Novel, selective CDK9 inhibitors for the treatment of HIV infection.

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-to-date review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC(50) < 100 nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.

Temporary cerebral histic hypoxia in simulated microgravity.

The authors determined in their previous examinations that the vertical component of diagonal optokinetic nystagmus (DOKN) decreases considerably more in the conditions of hypoxia and antiorthostatic posture than does the horizontal component. Relying on these findings, they reasoned that the tectal and pretectal gaze centers, which organize vertical eye movement, are more sensitive to both hypoxia and antiorthostatic posture than is the pontine gaze center, which directs horizontal eye movement. In their present examinations, the authors sought to discover how cranial shifting of body fluids alters the DOKN and cardiopulmonary dynamics. They established that, at-30-degree antiorthostatic posture during 3 hours' loading, the diminution of pulse rate and systolic blood pressure is accompanied by continuous enhancement of diastolic blood pressure, diminishment of the carbonometric value, and augmentation of respiratory rate. The disturbances of DOKN, which mimicked previous similar findings under conditions of hypoxia and antiorthostatic posture, may be caused by the hypocapnia that is induced by antiorthostatic posture and that produces histic hypoxia. However, hypocapnia does not exclude the possibility of cerebrovascular injury, which was detected during animal experiments in microgravity or in simulated microgravity. To resolve this issue ultimately, further investigations are necessary.

Effect of microgravitation on the human equilibrium.

The 38-year period of human space exploration has gained for us a lot of experience in the problem of space motion sickness. The authors collected some causes of space sickness from the literature and from their research results. We collaborated with the Soviet-Russian space researchers and elaborated those vestibular research methods that were carried out by human space missions in the Soviet-Russian space station, on Earth, and after flight: spontaneous eye movement, foveal and peripheral optokinetic nystagmus, and vestibular stimulation. Using an earthly model of the effect of microgravitation on the human body, we tried to provide explanations of the origin of space motion sickness.

Antiorthostatic posture as an earth model of the effect of microgravity on the human body.

We examined the horizontal and vertical component of diagonal optokinetic nystagmus (DOKN) in sitting posture and in the last 15 minutes of antiorthostatic posture at -30 degrees lasting 3 hours. The antiorthostatic posture is suited to the earthy model of the fluid shifting observed in microgravity. We found that the frequency of the vertical component of DOKN is rarer in antiorthostatic posture than in sitting posture. Moreover, the amplitude of the vertical component of DOKN is lower in antiorthostatic posture than is the amplitude of the horizontal component. According to our examinations, we suppose that the frequency and amplitude of vertical OKN are directed by different cerebral structures. Furthermore, we found that the heart rate becomes slower and the diastolic pressure is augmented after antiorthostatic posture and visual stimulation.

Prevention of motion sickness with selegilinum hydrochloricum.

Summarizing, it may be concluded that selegilinum hydrochloricum significantly prolongs the time before the development of nausea and vomiting provoked by vestibular stimulation. The drug controls, within a short period, the provoked discomfort, and restores normal condition rapidly. It prevents the changes in blood pressure, pulse rate, and cutaneous galvanic resistance following Coriolis stimulus. Due to these properties Jumex may be used for the prevention, moderation of motion sickness, one of the widespread phenomena of our age, without decreasing working capacity.

[Cardiac and cardiopulmonary changes in systemic lupus erythematosus]. / A systemás lupus erythematosus cardialis és cardiopulmonalis elváltozásai.

(SLE) One hundred patients suffering from systemic lupus erythematosus (SLE) were examined by clinical, non invasive cardiological, radiological and laboratory methods. Valve diseases were revealed by M-mode echocardiographic examination in 17 patients. 14 patients had various conduction disturbances. Out of the remaining 83 patients not having any valve disease, systolic dysfunction of the myocardium was detectable in 17 persons and pericardial effusion in 3 persons. Spirometric alterations have been found in 64 persons and cor pulmonale has been diagnosed in 8 persons.

Serum steroid hormone levels in systemic lupus erythematosus (SLE).

Dehydroepiandrosterone (D), D sulphate (DS), testosterone (T) and oestradiol (OE2) were determined by radioimmunoassay; cortisol (F) by a spectrofluorimetric method in the serum of 54 female patients with SLE. The values were evaluated in two age groups (32 patients with active ovarian function and 22 in menopause). The serum cortisol, T and DS levels were decreased, and there was no difference in that of free (unconjugated) D and OE2 concentrations compared to normal female subjects.

Relationship of Systemic Lupus Erythematosus (SLE) to Rheumatoid Arthritis (RA), Discoid Lupus Erythematosus (DLE) and Sjögren's Syndrome: A Clinical Study.

In clinical and laboratory examinations carried out since 1954 we found the combination of SLE, RA, DLE and Sjögren's syndrome in 33% of 771 patients. In 61% of our 171 LE cell-positive cases there was classical RA which is a further proof of the close connection between these two diseases.

The effect of X-rays and EMS on the behavior of the transposing element, TE98, in Drosophila melanogaster.

The sensitivity of TE98 (carrying w+R and rst+) to X-rays does not differ significantly from the mutability of curled and karmoisin loci. In addition no spontaneous mutants of TE98 were recovered, indicating its extreme stability. On the effect of EMS no white mutants were found supporting the view that the w+ gene of TE98 is duplicated.

Genetic characterization of the region between 86F1,2 and 87B15 on chromosome 3 of Drosophila melanogaster.

The region between 86F1,2 and 87B15 on chromosome 3 of Drosophila melanogaster, which contains about 27 polytene chromosome bands including the 87A7 heat-shock locus, has been screened for EMS-induced visible and lethal mutations. We have recovered 268 lethal mutations that fall into 25 complementation groups. Cytogenetic localization of the complementation groups by deficiency mapping is consistent with the notion that each band encodes a single genetic function. We have also screened for mutations at the 87A7 heat shock locus, using a chromosome that has only one copy of the gene encoding the 70,000 dalton heat-shock protein (hsp70). No lethal or visible mutations at 87A7 were identified from 10,719 mutagenized chromosomes, and no female-sterile mutations at 87A7 were recovered from the 1,520 chromosomes whose progeny were tested for female fertility. We found no evidence that a functional hsp70 gene is required for development under laboratory conditions.

Effects of perineurally applied cytostatic, cytotoxic and chelating agents upon peripheral and central processes of primary nociceptive neurons.

After perineural application, the effects of mannomustine, cyclophosphamide, tetrameskylmannite, 6-mercaptopurine, azathioprine and d-penicillamine upon structure of peripheral nerves and the substantia gelatinosa Rolandi were studied by means of neurohistochemical techniques and compared to those of the microtubule inhibitors Vinblastine, Vincristine and colchicine. While the cytostatic and cytotoxic drugs induced only sporadic degeneration in the structure of the peripheral nerve and, accordingly, caused only a minor extent of transganglionic degenerative atrophy in the Rolando substance, the chelating agent d-penicillamine causes massive Wallerian degeneration after perineural application and, consequently, induces an extensive degenerative atrophy in the Rolando substance. The destructive effect of d-penicillamine upon conduction properties of the impaired nerve has been established also by means of electrophysiological recording. All the drugs studied differ fundamentally from microtubule inhibitors like the Vinca alcaloids that, by virtue of their blocking effect of axoplasmic transport, induce degenerative atrophy in the Rolando substance after perineural application without causing Wallerian degeneration in the peripheral nerve. Accordingly Vinca alcaloids are the most promising candidates as locally applied therapeutics in intractable pain.