Conceptions of Potency, Purity, and Synergy-by-Design

Sowa Rigpa institutions and practitioners have growing interest in examining and legitimizing Sowa Rigpa formulas vis-à-vis pharmacological research methods, seeking scientific validation of what they view as ‘potency’ and ‘purity’ for their formulas. Likewise, the pharmacology researchers have demonstrated renewed interest in herbal medical traditions in mining for new drugs to address resistance, toxicity, and optimize what they view as ‘potency’ and ‘purity.’ However, differing conceptualizations emerge when the pharmacological drug discovery process is examined to determine what is being analyzed, how it is doing so, and what assumptions underlie such methods. Whether a formula is ‘active,’ ‘toxic’ or ‘effective’ hinges on assumptions, processes, and methods that typically have low fidelity to how Sowa Rigpa formulations function from the Tibetan tradition’s perspective and are actually administered to patients. This paper argues that standard mainstream biochemical pharmacology screening methods may not be suitable for analyzing Sowa Rigpa formulas, as they are traditionally compounded and understood to function in concert with multiple physiological pathways, rather than one specific target. We examine the pharmaceutical research processes to identify points of adherence and divergence with conceptions of ‘potency’ and ‘purity' in Tibetan medical theory, and believe pharmacological research institutions will be receptive to traditional Sowa Rigpa menjor (sman sbyor), or ‘medicine compounding,’ theory due to benefits it could provide biomedical drug discovery via complementary understandings of compound synergy and distinctly different concepts of toxicity and purity. Accordingly, we suggest that efficacy, activity and safety of Tibetan medicinal formulas will be more accurately assessed by retaining fidelity to its own conceptions of potency and purity

Specific β-Tubulin Isotypes Can Functionally Enhance or Diminish Epothilone B Sensitivity in Non-Small Cell Lung Cancer Cells

Epothilones are a new class of microtubule stabilizing agents with promising preclinical and clinical activity. Their cellular target is β-tubulin and factors influencing intrinsic sensitivity to epothilones are not well understood. In this study, the functional significance of specific β-tubulin isotypes in intrinsic sensitivity to epothilone B was investigated using siRNA gene knockdown against βII-, βIII- or βIVb-tubulins in two independent non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and Calu-6. Drug-treated clonogenic assays showed that sensitivity to epothilone B was not altered following knockdown of βII-tubulin in both NSCLC cell lines. In contrast, knockdown of βIII-tubulin significantly increased sensitivity to epothilone B. Interestingly, βIVb-tubulin knockdowns were significantly less sensitive to epothilone B, compared to mock- and control siRNA cells. Cell cycle analysis of βIII-tubulin knockdown cells showed a higher percentage of cell death with epothilone B concentrations as low as 0.5 nM. In contrast, βIVb-tubulin knockdown cells displayed a decrease in epothilone B-induced G2-M cell cycle accumulation compared to control siRNA cells. Importantly, βIII-tubulin knockdowns displayed a significant dose-dependent increase in the percentage of apoptotic cells upon treatment with epothilone B, as detected using caspase 3/7 activity and Annexin-V staining. Higher concentrations of epothilone B were required to induce apoptosis in the βIVb-tubulin knockdowns compared to control siRNA, highlighting a potential mechanism underlying decreased sensitivity to this agent. This study demonstrates that specific β-tubulin isotypes can influence sensitivity to epothilone B and may influence differential sensitivity to this promising new agent

Incidence and Correlates of HIV-1 RNA Detection in the Breast Milk of Women Receiving HAART for the Prevention of HIV-1 Transmission

The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission.Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2-5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection.Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97-1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log(10) copies/ml (range 2.0-3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10(6) cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8-44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5-56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54-1.7).The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA

Conceptions of Potency, Purity, and Synergy-by-Design: Toward Developing a Sowa Rigpa Medical Theory-based Approach to Pharmaceutical Research

Sowa Rigpa institutions and practitioners have growing interest in examining and legitimizing Sowa Rigpa formulas vis-à-vis pharmacological research methods, seeking scientific validation of what they view as ‘potency’ and ‘purity’ for their formulas. Likewise, the pharmacology researchers have demonstrated renewed interest in herbal medical traditions in mining for new drugs to address resistance, toxicity, and optimize what they view as ‘potency’ and ‘purity.’ However, differing conceptualizations emerge when the pharmacological drug discovery process is examined to determine what is being analyzed, how it is doing so, and what assumptions underlie such methods. Whether a formula is ‘active,’ ‘toxic’ or ‘effective’ hinges on assumptions, processes, and methods that typically have low fidelity to how Sowa Rigpa formulations function from the Tibetan tradition’s perspective and are actually administered to patients. This paper argues that standard mainstream biochemical pharmacology screening methods may not be suitable for analyzing Sowa Rigpa formulas, as they are traditionally compounded and understood to function in concert with multiple physiological pathways, rather than one specific target. We examine the pharmaceutical research processes to identify points of adherence and divergence with conceptions of ‘potency’ and ‘purity\u27 in Tibetan medical theory, and believe pharmacological research institutions will be receptive to traditional Sowa Rigpa menjor (sman sbyor), or ‘medicine compounding,’ theory due to benefits it could provide biomedical drug discovery via complementary understandings of compound synergy and distinctly different concepts of toxicity and purity. Accordingly, we suggest that efficacy, activity and safety of Tibetan medicinal formulas will be more accurately assessed by retaining fidelity to its own conceptions of potency and purity

Approaches for the development of antiviral compounds : the case of hepatitis C virus

Traditional methods for general drug discovery typically include evaluating random compound libraries for activity in relevant cell-free or cell-based assays. Success in antiviral development has emerged from the discovery of more focused libraries that provide clues about structure activity relationships. Combining these with more recent approaches including structural biology and computational modeling can work efficiently to hasten discovery of active molecules, but that is not enough. There are issues related to biology, toxicology, pharmacology, and metabolism that have to be addressed before a hit compound becomes nominated for clinical development. The objective of gaining early preclinical knowledge is to reduce the risk of failure in Phases 1, 2, and 3, leading to the goal of approved drugs that benefit the infected individual. This review uses hepatitis C virus (HCV), for which we still do not have an ideal therapeutic modality, as an example of the multidisciplinary efforts needed to discover new antiviral drugs for the benefit of humanity