Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension.

ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.

Comparison of analytical methods for the evaluation of antibody responses against epitopes of polymorphic protein antigens.

Surface exposed protein antigens of the malaria parasite Plasmodium falciparum frequently harbor multiple dimorphic amino acid positions. These are associated with parasite immune evasion and represent a major obstacle for subunit vaccine design. Here, we have analyzed the flexibility of the humoral immune response against a semiconserved sequence (YX(44)LFX(47)KEKMX(52)L) of the key malaria blood stage vaccine candidate merozoite surface protein-1 (MSP-1). Monoclonal antibodies (mAbs) raised against one of the six described natural sequence variants of MSP-1(43-53) were analyzed for cross-reactivity with the other allelic forms, which differ in one to three positions from the immunizing sequence. Enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) spectroscopy demonstrated marked differences in mAb binding avidity to the variant sequences and isothermal titration calorimetry (ITC) provided evidence for a very low affinity of some of the interactions. In immunofluorescence analysis (IFA) and Western blotting analysis, the mAbs nevertheless stained all analyzed parasite clones expressing MSP-1(43-53) variant sequences. When used for the evaluation of humoral immune responses in clinical malaria vaccine trials, these two commonly used methods may thus not be suitable to distinguish biologically functional high affinity antibody responses from irrelevant low-affinity cross-reactivities.

The potential of Artemisia annua L. as a locally produced remedy for malaria in the tropics: agricultural, chemical and clinical aspects.

The plant Artemisia annua L. (Asteraceae) is listed in the Chinese pharmacopoeia as a remedy for various fevers including malaria, and contains the well-established antimalarial compound artemisinin. In this study, a hybrid form of A. annua was successfully cultivated in Central Africa. The aerial parts of the plant contained 0.63-0.70% artemisinin per dry weight, and approximately 40% of this artemisinin could be extracted by simple tea preparation methods. Five malaria patients who were treated with A. annua tea showed a rapid disappearance of parasitaemia within 2-4 days. An additional trial with 48 malaria patients showed a disappearance of parasitaemia in 44 patients (92%) within 4 days. Both trials showed a marked improvement of symptoms. In our opinion, these results justify further examinations of the antimalarial effect of A. annua preparations.

The murine ortholog of matrix metalloproteinase 19: its cloning, gene organization, and expression.

We have isolated a murine cDNA orthologous to the human matrix metalloproteinase 19 (hMMP-19). The murine MMP-19 cDNA was amplified by RT-PCR using specific primers whose DNA sequences were derived from both murine MMP-19 genomic DNA and partial cDNA sequences. The murine MMP-19 (mMMP-19) is 79% identical to the human ortholog and encodes a protein of 527 amino acids with a deduced molecular mass of 59.1kDa. Analyzing the exon/intron junctions we revealed that the murine MMP-19 gene consists of nine exons and eight introns, and thus differs from the gene organization of other matrix metalloproteinases. Furthermore, a 587bp fragment of the mMMP-19 promoter containing a TATA box and an AP-1 binding motif was cloned, and 3.3kb transcripts of the MMP-19 gene were identified in liver, kidney, spleen, and colon. Finally, immunostaining of murine heart cryosections showed that mMMP-19, like its human counterpart, is expressed in the arterial tunica media of large blood vessels. By cloning mMMP-19 and unraveling its genomic structure, we have obtained valuable information for further study of the function of this MMP in vivo.

Structure of the human MMP-19 gene.

The recently identified MMP-19 belongs to the multi-protein family of zinc-binding matrix metalloproteinases (MMP). In order to analyze its genomic organization and to identify transcription factor binding sites that may be involved in the regulation of human MMP-19 expression, the gene coding for MMP-19 has been cloned and sequenced. The MMP-19 gene spans over 7.6kb and is composed of nine exons and eight introns. Furthermore, a 1.9kb fragment of 5'-flanking DNA was isolated and the transcription start point mapped. Nucleotide sequence analysis of its 5'-flanking region revealed several potential transcription factor binding sites typical of MMP promoters. Thus, a TATA-box, a consensus AP-1 binding element, and a putative PEA3 site were identified. The 1.9kb MMP-19 promoter fragment and several deletion constructs thereof were able to drive transcription of the luciferase reporter gene in transiently transfected CHO cells. Finally, it has been shown by an electrophoretic mobility shift assay that the AP-1 consensus sequence is able to bind a HeLa nuclear extract derived AP-1 factor.

Age differences in health care spending, fiscal year 1976.

