a rearrangement of VH CDR3

The 2.0-Å resolution x-ray crystal structure of a novel trimeric antibody fragment, a “triabody,” has been determined. The trimer is made up of polypeptides constructed in a manner identical to that previously described for some “diabodies”: a V_L domain directly fused to the C terminus of a V_H domain—i.e., without any linker sequence. The trimer has three Fv heads with the polypeptides arranged in a cyclic, head-to-tail fashion. For the particular structure reported here, the polypeptide was constructed with a V_H domain from one antibody fused to the V_L domain from an unrelated antibody giving rise to “combinatorial” Fvs upon formation of the trimer. The structure shows that the exchange of the V_L domain from antibody B1-8, a V_λ domain, with the V_L domain from antibody NQ11, a V_κ domain, leads to a dramatic conformational change in the V_H CDR3 loop of antibody B1-8. The magnitude of this change is similar to the largest of the conformational changes observed in antibody fragments in response to antigen binding. Combinatorial pairing of V_H and V_L domains constitutes a major component of antibody diversity. Conformationally flexible antigen-binding sites capable of adapting to the specific CDR3 loop context created upon V_H–V_L pairing may be employed by the immune system to maximize the structural diversity of the immune response.     

HPLC in biopharmaceutical investigations of drugs representing pyrimidine derivatives (A review)

Pyrimidine derivatives are widely used for the treatment of viral diseases and cancer. The analysis of pyrimidine derivatives is typically performed using various chromatographic techniques, in particular, reversed-phase high performance liquid chromatography (HPLC). The separation is typically carried out with (7–30)-cm-long C₈ and C₁₈ silica gel columns, mainly at room temperature, and a 1–1.5 ml-min eluent flow rate. The column is eluted in an isocratic or gradient system, and a variety of mobile phases have been proposed. The detection is based on optical absorption or fluorescence measurements, or makes use of mass spectrometry. Various methods of extraction of pyrimidine derivatives from biological samples are discussed, and the corresponding detection limits are presented. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 5, pp. 26–34, May, 2007.     

Influence of tumours on normal cells and optimal chemotherapy regimens: the case of several drugs and toxicity constraints.

Cancer chemotherapy with the application of several drugs is studied. The negative and inhibiting effect of the tumour on normal cells is taken into account. Under certain hypotheses, we determine the optimal regimen that minimizes the tumour burden at the end of a fixed period of therapy while maintaining several normal cell populations above prescribed levels. More precisely, it is demonstrated that the optimal drug administration corresponds to the strategy of intensive chemotherapy.     

The characteristics of cardiomyopathy in different geographical regions]

Region-specific characteristics of hypertrophic cardiomyopathy (HC) and dilated cardiomyopathy (DC) were compared for 108 relevant patients living in Dubai (United Arab Emirates) and Moscow (Russia). Out of 49 citizens of Dubai 17 had HC, 32 DC, and 59 Moscow patients had HC in 23, DC in 36 cases. It was found that HC in Dubai tends to run a silent latent course, involving mainly basal septum and right ventricle. Apical lesions were more typical for Moscow citizens who also display more severe myocardial impairment. DC in Dubai produces weaker cardiac insufficiency and arrhythmia. Incidence of idiopathic and periportal DC proved higher in Dubai, while alcohol and virus infection underlie DC more frequently in Moscow.     

Hemodynamic effects of the treatment of hypertension with the calcium channel blocker diltiazem

The 1.5-benzotthazepine derivative diltiazem, which blocks slow calcium channels, is an effective hypotensive agent, used for the treatment of moderate hypertension. Treatment with diltiazem alone, its dose adjusted on an individual basis, controlled arterial blood pressure in 58% of the patients. With a 240 mg daily dose, blood pressure was controlled in 12 of 52 patients; when the daily dose was increased to 360 mg, blood pressure was controlled in another 18 patients. In the remaining 22 patients, blood pressure was only controlled after captopril was added in a daily dose of at least 50 mg. The drop of arterial blood pressure was associated with falling total peripheral resistance and end diastolic blood volume, and was accompanied by an increase in left-ventricular ejection fraction and myocardial oxygen want.     

Diagnostic and treatment problems in sarcoidosis in the therapist's practice

Altogether 231 sarcoidosis patients were observed. Chest x-ray showed stage I in 116 patients, stage II in 111 patients. Corticosteroid therapy was provided to stage II patients only, with signs of alveolitis activity, for which assessment lung scintigraphy with 67Ga, investigation of bronchoalveolar rinse and determination of the blood angiotensin converting enzyme should be performed. Various extrapulmonary manifestations like hepatosplenomegaly, skin rash, cardiac arrhythmia and conduction disorder, urinary syndrome, etc., were revealed in 28 patients. The authors discussed variants of a course of lesions of the internal organs in sarcoidosis, difficulties of their diagnosis, and indications for steroid therapy. They also recommend a further study of the extrathoracic manifestations of sarcoidosis which frequently determine prognosis of this disease (first of all, cardiac, renal and nervous system affections), serve indicators of its activity (erythema nodosum, uveitis, parotitis, etc.) and present considerable diagnostic difficulties.