Of the $120.4 billion spent by the Nation for personal health care in fiscal year 1976, 29% was spent for those aged 65 or older, 15% for those under age 19, and the remaining 56% for those aged 19-64. The average health bill reached $1,521 for the aged, $547 for the intermediate age group, and $249 for the young. Public funds financed 68% of the health expenses of the aged with Medicare and Medicaid together accounting for 59%. Private sources paid 74% of the health expenses of the young and 70% of the expenses of those aged 19-64. Third-party payments met 65% of the health expenditures of all those under age 65.

Private health insurance in 1975: coverage, enrollment, and financial experience.

More improvement in the scope than in the quality of private health insurance coverage took place during 1975. Four-fifths of the population under age 65 was covered for hospital and surgical care, and nearly that proportion was protected against the costs of physicians' in-hospital visits, X-ray and laboratory examinations, and prescribed out-of-hospital drugs. The $33.6 billion in premiums paid by consumers resulted in the return of only $28.9 billion in benefits, which covered just 44% of their total personal health care expenditures. Major-medical insurance, held by an estimated 43% of the population, helped to overcome some of the deficiencies of private insurance--dollar limitations on health care services, ceilings on the duration of hospital stays, and exclusions for some types of care. It also provided economic protection against catastrophic expenses. Premiums and subscription income rose faster than benefits as private insurers attempted to keep their coverage in line with rising health care costs. The overall underwriting gain was due largely to a $952.4 million gain in group business by the insurance companies.

National health expenditures, fiscal year 1976.

The Nation's spending for health in fiscal year 1976 reached $139.3 billion, or $638 per person, according to preliminary figures. This total was 14 percent higher than the $122.2 billion spent for health in 1975. In the 2 years since price controls on the health industry were lifted, expenditures have risen $33.0 billion (31 percent). During this period, the economy has grown at a relatively slow pace with the gross national product increasing 18 percent. Thus, the percentage of the GNP attributed to health care reached 8.6 percent in 1976. Public and private spending rose 16 percent and 13 percent, respectively, in 1976, with the rise in public expenditures appreciably below the 22-percent increase of 1975. Third-party financing affected slightly more than two-thirds of all personal health care--the private insurance share at 26 percent and that of government 40 percent.

Age differences in health care spending, fiscal year 1975.

This report of health care spending in fiscal year 1975 reveals that of the $103.2 billion spent by the Nation for personal health care, 15 percent was spent for those under age 19, 56 percent for persons aged 19-64, and 29 percent for those aged 65 or older. The average health care bill for the oldest group was $1,360; it was $472 for the intermediate age group and $212 for the young. Third-party payments met 71 percent of the aged group's health care expense and 66 percent of the health expenditures of persons under age 65. Public funds paid for one-fourth of the health expenses of the young, nearly one-third of the health bills of those aged 19-64, and two-thirds of those of the aged. Medicare alone paid 72 percent of the hospital expense for the aged and 54 percent of their doctor bills. The average direct payment by the consumer amounted to $390 for those aged 65 and older and $128 for persons under age 65.

Private health insurance in 1974: a review of coverage, enrollment, and financial experience.

In 1974, more than three-fourths of the civilian population had substantial economic protection through private health insurance against the costs of hospital and surgical care. Smaller proportions were covered at least in part for other health care costs, usually after payment of deductibles and coinsurance. Consumers got back 87 percent of their premium dollars in the form of benefits. The rise in premium income in 1974 lagged 4 percentage points behind the growth in claims incurred. The result was a net underwriting loss of $359.7 million or 1.3 percent of premium income. Most consumers bought their health insurance protection through insurance companies, although Blue Cross-Blue Shield plans served about two-fifths of the insured population for hospital-associated care. In addition, about 6 percent received health care through independent prepayment and self-insured plans.

National health expenditures, fiscal year 1975.

According to preliminary estimates of the Nation's health spending in fiscal year 1975, health expenditures reached $118.5 billion, or $547 per person. Total health spending showed a 14-percent rise, significantly higher than the increase in 1974 when price controls in the health industry were in effect for most of the year. The acceleration of health spending during 1975 was accompanied by a slackening in the growth of the gross national product. Expenditures for this purpose, as a share of the GNP, thus rose significantly to 8.3 percent. Public spending grew two and one-half times as fast as private spending in 1975, mainly because of the continuing expansion of Medicare and Medicaid. Third parties financed an estimated two-thirds of all personal health care spending, with the government share 40 percent and that of private insurance 27 percent.